AU2013263761A1 - Facially amphiphilic polymers and oligomers and uses thereof - Google Patents

Abstract

The present invention discloses methods of use of facially amphiphilic polymers and oligomers, including pharmaceutical uses of the polymers and oligomers as antimicrobial agents and antidotes for hemorrhagic complications associated with heparin therapy. The present invention also discloses novel facially amphiphilic polymers and oligomers and their compositions, including pharmaceutical compositions. The present invention further discloses the design and synthesis of facially amphiphilic polymers and oligomers. H:\tzm\Interwoven\NRPortbl\DCC\TZM\5850592_1.DOC - 27/11/13

Description

FACIALLY AMPHIPHILIC POLYMERS AND OLIGOMERS AND USES THEREOF BACKGROUND OF THE INVENTION Field of the Invention [0002] The present invention relates to methods of use of facially amphiphilic polymers and oligomers, including pharmaceutical uses of the polymers and oligomers as antimicrobial agents and antidotes for hemorrhagic complications associated with heparin therapy. The present invention also relates to novel facially amphiphilic polymers and oligomers and their compositions, including pharmaceutical compositions. The present invention further relates to the design and synthesis of facially amphiphilic polymers and oligomers. Related Art [0003] Amphiphilic molecules exhibit distinct regions of polar and nonpolar character. These regions can result from substitution of hydrophobic and hydrophilic substituents into specific and distinct regions of conformationally defined molecules. Alternatively, a conformationally flexible molecule or macromolecule can adopt an ordered structure in which the hydrophobic and hydrophilic substituents on the molecule segregate to different areas or faces of the molecule. Commonly occurring amphiphilic molecules include WO 2004/082634 PCT/US2004/008155 -2 surfactants, soaps, detergents, peptides, proteins and copolymers. These molecules have the capacity to self-assemble in appropriate solvents or at interfaces to form a variety of amphiphilic structures. The size and shape of these structures varies with the specific composition of the amphiphilic molecule and solvent conditions such as pH, ionic strength and temperature. [00041 Amphiphilic peptides with unique broad-spectrum antimicrobial properties have been isolated from a variety of natural sources including plants, frogs, moths, silk worms, pigs and humans (H. G. Boman lmnmunol Rev. 2000 173:5-16; R. E. Hancock and R. Lehrer, Trends Biotechnol. 1998 16:82-88). These compounds include the magainin 1 and dermaseptin SI isolated from the skin of ftogs and the cecropin A isolated from the cecropia moth. These naturally occurring compounds have broad-spectrum antibacterial activity and they do not appear prone to the development of bacteria resistance. These compounds are of relatively low molecular weight and have a propensity to adopt an a-helical conformation in hydrophobic media or near a hydrophobic surface and as a result are facially amphiphilic, with one-third to two-thirds of the cylinder generated by the helical peptide has hydrophobic side chains while the remainder has hydrophilic side chains. The hydrophilic side chains are primarily positively-charged at neutral pH. [00051 Hydrophobic amino acids compose 40-60% of the total number of residues in most anti-microbial peptides. The selectivity of the amphiphilic peptides (e.g. for bacteria vs. human erythrocytes) depends on the overall hydrophobicity. The biological activity of the compounds depends on the ratio of charged (c) to hydrophobic (h) residues. When the ratio is varied from 1:1 (c:h) to 1:2 (c:h) peptides with more hydrophobic residues tend to be more active toward erythrocyte membranes. Related peptides have been isolated from mammals and these anti-microbial peptides have been suggested to be an important component of the innate immune response. (Gennaro, R. et al. Biopoyhners (Peptide Science) 2000, 55, 31) [0006] Secondary structures other than helices may also give rise to amphiphilic compounds. The protegrins are a related series of anti-microbial WO 2004/082634 PCT/US2004/008155 -3 peptides. (J. Chen et al, Biopolyiers (Peptide Science), 2000 55 88) The presence of a pair of disulfide bonds between Cys 6 -Cys 15 and Cys 8 -Cys 1 3 results in a monomeric amphiphilic anti-parallel p-sheet formed by the chain termini and linked by a p-tum. The amphiphilic p -sheet confonnation is essential for anti-microbial activity against both gram-positive and gram negative bacteria. [00071 Following the initial discovery of cecropins and magainins, antimicrobial peptides have become a large and growing class of biologically interesting compounds (Zasloff, M., Curr. Opin. Immiunol. 4:3-7 (1992); Zasloff, M., Trends Pharmacol. Sci. 21:236-238 (2000)). These compounds represent the first line of defense against microbes for many species, including plants, insects, worms, and mammals (Boman, H.G., inmunol. Rev. 173:5-16 (2000); Hancock, R.E., and Lehrer, R., Trends Biotechnol. 16:82-88 (1998)). In mammals, the peptides are produced and secreted by skin, mucosal surfaces and neutrophils. There are many different classes of natural host defense peptides (Zasloff, M., Curr. Opin. Immnunol. 4:3-7 (1992); Zasloff, M., Trends Pharinacol. Sci. 21:236-238 (2000); Steiner, H., et al., Nature, 292:246-248 (1981); Ganz, T., et al, Eur. J. Haenatol. 44:1-8 (1990); Tang., Y.Q., et al., Science 286:498-502 (1999); Ganz, T., et al., J. Clin. Invest. 76:1427-1435 (1985); Landon, C., et al., Protein Sci. 6:1878-1884 (1997); Zhao, C., et al., FEBS Lett. 346:285-288 (1994); Peggion, B., et al., Biopolymers (Peptide Science) 43:419-431 (1998); Dempsey, C.E., Biochin. Biophtys. Acta 1031:143-161 (1990)), but, in general, most contain between 20-40 amino acid residues and adopt an amphiphilic secondary structure as shown in Figure 2. [00081 The cytotoxic activity of the cationic and amphiphilic host defense peptides is also specific for bacteria over mammalian cells. This specificity is most likely related to fundamental differences between the two membrane types. For example, bacteria have a large proportion of negatively charged phospholipid headgroups on their surface, while, in contrast, the outer leaflet of animal cells is composed mainly of neutral lipids (Zasloff, M., Nature WO 2004/082634 PCT/US2004/008155 -4 415:389-395 (2002)). The presence of cholesterol in the animal cell membrane also appears to reduce the activity of the antimicrobial peptides. [0009] The bactericidal activity of the host defense peptides is very rapid, occurring within minutes after exposure of bacteria to lethal doses of peptide. Several mechanisms have been proposed for the process of cell killing. According to the carpet mechanism, host defense peptides aggregate parallel to the membrane surface (Gazit, E., et al., Biohemistry 34:11479-11488 (1995); Pouny, Y., et al., Biochemistry 31:12416-12423 (1992)), leading to thinning and, ultimately, rupture of the membrane. In the so-called barrel stave mechanism, the bound peptides on the cell surface self-associate into transmembrane helical bundles that fonn stable aqueous pores in the membrane (Merrifield, R.B., et al., Ciba Found. Symp. 186:5-20 (1994)). According to a third possible mechanism (DeGrado, W.F., et al., Biophys. J 37:329-338 (1982)), the peptides initially bind only to the outer leaflet of the bilayer, leading to an increase in the lateral surface pressure of the outer leaflet relative to the inner leaflet of the bilayer. This pressure imbalance results in translocation of the peptides into the interior of the bilayer, with concomitant formation of transient openings in the membrane that allow hydration of the polar sidechains of the peptide and leakage of cellular contents. Most antimicrobial peptides probably act by more than one of these mechanisms. Additionally, some classes may interact with periplasmic or intercellular targets (Zasloff, M., Trends Phariacol. Sci. 21:236-238 (2000)). [00101 in addition to antibacterial activity, several of the host defense peptides possess antifungal activity. Examples of mammalian, insect and amphibian peptides with demonstrated antifungal activities include defensins, protegrins, lactoferrin-B, cecropins, and dermaseptins (DeLucca, A.J., and Walsh, T.J., Antimicob. Agents Chenother. 43:1-11 (1999)). The mechanism of cytotoxic action appears to be similar to that for bacteria, leading to rapid lysis of the fungal membrane. [0011] Several host defense peptides also possess antiviral activity and inhibit the replication of both DNA and RNA viruses. See, for example, Sinha, S., et WO 2004/082634 PCT/US2004/008155 -5 al., Antimicrob. Agents Chemother. 47:494-500 (2003); Belaid, A., et al., J. Med. Virol. 66:229-234 (2002); Egal, M., et al., Int. J. Antimicrob. Agents 13:57-60 (1999); Andersen, J.H., et al., Antiviral Rs. 51:141-149 (2001); and Bastian, A., and Schafer, H., Regl. Pept. 15:157-161 (2001). [00121 The human alpha-defensins have also been shown to inhibit the replication of HIV-1 isolates in vitro (Zhang, L., et al., Science 298: 995-1000 (2002). The antimicrobial peptides melittin and cecropin have also been reported to inhibit HIV-1 replication and it is suggested that they exert their activity by suppressing HIV gene expression (Wachinger, M., et al., J. Gen. Virol. 79:731-740 (1998)). [0013] Although host defense peptides are found in a wide variety of species and are composed of many different sequences, their physiochemical properties are remarkably similar. They adopt an amphiphilic architecture with positively charged groups segregated to one side of the secondary structure and hydrophobic groups on the opposite surface. For example, magainin and some of the other naturally occurring antibacterial peptides contain positively charged amino acids and a large hydrophobic moment. Although these peptides exhibit considerable variation in their chain length, hydrophobicity and distribution of charges, they have a high propensity to adopt a-helical conformations in a hydrophobic environment, e.g., a cell surface or a natural or synthetic membrane (Oren, Z., and Shai, Y., Biopolymers (Peptide Science) 47:451-463 (1998)). The periodic distribution of hydrophobic and hydrophilic side chains in their amino acid sequences allows the segregation of the hydrophobic and hydrophilic side chains to opposite faces of the cylinder formed by the helix. These structures can be described as facially amphiphilic regardless of whether the secondary structure is a helix or sheet type fold. In fact, it is the overall physiochemical properties that are responsible for the biological activity of these peptides and not the precise sequence (Zasloff, M., Curr. Opin. Immunol. 4:3-7 (1992); Zasloff, M., Trends Pharmacol. Sci. 21:236-238 (2000); Hancock, R.E., and Lehrer, R., Trends Biotechnol. 16:82-88 (1998); DeGrado, W.F., et al., J Amer.

WO 2004/082634 PCT/US2004/008155 -6 Chem. Soc. 103:679-681 (1981); DeGrado, W.F., Adv. Prot. Chem. 39:51-124 (1988); Tossi, A., et al., Biopolyners 55:4-30 (2000); Merrifield, E.L., et al., Int. J. Pept. Protein Res. 46:214-220 (1995); Merrifield, R.B., et al, Proc Natl Acad Sci (USA) 92:3449-3453 (1995)). Thus, facial amphiphilicity, i.e., the alignment of polar (hydrophilic) and nonpolar (hydrophobic) side chains on opposite faces of a secondary structural element formed by the peptide backbone, and not amino acid sequence or any particular secondary/tertiary structure, chirality or receptor specificity, is responsible for the biological activity of these peptides. [0014] The design of non-biological polymers with well-defined secondary and tertiary structures has received considerable attention in the past few years (Gellman, S.H., Acc. Chem. Res. 31:173-180 (1998); Barron, A.E., and Zuckermann, R.N., Curr. Opin. Chen. Biol. 3:681-687 (1999); Stigers, K.D., et al., Curr. Opin. Chem. Bio., 3:714-723 (1999)). Using these principles, investigators have designed synthetic antimicrobial peptides by idealizing the amphiphilic a-helical arrangement of sidechains observed in the natural host defense peptides, leading to a large number of potent and selective antimicrobial compounds (Tossi, A., et al., Biopolyners 55:4-30 (2000); DeGrado, W.F., Adv. Protein. Chem. 39:51-124 (1988); Maloy, W.L., and Kari, U.P., Biopolymers 37:105-122 (1995); Zasloff, M., Curr. Opin. Immunol. 4:3-7 (1992); Boman, H.G., et al., Eur. J. Biochem. 201:23-31 (1991); Oren, Z., and Shai, Y., Biopolymers 47:451-463 (1998)). [00151 p-peptides have also provided another avenue to test and further elucidate the features required for the construction of bactericidal agents. p peptides adopt L+2 helices, which have an approximate 3-residue geometric repeat. Thus, if polar and apolar sidechains are arranged with precise three residue periodicity in the sequence of a p-peptide, they should segregate to opposite sides of the helix. Using this approach, DeGrado and co-workers (Hamuro, Y., et al., J. Amer. Chem. Soc. 121:12200-12201 (1999); Liu, D., and DeGrado, W.F., J. Amer. Chem. Soc., 123:7553-7559 (2001)) have designed synthetic P-peptide oligomers that are roughly equipotent in WO 2004/082634 PCT/US2004/008155 -7 antimicrobial activity to many naturally occurring peptide antibiotics. The antimicrobial activities of these p-peptides and their specificities for bacterial cells over mamnalian cells can be controlled by fine-tuning their hydrophobicities and chain lengths. Gellman and coworkers have also synthesized cyclically constrained p-peptides possessing potent antimicrobial activity and minimal activity against mammalian cells (Porter, E.A., et al., Nature 404:565 (2000)). [00161 Non-peptidic antimicrobial polymers have also been developed. For example, suitably substituted polymers lacking polyamide linkages that are capable of adopting amphiphilic conformations have been designed and synthesized. Solid phase chemistry technology has been utilized to synthesize a class of meta substituted phenylacetylenes that fold into helical structures in appropriate solvents (Nelson, J.C., et al, Scieice 277:1793-1796 (1997); Prince, R.B., et al., Angew. Chem. Int. Ed. 39:228-231 (2000)). These molecules contain an all hydrocarbon backbone with ethylene oxide side chains such that when exposed to a polar solvent (acetonitrile), the backbone collapses to minimize its contact with this polar solvent. As a result of the meta substitution, the preferred folded conformation is helical. This helical folding is attributed to a "solvophobic" energy term; although, the importance of favorable n-n aromatic interactions in the folded state are also likely to be important. Furthermore, addition of a less polar solvent (CHCl 3 ) results in an unfolding of the helical structure demonstrating that this folding is reversible. [00171 Regioregular polythiophenes (5 and 6) have been shown to adopt amphiphilic conformations in highly ordered n-stacked arrays with hydrophobic side chains on one side of the array and hydrophilic side chains on the other side. These polymers form thin films useful in the construction of nanocircuits. (Bjornholm et al., J Am. Chem. Soc.,1998 120, 7643) These materials would be facially amphiphilic as defined herein; however, no biological properties have been reported for these compounds.

WO 2004/082634 PCT/US2004/008155 R Me 3

*N(CH

2

)

3 NHCOC CONH(CH 2

)

3 Me S

CI

S C12H25 7 5: R=CH 2

CO

2 ~NMe 4 * 6: R=(CH 2

CH

2

O)

3 Me [0018] Antimicrobial peptides have been incorporated onto surfaces or bulk materials, with some retention of antimicrobial properties. Haynie and co workers at DuPont have investigated the activity of antibacterial peptides that have been covalently attached to solid surfaces (S. L. Haynie et al., Antimicrobial Agents Cheimother., 1995 39:301-7; S. Margel et al, J. Biomed. M water. Res., 1993, 27:1463-76). A variety of natural and de novo designed peptides were synthesized and tested for activity while still attached to the solid support. The activity of the peptides decreased when attached to the solid support although the peptides retained their broad spectrum of activity. For example, a de novo designed peptide referred to as E14LKK was reported to have a MBC (minimum bactericidal activity) of 31 ptg/ml in solution as opposed to 1.5mg/ml when attached to a solid phase bead. The peptides were attached to the resin with a 2 to 6-carbon alkyl linker. The porosity of Pepsyn K, the resin used in the synthesis, is small (0.1 to 0.2 jim) compared to the bacteria, so the microbes may have been unable to penetrate into the interior of the resin. Thus the great majority of the peptide would not be available for binding to cells. The antimicrobial activity did not arise from a soluble component; no leached or hydrolyzed peptide was observed and the soluble extracts were inactive. These studies indicate quite convincingly that antimicrobial peptides retain their activity even when attached to a solid support. However, there is a need to optimize the presentation of the peptides to increase their potency.

WO 2004/082634 PCT/US2004/008155 -9 [0019] Other antimicrobial polymeric materials have been reported which contain chemical functionalities known to be antimicrobial (J. C. Tiller et al., Proc Natl Acad Sci U S A, 2001 98:5981-85). A large portion of this work uses chemical functions such as alkylated pyridinium derivatives, which are known to be toxic to mammalian cells. The antibiotic ciprofloxacin has been grafted into a degradable polymer backbone (G. L. Y. Woo, et al., Biomaterials 2000 21:1235-1246). The activity of this material relies on cleavage of the active component from the polymer backbone. [0020] In addition, Mandeville et al., U.S. Patent No. 6,034,129, disclose anti infective vinyl copolymers, wherein monomers with hydrophobic and hydrophilic side chains have been randomly polymerized to produce polymers with amphiphilic properties. These materials are produced by polymerization of hydrophobic and hydrophilic acrylate monomers. Alternately, the hydrophobic side chain is derived from a styrene derivative which is copolymerized with a hydrophilic acrylate monomer'wherein an ionic group is linked to the carboxylic, acid. [00211 Tew et aL. (Tew, G.N., et al., Proc. NatL. Acad. Sci. (USA) 99:5110 5114 (2002)) disclose the design and synthesis of a series of biomimetic, facially amphiphilic arylamide polymers possessing antimicrobial activity. The arylamide polymers were designed using de novo computational design techniques. [00221 WIPO Publ. No. WO 02/100295 discloses facially amphiphilic polyamide, polyester, polyurea, polycarbonate, and polyurethane polymers with anti-infective activity, and articles made from them having biocidal surfaces. WIPO Publ. No. WO 02/100295 is fully incorporated by reference herein in its entirety. [00231 WIPO Publ. No. WO 02/072007 discloses a number of facially amphiphilic polyphenylene and heteroarylene polymers, including polyphenylalkynyl polymers, with anti-infective activity and articles made therefrom having biocidal surfaces. WIPO publication no. WO 02/072007 is fully incorporated by reference herein in its entirety.

WO 2004/082634 PCT/US2004/008155 -10 [00241 An alternative method to make amphiphilic polymers is to produce block copolymers comprised of hydrophobic blocks (A) and hydrophilic blocks (B), commonly polypropyleneoxy and polyethylenoxy segments respectively, into A-B, A-B-A or similar copolymers. These copolymers also are not facially amphiphilic as defined herein. BRIEF DESCRIPTION OF THE DRAWINGS [00251 Specific embodiments of the invention have been chosen for the purpose of illustration and description but are not intended in any way to restrict the scope of the invention. These embodiments are shown in the accompanying drawings wherein: [00261 FIG. 1 shows a cartoon depicting the separation of hydrophobic and hydrophilic side chains onto opposite faces of the polymer backbone. [0027] FIG. 2 shows a schematic representation of the structure for the cationic and amphiphilic a-helical host defense peptide, magainin 1. [0028] FIG. 3 shows the general structure of facially amphiphilic polyamide or polyester copolymers of Formulae I and II, with representative monomer units for polyamides having aromatic components (Ia and Ila), and with representative monomer units for polyamides having both aromatic and aliphatic components (lb and IIb). [0029] FIG. 4 shows the general structure of polyamides with extended linking groups between aromatic monomer components. [0030] FIG. 5 shows the general structure of facially amphiphilic polyurea, polycarbonate and polyurethane copolymers of Formula IV, with corresponding representative monomer units (IVa, IVb and IVe, respectively). Two typical polyurea monomer units are exemplified in IVd and IVe. [0031] FIG. 6 shows the complete structure of a facially amphiphilic polyamide (IId) and polyurethane (IVf). [00321 FIG. 7 shows two examples of meta- and ortho -phenylene facially amphiphilic polyamide polymers (Ile and Ilf, respectively).

WO 2004/082634 PCT/US2004/008155 -11 [00331 FIG. 8 shows a synthetic scheme for preparation of polyamide polymers (XIa) and oligomers (XIb and XIc). [0034] FIG. 9 shows antimicrobial data for polyamide oligomers of Formulae I and I' [0035] FIG. 10 shows antimicrobial data for polyamide oligomers of Formulae II and II' Antimicrobial data for polyurea oligomers of Formulae IV and IV'(structures not shown) are also presented. [0036] FIG. 11 shows the time course for antibacterial activity of a polyurea oligomer of Formulae IV and IV. [0037] FIG. 12 shows the results of an experiment in which the antiviral activity of the compound 1 (DL-Ill-71) was tested by monitoring the percent infection by HLHX or YU2 viruses of U87/CD4/CCR5 and U87/CD4/CXCR4 cells. [0038] FIG. 13 shows the results of an experiment in which the antiviral activity of the compound 2 (DL-IV-1) was tested by monitoring the percent infection by HLHX or YU2 viruses of U87/CD4/CCR5 and U87/CD4/CXCR4 cells. [0039] FIG. 14 shows the results of an experiment in which the antiviral activity of the compound 3 (Compound E) was tested by monitoring the percent infection by HLHX, YU2, or VSV-2 viruses of U87/CD4/CCR5 and U87/CD4/CXCR4 cells. [00401 FIG. 15 shows the structure of oligomers used in the anticoagulation assays described in Example 11. Oligomers enclosed in boxes significantly antagonized the delay in plasma clotting caused by low molecular weight heparin. [0041] FIG. 16 shows the structure of the Pmx1O073, the oligomer tested in the assays described In Example I L [0042] FIG. 17 illustrates the antagonism of low molecular weight heparin effects measured for the oligomer Pmx 10073 on plasma clotting time in whole blood, as described in Example 11.

WO 2004/082634 PCT/US2004/008155 -12 [00431 FIG. 18 shows the antibacterial activities and selectivities for arylamide oligomers described in Example 12. [0044] FIG. 19 shows the antibacterial activities and selectivities for additional arylamide oligomers described in Example 12. [0045] FIG. 20 shows the results of vesicle leakage assays performed with compound 8 in Example 12. BRIEF SUMMARY OF THE INVENTION [0046] The present invention provides methods of use of facially amphiphilic polymers and oligomers, including pharmaceutical uses of the polymers and oligomers as antimicrobial agents and antidotes for hemorrhagic complications associated with heparin therapy. The present invention is also provides novel facially amphiphilic polymers and oligomers and their compositions, including pharmaceutical compositions. The present invention further provides methods for the design and synthesis of facially amphiphilic polymers and oligomers. R' -[-x-A1 -x-y-A2-y-I m- R2 RI-[-x-A1-x-z-y-A 2 -y-zm-R 2 (IV) [0047] The facially amphiphilic polymers and oligomers of the present invention include polyamide and polyester compounds of Formulae I and II wherein x is 0, NR or S, y is C=0, C=S or SO 2 , and A 1 and A 2 are aromatic, heteroaromatic or aliphatic moieties appropriately substituted with polar and nonpolar groups; and polyurea, polycarbamate, and polycarbonate compounds of Formula IV wherein x and y are 0, NR 3 or S, z is C=0, C=S or S02, and A 1 and A 2 are aromatic, heteroaromatic or aliphatic moieties appropriately substituted with polar and nonpolar groups. R1 and R 2 are end groups WO 2004/082634 PCT/US2004/008155 - 13 appropriate for the specific polymer chain and their design is well know in the art of designing and synthesizing polymers and oligomers. [0048] These facially amphiphilic polymers and oligomers are capable of adopting repeating secondary structural motifs that allow for the segregation of polar and nonpolar regions of the molecule into different spatial regions. The polymers and oligomers adopt amphiphilic conformations when placed in contact with the cell walls of microorganisms, and the amphiphilic molecules are capable of disrupting essential cell wall functions resulting in the death of the microorganism. [00491 Thus, the present invention is directed to a method of treating a microbial infection in an animal in need thereof, the method comprising administering to the animal an effective amount of a pharmaceutical composition comprising a polymer or oligomer of the invention, or an acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier or diluent. [0050] The invention is also directed to a method of treating a viral infection in an animal in need thereof, the method comprising administering to the animal an effective amount of a pharmaceutical composition comprising a polymer or oligomer of the invention, or an acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier or diluent. [0051] The invention is further directed to a method of treating a fungal infection in an animal in need thereof, the method comprising administering to the animal an effective amount of a pharmaceutical composition comprising a polymer or oligomer of the invention, or an acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier or diluent. [0052] The invention is also directed to a method of providing an antidote to low molecular weight heparin overdose in an animal in need thereof, the method comprising administering to the animal an effective amount of a pharmaceutical composition comprising a polymer or oligomer of the invention, or an acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier or diluent.

WO 2004/082634 PCT/US2004/008155 -14 [0053] The invention is further directed to polymers and oligomers of the invention. [00541 The present invention is also directed to a method of killing or inhibiting the growth of a microorganism, the method comprising contacting the microorganism with an effective amount of a polymer or oligomer of the invention, or an acceptable salt or solvate thereof. [0055] The present invention further provides a computational technique to evaluate the energy of polymer conformations and identify polymers which have the capability of exhibiting amphiphilic behavior and aid in identifying optimal sites for substitution of polar and nonpolar substituents that confer amphiphilic properties. DETAILED DESCRIPTION OF THE INVENTION 100561 Bacterial drug resistance is a significant current health problem throughout the world. Multiple drug resistance is being commonly seen in a number of human pathogens (Hiramatsu, K., et al., J. Antimicrob. Chiemother. 40:311-313 (1998); Montecalvo, M.A., et al., Antimficro. Agents Clienother. 38:1363-1367 (1994); Butler, J.C., et al., J Inyect. Dis. 174:986-993 (1996); Lyytikainen, 0., et al., J. Hosp. Infect. 31:41-54 (1995)), and the incidence of drug-resistant hospital infections is growing at a rapid rate. For example, in some U.S. hospitals, nosocomial pathogens, such as E. faecium and Acinetobacter species, have acquired multiple resistance determinants and are virtually untreatable with current antimicrobial agents (Threlfall, E.J., et al., Lancet 347:1053-1054 (1996); Bradley, J.S., and Scheld, W.M., Clin. Infect. Dis. 24 (Suppl. 2):S213-221 (1997)). Moreover, the threat of bio-terrorism is a further impetus for development of novel classes of antibiotics, particularly ones against which it will be difficult to develop resistant bacterial strains. [0057] The pharmaceutical scientific community is responding to this challenge by focusing on the development of new antibiotic drugs. Much of this work, however, is directed to synthesizing analogs of known drugs, such WO 2004/082634 PCT/US2004/008155 -15 as cephalosporins and quinolones, that, while potentially useful for a short time, will inevitably also encounter bacterial drug resistance and become ineffective. Thus, therapeutically effective antimicrobial drugs that act by novel mechanisms would provide an economy as well as a human health benefit. [00581 The defense host peptides are potentially exciting therapeutic agents because of their broad spectrum of activity, rapid bactericidal activity and very low incidence of development of bacterial resistance. However, significant pharmaceutical issues, including systemic toxicity and difficulty and expense of manufacturing, have severely hampered clinical progress. [00591 The non-peptidic polymers and oligomers of the present invention directly address these issues. These non-peptidic mimetics are significantly smaller and easier to prepare than their naturally occurring counterparts. They have the same mechanism of action as magainin (a naturally occurring host defense peptide), and are approximately equipotent and as broad in their spectrum of action as magainin. However, the non-peptidic mimetics are significantly less toxic towards human erythrocytes, much less expensive to prepare, and are expected to be much more stable in vivo. Importantly, because these compounds mimic the structure and biological activity of host defense peptides, the appearance of bacterial resistant strains is very unlikely to occur. [00601 Thus, the present invention provides non-peptidic, facially amphiphilic polymers and oligomers and methods of using of the polymers and oligomers in a number of applications, including their use in pharmaceutical applications as antimicrobial agents and as antidotes for hemorrhagic complications associated with heparin therapy. [0061] The polymers and oligomers of the present invention are compounds of Formulae I, II, and IV: WO 2004/082634 PCT/US2004/008155 -16 RI-[-x-A1-y-x-A2-y-].-R2M R'-[x-A1-x-y-A2-y-]eRW (II) R-+x-A1-x-z-y-A2-y-z]

R

2 (IV) or acceptable salts or solvates thereof, wherein R', R 2 , A 1 , A 2 , x, y, z and m are as defined below. [0062] The polymers and oligomers of the present invention are capable of adopting amphiphilic conformations that allow for the segregation of polar and nonpolar regions of the molecule into different spatial regions and provide the basis for a number of uses. For example, polymers and oligomers of the invention adopt amphiphilic conformations that are capable of disrupting the integrity of the cell membrane of microorganisms, resulting in the inhibition of growth or the death of the microorganisms. As a consequence, the polymers and oligomers have a broad range of antimicrobial activity and are effective against a variety of microorganisms, including gram-positive and gram negative bacterial, fungi, yeast, mycoplasmas, mycobacteria, protozoa, and the like. [0063] The polymers and oligomers of the present invention are useful as antimicrobial agents in a number of applications. For example, polymers and oligomers of the present invention, especially oligomers, can be used therapeutically to treat microbial infections in animals, including humans and non-human vertebrates such as wild, domestic and farm animals. The microbial infection in an animal is treated by administering to the animal an effective amount of a pharmaceutical composition of a polymer or oligomer of the invention. The polymer or oligomer compositions can be administered systemically or topically and can be administered to any body site or tissue. Because the polymers and oligomers have a broad range of antimicrobial activity, they are useful in treating a variety of infections in an animal. [00641 The facially amphiphilic conformations adopted by the polymers and oligomers of the present invention form the basis for another therapeutic use, WO 2004/082634 PCT/US2004/008155 -17 the use of the polymers and oligomers as antidotes for hemorrhagic complications associated with heparin therapy. Thus, the polymers and oligomers, especially the oligomers, can be used in a method of providing an antidote to heparin overdose in an animal by administering to the animal an effective amount of a pharmaceutical composition of the polymer or oligomer. [0065] The polymers and oligomers of the present invention can also be used as disinfectants or as preservatives. The polymers and oligomers can thus be used in a method of killing or inhibiting the growth of a microorganism by contacting the microorganism with an effective amount of the polymer or oligomer. For example, the polymers and oligomers of the invention can be used as disinfectants or preservatives in, for example, soaps, hand lotions, paints, cleansers, and polishers, and the like, or in, for example, foodstuffs, food containers, and food-handling implements, and are often administered for these purposes as a solution, dispersion, or suspension. The polymers and oligomers can also be incorporated into plastics that can be molded or shaped into articles, or attached or immobilized on a surface, to provide a surface mediated microbicide that kills or inhibits the growth of microorganisms in contact with the surface. [0066] Facially amphiphilic polymers and oligomers of the present invention can be homopolymers wherein one monomer is substituted, with both a nonpolar and a polar substituent or copolymers wherein one monomer is substituted with a polar substituent and the other monomer is substituted with a nonpolar substituent. Since the antimicrobial activity arises from the amphiphilic character conferred by a periodic pattern of side chains rather than the precise spatial arrangement of side chains, other substitution patterns are also expected to produce facially amphiphilic polymers and oligomers and they all are encompassed by the present invention. (See FIG. 1L) [0067] Polyamide and polyester polymers and oligomers of the present invention (FIG. 3) can be comprised solely of aromatic or heteroaromatic monomers or may include both aromatic and aliphatic monomers. One embodiment of the present invention is a copolymer with aromatic monomers WO 2004/082634 PCT/US2004/008155 - 18 and a-amino acid monomers. The polyamides and polyesters can be constructed either by repetitively linking amino (or hydroxy) acid monomers (FIG. 3, I) or by alternating diamine (or dihydroxy) and dicarboxylic acid monomers (FIG. 3, II). While the majority of aromatic rings in the examples depicted in Figures 3 and 4 have a meta substitution pattern, one skilled in the art would immediately appreciate that equivalent polymers could be designed with an ortho or a para orientation and these modifications can alter the conformation and the physical properties of the resulting polymer. Furthermore, although the copolymers in FIG. 3 ( Ia, Ila, and Ib) are depicted with one polar and one nonpolar substituent, other substitution patterns are equally plausible. The optimal substitution patterns are determined by the conformational properties of the polymer or oligomer backbone. [00681 Although polyamides and polyesters are the most commonly occurring examples of the present invention, other functional groups can be incorporated into the polymer or oligomer backbone with similar results. In particular, thioamides and thioesters are anticipated to have very similar properties. The distance between aromatic rings can significantly impact the geometrical pattern of the polymer and this distance can be altered by incorporating aliphatic chains of varying length, which can be optionally substituted or can comprise an amino acid, a dicarboxylic acid or a diamine. The distance between and the relative orientation of monomers also can altered by replacing the amide bond with a surrogate having additional atoms (see, for example, FIG. 4). Thus, replacing the carbonyl group with a dicarbonyl alters the distance between the monomers and the propensity of dicarbonyl unit to adopt an anti arrangement of the two carbonyl moiety and alter the periodicity of the polymer. Pyromellitic anhydride (FIG. 4, IVg) represents still another alternative to simple amide linkages which can significant alter the conformation and physical properties of the copolymer, [0069] For polymers of the present invention, the synthetic processes can be modified to produce different ranges in molecular weights and the anti microbial polymers of the present invention will have a molecular weight WO 2004/082634 PCT/US2004/008155 -19 selected to impart physical and chemical properties optimized for the particular application being contemplated. Traditional polymer syntheses produce a product with a range of molecular weights. The polymer chemist will readily appreciate that the chain length of these polymers can be varied by techniques know in the polymer art. Polymers of the present invention can range in molecular weight from about 300 Daltons up to about 1,000 kiloDaltons. Advancements in solid-phase and solution phase synthesis of amino acid oligomers have made available techniques to prepare homogeneous polymers or oligomers with defined sequence and size and these techniques can be adapted to the present invention. Modem methods of solid phase organic chemistry (E. Atherton and R. C. Sheppard, Solid Phase Peptide Synthesis A Practical Approach IRL Press Oxford 1989) now allow the synthesis of homodisperse, sequence-specific oligomers with molecular weights approaching 5,000 Daltons. 100701 Polyureas (FIG. 5, IWa), polycarbonates (FIG. 5, IVb) or polyurethane (FIG. 5, IVc) are carbonic acid derivatives and exhibit properties similar to polyamides (N. Samson et al. J. Apple. Polyin. Sci. 65, 2265 (1997)). FIG. 5, IVd and IVe, depict two different substitution patterns that can be utilized. Other substitution patterns are equally effective. 100711 The process for designing polymers and oligomers of the present invention simply requires a structure in which the repeating sequence of monomers matches the secondary structure adopted by the backbone. Once the periodicity is observed, monomers substituted with polar and nonpolar groups monomers must be prepared and introduced to produce a cationic, amphiphilic secondary. Aromatic polyamides and ureas frequently have only a few torsional degrees of freedom per repeat (typically two or four). In this case, the secondary structure adopted by these polymers and oligomers is most likely planar with polar and nonpolar groups extended from opposite sides of the backbone. In some cases, the desired facial amphiphilicity can be achieved through a simple design principal.

WO 2004/082634 PCT/US2004/008155 -20 [0072] Additional molecular features can be added to the macromolecular backbone to promote the desired secondary structure and disfavor other structures thereby combining elements of both positive and negative design. Conformational studies on biofoldamers (proteins and RNA), and early work with a variety of sequence-specific polymers, have shown that several elements are crucial in order for the polymers to adopt the desired folded conformation. Key elements include strong electrostatic interactions (i.e., intramolecular hydrogen bonding) between adjacent or more distant monomers and rigidification caused by the backbone torsions or by bulky functional groups. For example, the presence of multiple hydrogen bond donors and acceptors along the macromolecular backbone can lead to extensive intermolecular backbone interactions. Precise placement of well designed intramolecular interactions can stabilize desired secondary structures while at the same time blocking the backbone hydrogen bond donors which limits intermolecular aggregation problems. For example, in polyamide and polyurea polmers, a thioether was positioned between two amide nitrogens to form an internal hydrogen bond between the sulfur and amide nitrogens. This limits the torsional angle of the aromatic carbon-amide NH bond by forcing the NH group to be on the same side as the heteroatom, thereby helping to define the overall sheet-like secondary structure. The secondary structure for this backbone is predicted to be nearly planar. Similarly, the poly-anthranilate polymer (XIII) is designed based on the finding of Hamuro and Hamilton (Y. Hamuro et al., J Am. Chen. Soc. 1996 119:10587-93) that intramolecular hydrogen-bonding defines the secondary structure of this class of polyarylamides.

WO 2004/082634 PCT/US2004/008155 -21

NH

2 PO S- 0--H N N R / N N R2 0--H t-Bu NPO (XIa-c) (XIII) [0073] De novo design can provide a systematic approach to studying the important principles regarding biological potency and selectivity (24, 25). It is clear from the diversity of naturally occurring antimicrobial peptides that facial amphiphilicity is the key physiochemical property responsible for the biological activity of this class of peptides. Furthermore, the charge density, hydrophobicity, and degree of amphiphilicity, are a critically important parameters to maximize lethal activity against microbes while minimizing activity against mammalian cells. [00741 The present invention discloses facially amphiphilic polymers and oligomers. Polymers are generally defined as synthetic compounds assembled from monomer subunits that are polydisperse in molecular weight, and are most commonly prepared by one-pot synthetic procedures. The term "polymer" as used herein refers to a macromolecule comprising a plurality of repeating monomers or monomer units. The term includes homopolymers, which are formed from a single type of monomer, and copolymers, which are formed from two or more different monomers. In copolymers, the monomers may be distributed randomly (random copolymer), in alternating fashion (alternating copolymers), or in blocks (block copolymer). The polymers of the present invention are either homopolymers or alternating copolymers having about 2 monomer units to about 500 monomer units, with average molecular weights that range from about 300 Daltons to about 1,000,000 Daltons, or from about 400 Daltons to about 120,000 Daltons. Preferred polymers are WO 2004/082634 PCT/US2004/008155 -22 those having about 5 to about 100 monomer units, with average molecular weights that range from about 1,000 Daltons to about 25,000 Daltons. [0075] The term "oligomer" as used herein refers to as a homogenous polymer with a defined sequence and molecular weight. Modern methods of solid phase organic chemistry have allowed the synthesis of homodisperse, sequence-specific oligomers with molecular weights approaching 5,000 Daltons. An oligomer, in contrast to a polymer, has a defined sequence and molecular weight and is usually synthesized either by solid phase techniques or by step-wise solution chemistry and purified to homogeneity. Oligomers of the present invention are those having about 1 monomer unit to about 25 monomer units, with molecular weights that range from about 300 Daltons to about 6,000 Daltons. Preferred oligomers are those having about I monomer unit (2 monomers) to about 10 monomer units, with molecular weights that range from about 300 Daltons to about 2,500 Daltons. [0076] The term "polymer backbone," "oligomer backbone," or "backbone" as used herein refers to that portion of the polymer or oligomer which is a contiuous chain comprising the bonds formed between monomers upon polymerization. The composition of the polymer or oligomer backbone can be described in terms of the identity of the monomers from which it is formed without regard to the composition of branches, or side chains, of the polymer or oligomer backbone. [00771 The term "polymer side chain," "oligomer side chain," or "side chain" refers to portions of the monomer which, following polymerization, forms an extension of the polymer or oligomer backbone, In homopolymers and homooligomers, all the side chains are derived from the same monomer. [0078] The tenn "microorganism." as used herein includes bacteria, algae, fungi, yeast, mycoplasmas, mycobacteria, parasites and protozoa. [00791 The term "antimicrobial," "microbiocidal," or "biocidal" as used herein means that the materials inhibit, prevent, or destroy the growth or proliferation of microorganisms. This activity can be either bacteriocidal or bacteriostatic. The term "bactoriocidal" as used herein means the killing of microorganisms.

WO 2004/082634 PCT/US2004/008155 -23 The term "bacteriostatic" as used herein means inhibiting the growth of microorganisms which can be reversible under certain conditions, [00801 The term "alkyl" as used herein by itself or as part of another group refers to both straight and branched chain radicals from 1 to 12 carbons, such as methyl, ethyl, propyl, isopropyl, butyl, t-butyl, isobutyl, pentyl, hexyl, isohexyl, heptyl, 4,4-dimethylpentyl, octyl, 2,2,4-trimethylpentyl, nonyl, decyl, undecyl, dodecyl. [0081] The term "alkenyl" as used herein refers to a straight or branched chain radical of 2-20 carbon atoms, unless the chain length is limited thereto, including, but not limited to, ethenyl, 1-propenyl, 2-propenyl, 2-methylpropenyl, 1-butenyl, 2-butenyl, and the like. Preferably, the alkenyl chain is 2 to 10 carbon atoms in length, more preferably, 2 to 8 carbon atoms in length most preferably from 2 to 4 carbon atoms in length. [00821 The term "alkynyl" as used herein refers to a straight or branched chain radical of 2-20 carbon atoms, unless the chain length is limited thereto, wherein there is at least one triple bond between two of the carbon atoms in the -chain, including, but not limited to, acetylene, 1-propylene, 2-propylene, and the like. Preferably, the alkynyl chain is 2 to 10 carbon atoms in length, more preferably, 2 to 8 carbon atoms in length, most preferably from 2 to 4 carbon atoms in length. [0083] The term "alkylene" as used herein refers to an alkyl linking group, i.e., an alkyl group that links one group to another group in a molecule. [00841 The tenn "alkoxy" as used herein refers to mean a straight or branched chain radical of 1 to 20 carbon atoms, unless the chain length is limited thereto, bonded to an oxygen atom, including, but not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, and the like. Preferably the alkoxy chain is 1 to 10 carbon atoms in length, more preferably 1 to 8 carbon atoms in length, and even more preferred I to 6 carbon atoms in length. [0085] The term "aryl" as used herein by itself or as part of another group refers to monocyclic or bicyclic aromatic groups containing from 6 to 12 WO 2004/082634 PCT/US2004/008155 -24 carbons in the ring portion, preferably 6-10 carbons in the ring portion, such as the carbocyclic groups phenyl, naphthyl or tetrahydronaphthyl. [0086] The term "arylene" as used herein by itself or as part of another group refers to an aryl linking group, i.e., an aryl group that links one group to another group in a molecule. [0087] The term "cycloalkyl" as used herein by itself or as part of another group refers to cycloalkyl groups containing 3 to 9 carbon atoms, more preferably, 3 to 8 carbon atoms. Typical examples are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and cyclononyl. 10088] The term "halogen" or "halo" as used herein by itself or as part of another group refers to chlorine, bromine, fluorine or iodine. [0089] The term "hydoxy" or "hydroxyl" as used herein by itself or as part of another group refers to an -OH group. [0090] The term "heteroaryl" as used herein refers to groups having 5 to 14 ring atoms; 6, 10 or 14 7n-electrons shared in a cyclic array; and containing carbon atoms and 1, 2 or 3 oxygen, nitrogen or sulfur heteroatoms. Examples of heteroaryl groups include thienyl, imadizolyl, oxadiazolyl, isoxazolyl, triazolyl, pyridyl, pyrimidinyl, pyridazinyl, furyl, pyranyl, thianthrenyl, pyrazolyl, pyrazinyl, indolizinyl, isoindolyl, isobenzofuranyl, benzoxazolyl, xanthenyl, 2H-pyrrolyl, pyrrolyl, 3H-indolyl, indolyl, indazolyl, purinyl, 4H quinolizinyl, isoquinolyl, quinolyl, phthalazinyl, naphthyridinyl, quinazolinyl, phenanthridinyl, acridinyl, perimidinyl, phenanthrolinyl, phenazinyl, isothiazolyl, phenothiazinyl, isoxazolyl, furazanyl, and phenoxazinyl groups. Especially preferred heteroaryl groups include 1,2,3-triazole, 1,2,4-triazole, 5 amino 1,2,4-triazole, imidazole, oxazole, isoxazole, 1,2,3-oxadiazole, 1,2,4 oxadiazole, 3-amino-1,2,4-oxadiazole, 1,2,5-oxadiazole, 1,3,4-oxadiazole, pyridine, and 2-aminopyridine. [0091] The tenn "heteroarylene" as used herein by itself or as part of another group refers to a heteroaryl linking group, i.e., a heteroaryl group that links one group to another group in a molecule.

WO 2004/082634 PCT/US2004/008155 -25 [0092] The term "heterocycle" or "heterocyclic ring", as used herein except where noted, represents a stable 5- to 7-membered mono- or bicyclic or stable 7- to 1 0-membered bicyclic heterocyclic ring system. any ring of which may be saturated or unsaturated, and which consists of carbon atoms and from one to three heteroatoms selected from the group consisting of N, 0 and S, and wherein the nitrogen and sulfur heteroatoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quaternized, and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring. Especially useful are rings containing one oxygen or sulfur, one to three nitrogen atoms, or one oxygen or sulfur combined with one or two nitrogen atoms. The heterocyclic ring may be attached at any heteroatom or carbon atom which results in the creation of a stable structure. Examples of such heterocyclic groups include piperidinyl, piperazinyl, 2-oxopiperazinyl, 2 oxopiperidinyl, 2-oxopyrrolodinyl, 2-oxoazepinyl, azepinyl, pyrrolyl, 4 piperidonyl, pyrrolidinyl, pyrazolyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolidinyl, isoxazolyl, isoxazolidinyl, morpholinyl, thiazolyl, thiazolidinyl, isothiazolyl, quinuclidinyl, isothiazolidinyl, indolyl, quinolinyl, isoquinolinyl, benzimidazolyl, thiadiazoyl, benzopyranyl, benzothiazolyl, benzoxazolyl, furyl, tetrahydrofuryl, tetrahydropyranyl, thienyl, benzothienyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, and oxadiazolyl. Morpholino is the same as morpholinyl. [0093] The term "alkylamino" as used herein by itself or as part of another group refers to an amino group which is substituted with one alkyl group having from 1 to 6 carbon atoms. The term "dialkylamino" as used herein by itself or as part of an other group refers to an amino group which is substituted with two alkyl groups, each having from 1 to 6 carbon atoms. [0094] The tenn "alkylthio" as used herein by itself or as part of an other group refers to an thio group which is substituted with one alkyl group having from 1 to 6 carbon atoms.

WO 2004/082634 PCT/US2004/008155 - 26 [0095] The term "lower acylamino" as used herein by itself or as part of an other group refers to an amino group substituted with a C 1

-C

6 alkylcarbonyl group. [0096] The phrase "groups with chemically nonequivalent termini" refers to functional groups such as esters amides, sulfonamides and N-hydroxyoximes where reversing the orientation of the substituents, e.g. RC(=0)OR 2 vs.

R'O(O=)CR

2 , produces unique chemical entities. [0097] The term "basic heterocycle" as used herein denotes cyclic atomic array which includes a nitrogen atom that has a pKa greater than about 5 and that is protonated under physiological conditions. Representative basic heterocycles are pyridine, quinoline, imidazole, imidazoline, cyclic guanidines, pyrazole, pyrazoline, dihydropyrazoline, pyrrolidine, piperidine, piperazine, 4-alkylpiperazine, and derivatives thereof, such as 2 aminopyridine, 4-aminopyridine, 2-aminoimidazoline, 4-aminoimidazoline or VII, here X is 0, N, S or absent and i is 2 to 4. 1 N _ 1K / (CH) (VII) H [0098] The term "amphiphilic" as used herein describes a three-dimensional structure having discrete hydrophobic and hydrophilic regions. An amphiphilic polymer or oligomer requires the presence of both hydrophobic and hydrophilic elements along the polymer backbone. The presence of hydrophobic and hydrophilic groups is a necessary, but not sufficient, condition to produce an amphiphilic oligomer or polymer. Polymers frequently adopt a random. or disordered conformation in which the side chains are located randomly in space and there are no distinctive hydrophobic and hydrophilic regions. 101001 The term "facially amphiphilic" or "facial amphiphilicity" as used herein describes polymers and oligomers with polar (hydrophilic) and nonpolar (hydrophobic) side chains that adopt conformation(s) leading to WO 2004/082634 PCT/US2004/008155 -27 segregation of polar and nonpolar side chains to opposite faces or separate regions of the structure. This structure can comprise any of the energetically accessible low-energy conformations for a given polymer or oligomer backbone. Additionally random or block copolymers may adopt random backbone conformations that do not lead to distinct hydrophilic and hydrophobic regions or which do not segregate along different faces of the polymer. These copolymers are not facially amphiphilic as defined herein. [0101] The term "naturally occurring amino acids" refers to the L-isomers of the naturally occurring amino acids, The naturally occurring amino acids are glycine, alanine, valine, leucine, isoleucine, serine, methionine, threonine, phenylalanine, tyrosine, tryptophan, cysteine, proline, histidine, aspartic acid, asparagine, glutamic acid, glutamine, carboxyglutamic acid, arginine, ornithine and lysine. Unless specifically indicated, all amino acids referred to in this application are in the L-form. [01021 The term "side chain of a naturally occurring amino acid" as used herein refers to the substituent on the C-carbon of a amino acid. The term "polar side chain of a naturally occurring amino acid" refers to the side chain of a positively charged, negatively charged or hydrophilic amino acid. The term "nonpolar side chain of a naturally occurring amino acid" refers to the side chain of a hydrophobic amino acid. [0103] The term "positively charged amino acid" or "cationic amino acid" as used herein includes any naturally occurring or unnatural amino acid having a positively charged side chain under normal physiological conditions. Examples of positively charged naturally occurring amino acids are arginine, lysine and histidine. [0104] The term "hydrophilic amino acid" means any amino acid having an uncharged, polar side chain that is relatively soluble in water. Examples of naturally occurring hydrophilic amino acids are seine, threonine, tyrosine, asparagine, glutamine, and cysteine. [0105] The term "hydrophobic amino acid" means any amino acid having an uncharged, nonpolar side chain that is relatively insoluble in water. Examples WO 2004/082634 PCT/US2004/008155 -28 of naturally occurring hydrophobic amino acids are alanine, leucine, isoleucine, valine, proline, phenylalanine, tryptophan and methionine. [01061 The terms "treat," "treated," or "treating" as used herein refers to both therapeutic treatment and prophylactic or preventative measures, wherein the object is to prevent or slow down (lessen) an undesired physiological condition, disorder or disease, or obtain beneficial or desired clinical results. For purposes of this invention, beneficial or desired clinical results include, but are not limited to, alleviation of symptoms; diminishment of extent of condition, disorder or disease; stabilized (i.e., not worsening) state of condition, disorder or disease; delay in onset or slowing of condition, disorder or disease progression; amelioration of the condition, disorder or disease state, remission (whether partial or total), whether detectable or undetectable; or enhancement or improvement of condition, disorder or disease. Treatment includes eliciting a clinically significant response, without excessive levels of side effects. Treatment also includes prolonging survival as compared to expected survival if not receiving treatment. [0107] The term "animal" as used herein includes, but is not limited to, humans and non-human vertebrates such as wild, domestic and farm animals, [01081 The polymers and oligomers of the present invention have been shown to possess antimicrobial activity. Thus, the polymers and oligomers of the present invention can be used as antimicrobial agents and, for example, can be used in a method of treating microbial infections in an animal. [0109] Thus, the invention is directed to a method of treating a microbial infection in an animal in need thereof, by administering to the animal a polymer or oligomer of the invention. [0110] For example, in some aspects, the invention is directed to a method of treating a microbial infection in an animal in need thereof, the method comprising administering to the animal an effective amount of a pharmaceutical composition comprising a polymer or oligomer of Formula I:

R

1 [x-[Ary-x-A2-y-m-R 2

G)

WO 2004/082634 PCT/US2004/008155 - 29 or an acceptable salt or solvate thereof, wherein: x is NR', -N(R 8 )N(R)-, 0, or S; y is C=0, C=S, O=S=0, or -C(=0)C(=0) and R 8 is hydrogen or alkyl;

A

1 and A 2 are independently optionally substituted arylene or optionally substituted heteroarylene, wherein: (i) Ai and A 2 are independently optionally substituted with one or more polar (PL) group(s), one or more non-polar (NPL) group(s), or a combination of one or more polar (PL) group(s) and one or more non-polar (NPL) group(s); or (ii) A 1 is optionally substituted arylene or optionally substituted heteroarylene and A 2 is a C 3 to CS cycloalkyl or -(CH2)q-, wherein q is I to 7, wherein A1 and A2 are independently optionally substituted with one or more polar (PL) groupss, one or more non-polar (NPL) group(s), or a combination of one or more polar (PL) group(s) and one or more non-polar (NPL) group(s); or (iii) A 2 is optionally substituted arylene or optionally substituted heteroarylene, and A1 is a C 3 to Cs cycloalkyl or -(CH2)q-, wherein q is 1 to 7, wherein A 1 and A 2 are independently optionally substituted with one or mqre polar (PL) group(s), one or more non-polar (NPL) group(s), or a combination of one or more polar (PL) group(s) and one or more non-polar (NPL) group(s); R is (i) hydrogen, a polar (PL) group, or a non-polar (NPL) group, and R2 is -x-A-y-R 1 , wherein R 1 ' is hydrogen, a polar (PL) group, or a non-polar (NPL) group; or (ii) R 1 and R2 are independently hydrogen, a polar (PL) group, or a non-polar (NPL) group; or (iii) R' and R 2 together are a single bond; WO 2004/082634 PCT/US2004/008155 -30 NPL is a nonpolar group independently selected from the group consisting of

-B(OR

4

)

2 and -(NR- )qlPL-NPL-(CH 2 )pNPL-(NR )q2NPL -R 4 ', wherein: R3, R 3 , and R?" are independently selected from the group consisting of hydrogen, alkyl, and alkoxy;

R

4 and 4 ' are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and heteroaryl, any of which is optionally substituted with one or more alkyl or halo groups; UNPL is absent or selected from the group consisting of 0, S, S(=0), S(=0) 2 , NR 3 , -C(= 0)-, -C(=0)-N=N-NR 3 -, -C(=0)-NR 3 -N=N-,

-N=N-NR

3 -, -C(=N-N(R 3

)

2 )-, -C(=NR 3 )-, -C(=0)O-, -C(=0)S-, -C(=S)-, -0-P(=0) 2 0-, -R30-, -RS-, -S-C=N- and

-C(=O)-NR

3 -O- , wherein groups with two chemically nonequivalent termini can adopt both possible orientations; the -(CH2)pNPL- alkylene chain is optionally substituted with one or more amino or hydroxy groups, or is unsaturated; pNPL is 0 to 8; qINPL and q2NPL are independently 0, 1 or 2; PL is a polar group selected from the group consisting of halo, hydroxyethoxymethyl, methoxyethoxymethyl, polyoxyethylene, and -(NR")qlPL-UPL(CH 2 )pPL-(NR 5 ')q 2 PL-V, wherein: R2, R , and R are independently selected from the group consisting of hydrogen, alkyl, and alkoxy; UPL is absent or selected from the group consisting of 0, S, S(=O), S(=0) 2 , NR, -C(=0)-, -C(=O)-N=N-NR 5 -, -C(=0)-N 5 -N=N-,

-N=N-NR

5 -, -C(=N-N(R) 2 )-, -C(=NR 5 )-, -C(=0)O-, -C(=0)S-, -C(=S)-, -0-P(=0) 2 0-, -R0-, -R 5 S-, -S-C=N- and

-C(=O)-NR

5 -0-, wherein groups with two chemically nonequivalent termini can adopt both possible orientations; V is selected from the group consisting of nitro, cyano, amino, hydroxy, alkoxy, alkylthio, alkylamino, dialkylamino, WO 2004/082634 PCT/US2004/008155 -31

-NH(CH

2 )pNH 2 wherein p is I to 4, -N(CH 2

CH

2

NH

2

)

2 , diazamino, amidino, guanidino, guanyl, semicarbazone, aryl, heterocycle and heteroaryl, any of which is optionally substituted with one or more of amino, halo, cyano, nitro, hydroxy, -NH(CH 2 )/NH2 wherein p is 1 to 4, N(CH 2

CH

2

NH

2

)

2 , amidino, guanidino, guanyl, aminosulfonyl, aminoalkoxy, aminoalkythio, lower acylamino, or benzyloxycarbonyl, wherein p is 1 to 4; the -(CH2)pPL- alkylene chain is optionally substituted with one or more amino or hydroxy groups, or is unsaturated; pPL is 0 to 8; qlPL and q2PL are independently 0, 1 or 2; and m is 1 to about 500; and a pharmaceutically acceptable carrier or diluent. [0111] Polymers and oligomers of Formula I that are preferred for use in the disclosed method are those wherein x is NR', 0, or -N(R 8

)N(R

5 )-, and R 8 is hydrogen or C-C 6 alkyl. Also preferred are those polymers and oligomers wherein y is C=0, C=S, or O=S=0. Especially preferred are those polymers and oligomers wherein x is NR and y is C=0. For example, oligomers of Formula I wherein x is NH and y is C=O are especially preferred. Also preferred are oligomers of Formula I wherein x is 0 and y is C=0, or wherein x is -N(R)N(R 8 )- and R' is hydrogen, and y is C=0. 101121 Preferred are those polymers and oligomers of Formula I wherein A 1 or A 2 are independently optionally substituted o-, m-, or p-phenylene. Those oligomers wherein A 1 or A2 are optionally substituted n-phenylene are especially preferred. [0113] Preferred polymers and oligomers of Formula I are also those wherein

A

1 is optionally substituted arylene or optionally substituted heteroarylene and

A

2 is a C 3 to Cs cycloalkyl or -(CH2)q-, wherein q is 1 to 7, and wherein A 1 and A 2 are independently optionally substituted with one or more polar (PL) group(s), one or more non-polar (NPL) group(s), or a combination of one or WO 2004/082634 PCT/US2004/008155 -32 more polar (PL) group(s) and one or more non-polar (NPL) group(s). Especially preferred are oligomers of Formula I wherein A 1 is substituted arylene and A 2 is -(CH2)q-, wherein q is 1 or 2, and wherein one of A 1 and A 2 is substituted with one or more polar (PL) group(s), and the other of A 1 and A 2 is substituted with one or more non-polar (NPL) group(s). [01141 Also preferred are polymers and oligomers of Formula I wherein A 2 is optionally substituted arylene or optionally substituted heteroarylene, and A 1 is a C 3 to Cs cycloalkyl or -(CH2)q-, wherein q is 1 to 7, and wherein A 1 and

A

2 are independently optionally substituted with one or more polar (PL) group(s), one or more non-polar (NPL) group(s), or a combination of one or more polar (PL) group(s) and one or more non-polar (NPL) group(s). Especially preferred are oligomers of Formula I wherein A 2 is substituted arylene and A1 is -(CH2)q-, wherein q is I or 2, and wherein one of A 1 and A 2 is substituted with one or more polar (PL) group(s), and the other of A 1 andr

A

2 is substituted with one or more non-polar (NPL) group(s). [0115] In some aspects of the invention, preferred polymers and oligomers of Formula I are those wherein (i) RI is hydrogen, a polar (PL) group, or a non polar (NPL) group, and R 2 is -x-A1-y-R", wherein R" is hydrogen, a polar (PL) group, or a non-polar (NPL) group. Especially preferred are oligomers of Formula I wherein R is hydrogen, R 2 is -x-A1-y-R", and R" is a polar (PL) group, for example, hydroxy. [01161 In other aspects, preferred polymers and oligomers of Formula I are those wherein R1 and R 2 are independently hydrogen, a polar (PL) group, or a non-polar (NPL) group. Especially preferred are oligomers of Formula I wherein R' is hydrogen, and R 2 is a polar group, for example, amino or hydroxy. [0117] In some aspects of the invention, preferred polymers and oligomers of Formula I are those wherein NPL is -B(OR 4

)

2 . Preferred values of R 4 are hydrogen, C1-Cio alkyl, C 3 -C1 8 branched alkyl, C 2 -C1 0 alkenyl, C 2 -C, alkynyl,

C

3 -Cs cycloalkyl, C 6 -Cio aryl, and heteroaryl, any of which is optionally substituted with one or more C1-C 6 alkyl or halo groups.

WO 2004/082634 PCT/US2004/008155 -33 [01.18] In other aspects, preferred polymers and oligomers of Formula I are those wherein NPL is -(NR )qlNPL-UNPL-(CH2)pNPL-(NR3")q2NPL-R*, and R 3 , R, R3", R', UNPL, pNPL, qlNPL and q2NPL are as defined above. [0119] Preferred values for each of R 3 , R?', and R 3 " are hydrogen, C 1

-C

6 alkyl, and C 1

-C

6 alkoxy. Hydrogen is an especially preferred value for R3, R', and R . [0120] Preferred values of R 4 ' are hydrogen, C 1

-C

10 alkyl, C3-CIs branched alkyl, C 2

-C

10 alkenyl, C 2

-C

10 alkynyl, C 3

-C

8 cycloalkyl, C 6 -Cio aryl, and heteroaryl, any of which is optionally substituted with one or more C1-C 6 alkyl or halo groups. Values of R' that are more preferred are C 1 -Cio alkyl, C 3

-C

1 8 branched alkyl, C 2 -Cio alkenyl, C 2

-C

10 alkynyl, and C 6

-C

10 aryl, especially phenyl. Especially preferred values of R' are C 1

-C

10 alkyl and C 3

-CI

8 branched alkyl. Suitable C 1

-C

1 0 alkyl and C 3 -Cis branched alkyl groups are methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, n-pentyl, and isopentyl. [0121] Preferred values of UINPL are 0, S, S(=0), S(=0)2, NH, -C(=0)-, -C(=0)-N=N'-NH-, -C(=0)-NH-N=N-, -N=N-NH-, -C(=N-N(RW)2)-, -C(=NR3)-, -C(=0)O-, -C(=0)S-, -C(=-S)-, -O-P(=0)20-, -R3O-, -R'S-, -S-C=N- and -C(=0)-NR 3 -0-, wherein groups with two chemically nonequivalent termini can adopt both possible orientations. [0122] Values of UNPL that are more preferred are 0, S, NH, -C(=0)-, -C(=0) N=N-NH-, -C(=0)-NH-N=N-, -N=N-NH-, -C(=N-N(R 3

)

2 )-, -C(=NR 3 )-, C(=0)O-, -RS- and -R30-. Especially preferred values of UNPL are NH, C(=O)-, 0 and S. Especially preferred polymers and oligomers of Formula I also are those wherein UNPL is absent. [0123] In some aspects of the invention, preferred polymers and oligomers of Formula I are those wherein UNPL is -O-P(=0) 2 0-. [0124] Preferred values of pNPL are 0 to 6; values of pNPL of 0 to 4 are especially preferred, with values of pNPL of 0 to 2 most preferred. [0125] Preferred values of qlNPL and q2NPL are 0 or 1. Values of qlNPL and q2NPL of 0 or 1 are especially preferred, with a value of 0 being the most preferred for each of qlNPL and q2NPL.

WO 2004/082634 PCT/US2004/008155 - 34 [0126] In preferred polymers and oligomers of Formula I, the -(CH2)pNPL alkylene chain in NPL is unsubstituted or substituted with one or more amino or hydroxy groups. More preferred are those oligomers of Formula I wherein the -(CH2)pNPL- alkylene chain in NPL is either unsubstituted or substituted with one or more amino groups. [0127] An especially preferred value of NPL for polymers and oligomers of Formula I is C 1

-C

6 alkyl or aryl CpC 6 alkyl. Examples of preferred values for NPL are n-propyl, isopropyl, n-butyl, tert-butyl, and benzyl. [0128] In some aspects of the invention, preferred polymers and oligoners of Formula I are those wherein PL is -2')P (CH2)pPL-(NR, and R', R', RI", V, U , pPL, qlPL and q2PL are as defined above. [01291 Preferred values for R 5 , R, and R 5 are hydrogen, C 1

-C

6 alkyl, and

C

1

-C

6 alkoxy. Hydrogen is an especially preferred value for each of R, R", and R 5 '. [0130] Preferred values of UL are 0, S, S(=0) 5 S(=0) 2 , NiH, -C(=0)-, -C(=0)-N=N-NH-, -C(=O)-NH-N=N-, -N=N-NH-, -C(=N-N(R 5

)

2 )-, -C(=NRW)-, -C(=0)O-, -C(=0)S-, -C(=S)-, -O-P(=0)20-, -R'O-, -R"S-, -S-C=N- and -C(=O)-NR-O-, wherein groups with two chemically nonequivalent termini can adopt both possible orientations. Values of UPL that are more preferred are 0, S, NH. -C(=0)-, -C(=0)-N=N-NH-, -C(=0)-NH-N=N-, -N=N-NH-, -C(=N-N(R5)2)-, -C(=NR 5)-, -C(=O:)O-, -R5 S and -R 5 0-. Especially preferred values of UPL are 0, S, NH, and -C(=O). Preferred polymers and oligomers of Formula I are also those wherein UPL is absent. [0131] In some aspects of the invention, preferred polymers and oligomers of Formula I are those wherein UPL is -O-P(=O) 2 0-. [0132] Preferred values of V are nitro, cyano, amino, hydroxy, C 1

-C

6 alkoxy, C1-C 6 alkylthio, CI-C6 alkylamino, Cr-C6 dialkylamino, -NH(CH 2 )pNH 2 wherein p is I to 4, -N(CH 2

CH

2 NH2) 2 , diazamino, amidino, guanidino, guanyl, semicarbazone, C 6

-C

10 aryl, heterocycle, and heteroaryl, preferably any of which is optionally substituted with one or more of amino, halo, cyano, nitro, WO 2004/082634 PCT/US2004/008155 -35 hydroxy, -NH(CH 2 )pNH 2 , -N(CH 2

CH

2 N-1 2

)

2 , amidino, guanidino, guanyl, aminosulfonyl, aminoalkoxy, lower acylamino, or benzyloxycarbonyl. [01331 Suitable heteroaryl groups include indolyl, 3H-indolyl, 1H-isoindolyl, indazolyl, benzoxazolyl, pyridyl, and 2-aminopyridyl. Suitable heterocycle groups include piperidinyl, piperazinyl, imidazolidinyl, pyrrolidinyl, pyrazolidinyl, and morpholinyl. [0134] Values of V that are more preferred are amino, C-C 6 alkylamino,

C

1

-C

6 dialkylamino, -NH(CH2)pNH 2 wherein p is 1 to 4, -N(CH 2

CH

2

NH

2

)

2 , diazamino, amidino, guanidino, guanyl, and semicarbazone, preferably any of which is optionally substituted with one or more of amino, halo, cyano, nitro, hydroxy, -NH(CH 2 )pNH 2 , -N(CH 2

CH

2

NH

2

)

2 , amidino, guanidino, guanyl, aminosulfonyl, aminoalkoxy, lower acylamino, or benzyloxycarbonyl. [0135] Especially preferred values of V are amino, C 1

-C

6 alkylamino,

-NH(CH

2 )pN-H2 wherein p is 1 to 4, -N(CH 2 CH2NH 2

)

2 , diazamino, amidino, and guanidino, preferably any of which is optionally substituted with one or more of amino, halo, cyano, nitro, hydroxy, -NH(C-2)pNTH 2 wherein p is 1 to 4, -N(CH 2

CH

2

NH

2

)

2 , amidino, guanyl, guanidino, or aminoalkoxy. Values of V that are most preferred are amino and guanidino. [0136] Preferred values of pPL are 0 to 6, with values of pPL of 2 to 5 especially preferred. [0137] Preferred values of qlPL and q2PL are 0 or 1. Values of qlPL and q2PL of 0 or I are especially preferred, with a value of 0 being especially preferred for each of qlPL and q2PL. [0138] In preferred polymers and oligomers of Formula I, the -(CH 2 )pPL alkylene chain in PL is optionally substituted with one or more amino groups. [01391 Preferred polymers of Formula I are those in which m is 1 to about 500. Especially preferred are those polymers of Formula I wherein in is 1 to about 100, or wherein m is 1 to about 50. [0140] Oligomers of Formula I that are preferred are those wherein m is 1 to about 30, or m is 1 to about 25; more preferred are those wherein m is 1 to about 20, or those wherein m is 1 to about 10, or wherein m is I to about 5.

WO 2004/082634 PCT/US2004/008155 -36 [0141] Thus, the invention is also directed to a method of treating a microbial infection in an animal in need thereof, the method comprising administering to the animal an effective amount of a pharmaceutical composition comprising an oligomer of Formula I, or an acceptable salt or solvate thereof, wherein: [0142] x is NR 8 , y is C=O, and R is hydrogen;

A

1 is optionally substituted o-, n-, or p-phenylene and A 2 is -(CH2)q-, wherein q is 1 or 2, and wherein A 1 and A 2 are independently optionally substituted with one or more polar (PL) group(s), one or more non polar (NPL) group(s), or a combination of one or more polar (PL) group(s) and one or more non-polar (NPL) group(s); or

A

2 is optionally substituted o-, m-, or p-phenylene and A 1 is -(CH2)q-, wherein q is I or 2, and wherein A 1 and A 2 are independently optionally substituted with one or more polar (PL) groupss, one or more non polar (NPL) group(s), or a combination of one or more polar (PL) group(s) and one or more non-polar (NiL) group(s); R' and R 2 are independently hydrogen, a polar (PL) group, or a non-polar (NPL) group; NPL is )qlNPL- p NPL(CH2)pNPL-(NR-)q2NPL -',A wherein:

R

3 , R 3 , and R are independently selected from. the group consisting of hydrogen, C 1

-C

6 alkyl, and C 1

-C

6 alkoxy; R is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and heteroaryl, any of which is optionally substituted with one or more alkyl or halo groups; UNPL is absent or selected from the group consisting of 0, S, S(=0), S(=0) 2 , NR 3 , -C(=0)-, -C(=0)-N=N--NR -, -C(=0)-NR 3 -N=N-, -N=N-NIR-, -C(=N-N(R 3 )2)-, -C(=NR 3 )-, -C(=O)O-, -C(=0)S-, -C(=S)-, -0-P(=0) 2 0-, -R 3 0-, -KRS-, -S-C=N- and

-C(=O)-NR

3 -0- , wherein groups with two chemically nonequivalent termini can adopt both possible orientations; WO 2004/082634 PCT/US2004/008155 - 37 the -(CH2)pNPL- alkylene chain is optionally substituted with one or more amino or hydroxy groups, or the alkylene chain is unsaturated; pNPL is 0 to 8; qlNIPL and q2NPL are independently 0, 1 or 2; PL is a polar group selected from the group consisting of halo, hydroxyethoxymethyl, methoxyethoxymethyl, polyoxyethylene, and

-(NR

5 ')q iPLUK(CH2)pPL-(NR)q2PI-V, wherein: R5, RZ, and R 5 " are independently selected from the group consisting of hydrogen, alkyl, and alkoxy; UP is absent or selected from the group consisting of 0, S, S(=0), S(=0) 2 , NR', -C(=0)-, -C(=0)-N=N-NR-, -C(=0)-NR 5 -N=N-, -N=N-NRt, -C(=N-N(R 5

)

2 )-, -C(=NR 5 )-, -C(=0)O-, -C(=0)S-, -C(=S)-, -0-P(=0)20-, -R50-, -R 5 S-, -S-C=N- and -C(=O)-NR.5-O- , wherein groups with two chemically nonequivalent termini can adopt both possible orientations; V is selected from the group consisting of nitro, cyano, amino, hydroxy, alkoxy, alkylthio, alkylamino, dialkylamino,

-NIH(CH

2 )pNH 2 wherein p is I to 4, -N(CH 2

CH

2 NH2) 2 , diazamino, amidino, guanidino, guanyl, semicarbazone, aryl, heterocycle and heteroaryl, any of which is optionally substituted with one or more of amino, halo, cyano, nitro, hydroxy, -NIH(CH 2 )pNH 2 wherein p is I to 4,

-N(CH

2

CH

2

NH

2

)

2 , amidino, guanidino, guanyl, aminosulfonyl, aminoalkoxy, aminoalkythio, lower acylamino, or benzyloxycarbonyl; the -(CH2)pPL- alkylene chain is optionally substituted with one or more amino or hydroxy groups, or the alkylene chain is unsaturated; pPL is 0 to 8; qPL and q2PL are independently 0, 1 or 2; and m is 4 or 5; WO 2004/082634 PCT/US2004/008155 -38 and a pharmaceutically acceptable carrier or diluent. 10143] In some aspects, the invention is also directed to a method of treating a microbial infection in an animal in need thereof, the method comprising administering to the animal an effective amount of a pharmaceutical composition comprising a polymer or oligomer of Formula I' R x-A-y-x-B-y R2 , or an acceptable salt or solvate thereof, wherein: x is NR 3 , 0, or S; y is C=O, C=S, O=S=0, or -C(=0)C(=0)- ; and R 3 is hydrogen or alkyl; A and B are independently optionally substituted o-, in-, or p phenylene or optionally substituted heteroarylene, wherein: (i) A and B are independently optionally substituted with one or more polar (P) group(s), one or more non-polar (NP) group(s), or a combination of one or more polar (P) group(s) and one or more non-polar (NP) group(s); or (ii) A is optionally substituted o-, in-, or p-phenylene or optionally substituted heteroarylene and B is a C 3 to C 8 cycloalkyl or

(CH

2 )q-, wherein q is 1 to 7,wherein A and B are independently optionally substituted with one or more polar (P) group(s), one or more non-polar (NP) group(s), or a combination of one or more polar (P) group(s) and one or more non-polar (NP)group(s); or (iii) B is optionally substituted o-, in-, or p-phenylene or optionally substituted heteroarylene, and A is a C 3 to C 8 cycloalkyl or

-(CH

2 )q-, wherein q is 1 to 7,wherein A and B are independently optionally substituted with one or more polar (P) group(s), one or more non-polar (NP) group(s), or a WO 2004/082634 PCT/US2004/008155 -39 combination of one or more polar (P) group(s) and one or more non-polar (NP) group(s); R' is (i) -y-C and R2 is OH or NH 2 wherein C is selected from a group consisting of C 1

-C

6 alkyl, vinyl, 2-propenyl, H-x-(CH 2 )p-,

(CI-C

6 alkoxy)C(=O)(CH 2 )p-, C-C 6 alkoxy, benzyloxy, t-butoxy, pyridine and phenyl, any of which is optionally substituted with one or more substituents independently selected from a group consisting of halo, amino, nitro, cyano,

C

1

-C

6 alkoxy, C 1

-C

6 alkoxycarbonyl, and benzyl.oxycarbonyl, and wherein p is defined below; or (ii) is H and R 2 is -x-(CH 2 )p-W wherein x is as defined above, p is as defined below, W is H, N-maleimide, or V as defined below, and -(CH 2 )p- is optionally substituted with one or more hydroxyl groups; or (iii) -y-C and R2 is -x-(CH 2 )p-W wherein x is as defined above, p is as defined below, W is H, N-maleimide, or V as defined below, and -(CH2)p- is optionally substituted with one or more hydroxyl groups; or (iv) R' and R2 together are a single bond; NP is a nonpolar group independently selected from -B(OR) 2 (wherein B represents in this instance a boron atom), R4 or -(NR 3 )qlU-(CH2)p-(NR3)q2 -R 4 , wherein R3 is selected from the group consisting of hydrogen, alkyl, and alkoxy;

R

4 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and heteroaryl, any of which is optionally substituted with one or more alkyl, alkoxy, or halo groups; U is absent or selected from the group consisting of 0, S, S(=O), S(=0) 2 , NR, -C(=0)-, -C(=O)-N=N-NR 3 -, -C(=O)-NR 3

-N=N-,

WO 2004/082634 PCT/US2004/008155 -40 -N=N-NR 3 -, -C(=N-N(R 3

)

2 )-, -C(=NR 3 )-, -C(=O)O-, -C(=O)S-, -C(=S)-, -O-P(=0) 2 0- (wherein P represents in this instance a phosphorus atom), -R 3 -O-, -R 3 -S-, -S-C=N- and

-C(=O)-NR

3 -0-, wherein groups with two chemically nonequivalent termini can adopt both possible orientations; the -(CH 2 )p- alkylene chain is optionally substituted with one or more amino or hydroxyl groups, or the alkylene chain is unsaturated; p is independently 0 to 8; qi and q2 are independently 0 to 2; P is a polar group selected from the group consisting of halo, hydroxyethoxymethyl, methoxyethoxymethyl, polyoxyethylene, and

-(NR

3 )qi'U-(CH2)p-(NR 3 )q2-V, wherein; U and R 3 are as defined above; V is selected from the group consisting of nitro, cyano, thio, amino, hydroxyl, alkoxy, alkylthio, alkylamino, dialkylamino,

-NI(CH

2 )pMI- 2 , -N(CH 2

CH

2

NH

2

)

2 , diazamino, amidino, guanidino, guanyl, semicarbazone, alkoxycarbonyl, aryl, heterocycle and heteroaryl, any of which is optionally substituted with one or more of amino, halo, cyano, nitro, hydroxyl, -NH (CH2)pNH 2 , -N(CH 2

CH

2

NH

2

)

2 , alkylamino, dialkylamino, amidino, guanidino, guanyl, aminosulfonyl, aminoalkoxy, aminoalkylthio, lower acylamino, or benzyloxycarbonyl; the -(CH 2 )p- alkylene chain is optionally substituted with one or more amino or hydroxyl groups, or the alkylene chain is unsaturated; p, ql and q2 are as defined above; and m is 1 to about about 500; and a pharmaceutically acceptable carrier or diluent. [01441 In some aspects, the invention is also directed to a method of treating a microbial infection in an animal in need thereof, the method comprising administering to the animal an effective amount of a pharmaceutical WO 2004/082634 PCT/US2004/008155 -41 composition comprising a polymer or oligomer of Formula I', or an acceptable salt or solvate thereof, wherein: x is NR3 y is C=0; and RW is hydrogen or alkyl; A and B are independently optionally substituted o-, i-, or p-phenylene, wherein B is optionally substituted o-, i-, or p-phenylene, and A is -(CH2)q-, wherein q is 1, and wherein A is optionally substituted with one or more non-polar (NP) group(s) and B is optionally substituted with one or more polar (P) group(s); R' is H and R 2 is an amino group; NP is R4, wherein R4 is alkyl, alkenyl, or alkynyl, any of which is optionally substituted with one or more alkyl, alkoxy, or halo groups; P is-(NR 3 )qi U-(CH 2 )p-(NR 3 )q 2 -V, wherein: qI and q2 are each 0; p is 0 to 6; U is absent, 0, or C=0; V is selected from the group consisting amino, alkoxy, alkylamino, dialkylamino, -NH(CH 2 )pNHI 2 , -N(CH2CH 2

'TH

2

)

2 , diazamino, amidino, guanidino, and guanyl, any of which is optionally substituted with one or more of amino, halo, -NH(CH 2 )pNH 2 -,

-N(CH

2

CH

2

NIH

2

)

2 -, alkylamino, dialkylamino, amidino, guanidino, or guanyl, or aminoalkoxy; the -(CH 2 )p- alkylene chain is optionally substituted with one or more amino or hydroxyl groups; and m is 1 to 5; and a pharmaceutically acceptable carrier or diluent. [0145] In other aspects, the invention is also directed to a method of treating a microbial infection in an animal in need thereof, the method comprising administering to the animal an effective amount of a pharmaceutical composition comprising a polymer or oligomer of Formula I', or an acceptable salt or solvate thereof, wherein: WO 2004/082634 PCT/US2004/008155 - 42 x is NR3; y is C=O; and RW is hydrogen or alkyl; A and B are independently optionally substituted o-, in-, or p-phenylene, wherein A is optionally substituted o-, in-, or p-phenylene and B is (CH 2 )g., wherein q is 1, where A is optionally substituted with one polar (P) group or one non-polar (NP) group, and B is optionally substituted with one or more polar (P)group(s) or one or more non polar (NP) group(s); R' is H and R2 is an amino group; NP is -(NR 3 )q-U-(CH2)p-(NR 3 )q 2

-R

4 , wherein R4 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, and aryl, any of which is optionally substituted with one or more alkyl, alkoxy, or halo groups; U is absent; the -(CH2),- alkylene chain is optionally substituted with one or more amino or hydroxyl groups; p is independently 0 to 6; q and q2 are each 0; P is-(NR),iU-(CH 2 )p-(NR 3 )q 2 -V, wherein: qI and q2 are each 0; p is 0 to 6; U is absent, 0, or C=0; V is selected from the group consisting amino, alkoxy, alkylamino, dialkylamino, -N-H(CH 2 )pNH 2 -, -N(CH 2

CH

2 NH2)2, diazamino, amidino, guanidino, and guanyl, any of which is optionally substituted with one or more of amino, halo, -NH(CH 2

),NH

2 -,

-N(CH

2 C1 2

NH

2

)

2 , alkylamino, dialkylamino, amidino, guanidino, or guanyl, or aminoalkoxy; the -(CH 2 )p- alkylene chain is optionally substituted with one or more amino or hydroxyl groups; m is 1 to 5; and a pharmaceutically acceptable carrier or diluent.

WO 2004/082634 PCT/US2004/008155 -43 [0146] In other aspects, the invention is directed to a method of treating a microbial infection in an animal in need thereof, the method comprising administering to the animal an effective amount of a phannaceutical composition comprising a polymer or oligomer of Formula VII: R9/RIO H0 H R

R

2 (VH) 02 R.I m wherein one of R 9 or R1 0 and R is a polar (P) group and the other of R9 or R' and R" is a nonpolar (NP) group; P is a polar group selected from a group consisting of IIb, hydroxyethoxymethyl methoxyethoxy-methyl and polyoxyethylene -(CH2)-v (fib) wherein: V is selected from a group consisting of amino, hydroxyl, C1-C 6 alkylamino, C1-C 6 dialkylamino, NH(CH 2 )pNH 2 , N(CH 2

CH

2

NH

2

)

2 , amidine, guanidine, semicarbazone, imidazole, piperidine, piperazine, 4 alkylpiperazine and phenyl optionally substituted with an amino, C1-C 6 alkylamino, C1-C 6 dialkylamino or lower acylamino optionally substituted with one or more amino, lower alkylamino or lower dialkylamino; and, the alkylene chain is optionally substituted with an amino or hydroxyl group; p is independently 0 to 8; and, NP, R1 and R 2 are as defined in Formula I above; m is 1 to about 30, or is I to about 50; or an acceptable salt or solvate thereof; and a pharmaceutically acceptable carrier or diluent.

WO 2004/082634 PCT/US2004/008155 - 44 [01471 In yet other aspects, the invention is directed to a method of treating a microbial infection in an animal in need thereof, the method comprising administering to the animal an effective amount of a pharmaceutical composition comprising a polymer or oligomer of Formula IX: R9 / H N AyN2 H 'R 2 (IX) _m wherein: one of R 9 or R" is either a polar (P) group or a nonpolar (NP) group and the other of R 9 or R 11 is the other of a polar(P) group or a nonpolar (NP) group; NP is - (CH 2 )p-R 4 wherein R 4 is selected from a group consisting of hydrogen,

CI-C

4 alkyl, C 3

-C

1 2 branched alkyl, C 3 -Cs cycloalkyl, phenyl optionally substituted with one or more C 1

-C

4 alkyl groups, C1-C 4 alkoxy, or halo groups and heteroaryl optionally substituted with one or more CI-C 4 alkyl group, C-C4. alkoxy or halo groups, and p is as defined below; P is a polar group selected from a group consisting of IHIb, hydroxyethoxymethyl, methoxyethoxyinethyl and polyoxyethylene -(CH2)r-v (II1b) wherein: V is selected from a group consisting of amino, hydroxyl, C 1

-C

6 alkylamino,

CI-C

6 dialkylamino, NH(CH 2 )pNH 2 , N(CI 2

CH

2

NH

2

)

2 , amidine, guanidine, semicarbazone, imidazole, piperidine, piperazine, 4 alkylpiperazine and phenyl optionally substituted with an amino, CI-C 6 alkylamino, C 1

-C

6 dialkylamino or lower acylamino optionally WO 2004/082634 PCT/US2004/008155 -45 substituted with one or more amino, lower alkylamino or lower dialkylamino; and, the alkylene chain is optionally substituted with an amino or hydroxyl group; p is independently 0 to 8; RI and R2 are as defined in Formula I' above; m is 1 to about 500; or an acceptable salt or solvate thereof; and a pharmaceutically acceptable carrier or diluent. [0148] In some aspects of the invention, in the polymer or oligomer of Formula IX, RW is a polar side chain of a natural amino acids and R" is selected from a group consisting of methyl, ethyl, n-propyl, iso-propyl, n-butyl iso-butyl, sec-butyl, tert-butyl, n-pentyl, iso-pentyl, sec-pentyl, and benzyl. [0149] In yet other aspects, the invention is directed to a method of treating a microbial infection in an animal in need thereof, the method comprising administering to the animal an effective amount of a pharmaceutical composition comprising a polymer or oligomer of Fonnula IX, wherein RW is a nonpolar side chain of a natural amino acids and R' 1 is a polar group selected from a group consisting of 11b, hydroxyethoxymethyl, methoxyethoxymethyl and polyoxyethylene

-(CH

2 )tv (Ib) wherein: V is selected from a group consisting of amino, hydroxyl, C-C 6 alkylamino,

CI-C

6 dialkylamino, NI-(CH 2 )pNH2, N(CH 2

CH

2

NH

2

)

2 , amidine, guanidine, semicarbazone, imidazole, piperidine, piperazine, 4 alkylpiperazine, and phenyl optionally substituted with an amino, C 1 C 6 alkylamino, C 1

-C

6 dialkylamino or lower acylamino optionally substituted with one or more amino, lower alkylamino or lower dialkylamino; and, p is independently 0 to 8; R' and R2 are as defined in Formula I' above; WO 2004/082634 PCT/US2004/008155 - 46 m is I to about 500; or an acceptable salt or solvate thereof; and a pharmaceutically acceptable carrier or diluent. [01501 In yet other aspects, the invention is directed to a method of treating a microbial infection in an animal in need thereof, the method comprising administering to the animal an effective amount of a pharmaceutical composition comprising a polymer or oligomer of Formula I': wherein: x is NH and y is C=O or C=S; A and B are independently optionally substituted o-, m-, or p-phenylene, 2,5 thiophenylene or 2,5-pyrrolene; NP is a nonpolar group independently selected from R 4 or U-(CH 2 )p-R 4 wherein R 4 is selected from a group consisting of hydrogen, C 1

-C

4 alkyl, C 3

-C

1 2 branched alkyl, C 3 -Cs cycloalkyl, phenyl optionally substituted with one or more C 1

-C

4 alkyl groups, C1-C 4 alkoxy, or halo groups and heteroaryl optionally substituted with one or more C 1

-C

4 alkyl group, C 1

-C

4 alkoxy, or halo groups, and U and p are as defined below; P is a polar group selected from a group consisting of IIla, hydroxyethoxymethyl, methoxyethoxymethyl and polyoxyethylene -u--(CH 2 )-V (II1a) wherein: U is absent, 0, S, SO, So 2 , or NH; V is selected from a group consisting of amino, hydroxyl, C 1

-C

6 alkylamino, C1-C6 dialkylamino, NTH(CH 2 )pNH 2 , N(CH 2

CH

2 NH2) 2 , amidine, guanidine, semicarbazone, imidazole, piperidine, piperazine, 4 alkylpiperazine and phenyl optionally substituted with an amino, C 1

-C

6 alkylamino, CI-C 6 dialkylamino or lower acylamino optionally substituted with one or more amino, lower alkylamino or lower dialkylamino; and, WO 2004/082634 PCT/US2004/008155 - 47 the alkylene chain is optionally substituted with an amino or hydroxyl group; p is independently 0 to 8;and, m is I to about 500; or an acceptable salt or solvate thereof; and a pharmaceutically acceptable carrier or diluent. [01511 In some aspects, in the polymer or oligomer of Formula I, x is NR 3 , R 3 is hydrogen and y is C=O or C=S; A and B are independently optionally substituted o-, in-, or p-phenylene; NP is a nonpolar group independently selected from R 4 or -U-(CH 2 )p-R 4 wherein R 4 is selected from a group consisting of hydrogen, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, ni pentyl, iso-pentyl, and sec-pentyl, and U and p are as defined below; P is a polar group U-(CH 2 )p- V wherein U is absent or selected from a group consisting of 0 and S, and V is selected from a group consisting of amino, lower alkyl amino, lower dialkylamino, imidazole, guanidine,

NIH(CH

2 )pNH 2 , N(CH 2

CH

2

NH

2

)

2 , pyridine, piperidine, piperazine, and 4-alkylpiperazine; p is independently 0 to 8; and m is 1 to about 500. [0152] In other aspects, in the polymer or oligomer of Fonnula I', x is NR 3 , y is CO, and R is hydrogen; A and B are in- or p-phenylene wherein (i) A is substituted at the 2-position with a polar (P) group and B is substituted at the 5-position with a nonpolar (NP) group, (ii) A is substituted at the 2-position with a polar (P) group and at the 5-position with a nonpolar (NP) group and B is substituted at the 2-position with a nonpolar (NP) group and at the 5 position with a polar (P) group or, (iii) A is substituted at the 2-position with one of a polar (P) or nonpolar (NP) group and B is substituted at the 2-position with the other of a nonpolar (NP) or a polar (P) group; NP is a nonpolar group independently selected from R 4 or -U-R 4 wherein R 4 is selected from a group consisting of methyl, ethyl, n-propyl, iso-propyl, WO 2004/082634 PCT/US2004/008155 - 48 n-butyl, iso-butyl, sec-butyl, tert-butyl, n-pentyl, iso-pentyl, and see pentyl, and U and p are as defined below; p is independently 0 to 8; and, m is 1 to about 500. [0153] In some aspects, the invention is directed to a method of treating a microbial infection in an animal in need thereof, the method comprising administering to the animal an effective amount of a pharmaceutical composition comprising a polymer or oligomer of Formula XII: P I H R N' R 2 O O~ N. 0 01 M _m wherein: NP is a nonpolar group independently selected from a group consisting of methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert butyl, n-pentyl, iso-pentyl, and sec-pentyl, and U and p are as defined below; P is a polar group U-(CH 2 )p-V wherein U is selected from a group consisting of 0, S, or no atom and V is selected from a group consisting of amino, lower alkyl amino, lower dialkylamino, imidazole, guanidine,

NH(CH

2 )pNH 2 , and N(CH 2

CH

2

NH

2

)

2 , piperidine, piperazine, and 4 alkylpiperazine; p is independently 0 to 8; m is I to about 30, or is 1 to about 50; or an acceptable salt or solvate thereof; and a pharmaceutically acceptable carrier or diluent. [0154] In other aspects, the invention is directed to a method of treating a microbial infection in an animal in need thereof, the method comprising WO 2004/082634 PCT/US2004/008155 -49 administering to the animal an effective amount of a pharmaceutical composition comprising a polymer or oligomer of Formula XIV: P NP R R2 (XIV) wherein: NP is a nonpolar group independently selected from R 4 or -U-R 4 wherein R 4 is selected from a group consisting of methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, n-pentyl, iso-pentyl, and see pentyl, and U and p are as defined below; P is a polar group U-(CH2)p-V wherein U is selected from a group consisting of 0, S, or no atom and V is selected from a group consisting of amino, lower alkyl amino, lower dialkylamino, imidazole, guanidine,

NH(CH

2 )pNH2, N(CH 2

CH

2

NH

2 )2, piperidine, piperazine, and 4 alkylpiperazine; p is independently 0 to 8; and m is 1 to about 30, or is I to about 50; or an acceptable salt or solvate thereof; and a pharmaceutically acceptable carrier or diluent. [01551 In some aspects, the invention is directed to a method of treating a microbial infection in an animal in need thereof, the method comprising administering to the animal an effective amount of a pharmaceutical composition comprising a polymer or oligomer of Formula I' wherein: x is NR 3 , y is CO, and R 3 is hydrogen; A and B are o-phenylene wherein A is substituted at the 5-position with a polar (P) group and B is substituted at the 5-position with a nonpolar. (NP) group; WO 2004/082634 PCT/US2004/008155 -50 NP is a nonpolar group independently selected from R 4 or -U-R 4 wherein R 4 is selected from a group consisting of methyl, ethyl, n-propyl, iso-propyl, iso-butyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, iso-pentyl, and sec pentyl, and U and p are as defined below; P is a polar group U-(CH 2 )p-V wherein U is selected from a group consisting of 0, S, or no atom and V is selected from a group consisting of amino, lower alkyl amino, lower dialkylamino, imidazole, guanidine,

NH(CH

2 )pNH 2 , N(CH 2 C1 2

NH

2

)

2 , pyridine, piperidine, piperazine, and 4-alkylpiperazine; p is independently 0 to 8; and m is I to about 500; or an acceptable salt or solvate thereof; and a pharmaceutically acceptable carrier or diluent. [01561 In yet other aspects, the invention is directed to a method of treating a microbial infection in an animal in need thereof, the method comprising administering to the animal an effective amount of a pharmaceutical composition comprising a polymer or oligomer of Formula XIII:

P

0 R HN HN--R 2 (XIII) NP O wherein: NP is a nonpolar group independently selected from a the group consisting of methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert butyl, n-pentyl, iso-pentyl, and sec-pentyl, and U and p are as defined below; WO 2004/082634 PCT/US2004/008155 - 51 P is a polar group (CH 2 )p-V wherein V is selected from a group consisting of amino, lower alkyl amino, lower dialkylamino, guanidine, piperazine, and 4-alkylpiperazine; p is independently 0 to 8; and m is 1 to about 30, or is 1 to about 50; or an. acceptable salt or solvate thereof; and a pharmaceutically acceptable carrier or diluent. [0157] In some aspects, the invention is directed to a method of treating a microbial infection in an animal in need thereof, the method comprising administering to the animal an effective amount of a pharmaceutical composition comprising a polymer or oligomer of Formula XV:

R'

2 0 R 1 4 0 R 1' R- (XV) wherein either R1 and R 1 4 are independently polar (P) groups and R1 3 and R1 5 are independently nonpolar (NP) groups substituted at one of the remaining unsubstituted carbon atoms, or R 12 and R" are independently nonpolar (NP)groups and R1 3 and R 15 are independently polar (P) groups; NP is a nonpolar group independently selected from R 4 or -U-R 4 wherein R 4 is selected from a the group consisting of methyl, ethyl, n-propyl, iso propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, n-pentyl, iso-pentyl, and sec-pentyl, and U is defined below; P is a polar group U-(CH 2 )p-V wherein U is selected from a group consisting of 0 or S and V is selected from a group consisting of amino, lower alkyl amino, lower dialkylamino, guanidine, pyridine, piperazine, and 4-alkylpiperazine; p is independently 0 to 8; and WO 2004/082634 PCT/US2004/008155 -52 m is I to about 30, or I to about 50; or an acceptable salt or solvate thereof; and a pharmaceutically acceptable carrier or diluent. [0100] In some aspects, the invention is also directed to a method of treating a microbial infection in an animal in need thereof, the method comprising administering to the animal an effective amount of a pharmaceutical composition comprising a polymer or oligomer of Formula II: R-[-x-A1-x-y-A2-y-]m-R or an acceptable salt or solvate thereof, wherein: x is NR, 0, S, -N(R 8 )N(R)-, -N(R)-(N=N)-, -(N=N)-N(R)-, -C(R7R 7

')NR

8 -, -C(RR')O-, or -C(R 7

R

7 )S-; and y is C=0, C=-S, O=S=0, C(=0)C(=0)-, C(R 6

R

6 ')C=0 or C(RR')C=S; or x and y are taken together to be pyromellitic diimide; wherein R 8 is hydrogen or alkyl; R7 and R are independently hydrogen or alkyl, or R and RT together are -(CH 2 )p-, wherein p is 4 to S; and R 0 and R6' are independently hydrogen or alkyl, or R 6 and R 6 ' together are (CH 2

)

2

NR

12

(CH

2

)

2 , wherein R 12 is hydrogen, -C(=N)CH 3 or C(=NH)-NH 2 ;

A

1 and A 2 are independently optionally substituted arylene or optionally substituted heteroarylene, wherein A 1 and A 2 are independently optionally substituted with one or more polar (PL) group(s), one or more non-polar (NPL) group(s), or a combination of one or more polar (PL) group(s) and one or more non-polar (NPL) group(s); R1 is (i) hydrogen, a polar group (PL), or a non-polar group (NPL), and R2 is -x-A 1 -x-R', wherein A 1 is as defined above and is optionally substituted with one or more polar (PL) group(s), one or more non-polar (NPL) group(s), or a combination of one or more WO 2004/082634 PCT/US2004/008155 -53 polar (PL) groups) and one or more non-polar (NPL) group(s); or (ii) hydrogen, a polar group (PL), or a non-polar group (NPL), and R 2 is -x-A'-x-Rl, wherein A' is aryl or heteroaryl and is optionally substituted with one or more polar (PL) group(s), one or more non-polar (NPL) group(s), or a combination of one or more polar (PL) group(s) and one or more non-polar (NPL) group(s); (iii) -y-A 2 -y-R 2 , and R 2 is hydrogen, a polar group (PL), or a non-polar group (NPL); or (iv) --y-A' and R 2 is -x-A', wherein A' is aryl or heteroaryl and is optionally substituted with one or more polar (PL) group(s), one or more non-polar (NPL) group(s), or a combination of one or more polar (PL) group(s) and one or more non-polar (NPL) group(s); or (v) R 1 and R are independently a polar group (PL) or a non-polar group (NPL); or (vi) R 1 and R 2 together forn a single bond; NPL is a nonpolar group independently selected from the group consisting of

-B(OR

4 )2 and -(NR")qlNPL-UPL-(CH2)pNPL-(NR3')q2NPL -R 4 ', wherein:

R

3 , R, and R 3 " are independently selected from the group consisting of hydrogen, alkyl, and alkoxy;

R

4 and R 4 ' are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and heteroaryl, any of which is optionally substituted with one or more alkyl or halo groups; U'N is absent or selected from the group consisting of 0, S, S(=0), S(=0) 2 , NR 3 , -C(==0)-, -C(=0)-N=N-NR 3 -, -C(=0)-NR 3 -N=N-, -N=N-NR3-,-C(=N-N(RW)2)-, -C(=NR3)-, -C(=0)O-, -C(=0)S-, -C(=S)-, -0-P(=0) 2 0-, -R 3 0-, -R 3 S-, -S-C=N- and -C(=0)-NR 3 -0- , wherein groups with two chemically nonequivalent termini can adopt both possible orientations; WO 2004/082634 PCT/US2004/008155 -54 the -(CH2)pNTPL- alkylene chain is optionally substituted with one or more amino or hydroxy groups, or is unsaturated; pNPL is 0 to 8; qlNPL and q2NPL are independently 0, 1 or 2; PL is a polar group selected from the group consisting of halo, hydroxyethoxymethyl, methoxyethoxymethyl, polyoxyethylene, and -- (NR")q1PL-U-(CH2)pPL- w')q2PL-V, wherein: R', R', and R" are independently selected from the group consisting of hydrogen, alkyl, and alkoxy; UPL is absent or selected from the group consisting of 0, S, S(=0), S(=0)2, NR, -C(=0)-, -C(=0)-NN-NNR5 -, -C(=0)-NR 5 N-N-, -N=N-NW-, -C(=N-N(R 5 )2)-, -C(=NR 5 )-, -C(=0)O-, -C(=O)S-, -C(=S)-, -0-P(=O) 2 0-, -RiO-, -R 5 S-, -S-C=N- and -C(=0)-NRi-0- , wherein groups with two chemically nonequivalent termini can adopt both possible orientations; V is selected from the group consisting of nitro, cyano, amino, hydroxy, alkoxy, alkylthio, alkylamino, dialkylamino, -NH(CH2)pNH 2 wherein p is I to 4, -N(CH2CH 2

NH

2 )2, diazamino, amidino, guanidino, guanyl, semicarbazone, aryl, heterocycle and heteroaryl, any of which is optionally substituted with one or more of amino, halo, cyano, nitro, hydroxy, -NH(CH 2 )pNH 2 wherein p is I to 4,

-N(CH

2

CH

2

NH

2

)

2 , amidino, guanidino, guanyl, aminosulfonyl, aminoalkoxy, aminoalkythio, lower acylamino, or benzyloxycarbonyl; the -(CH2)pPL- alkylene chain is optionally substituted with one or more amino or hydroxy groups, or is unsaturated; pPL is 0 to 8; q1PL and q2PL are independently 0, 1 or 2; and m is 1 to about 500; and a pharmaceutically acceptable carrier or diluent.

WO 2004/082634 PCT/US2004/008155 - 55 101581 Polymers and oligomers of Formula II that are preferred for use in the disclosed method are those wherein x is NR 8 , 0, S, or -N(R8)N(R 5 )-, and R' is hydrogen or C 1

-C

6 alkyl Also preferred are those polymers and oligomers wherein y is C=0, C=S, or O=S=0. Especially preferred are those polymers and oligomers wherein x is NR and y is C=0. For example, oligomers of Formula II wherein x is NH and y is C=O are especially preferred. Also preferred are oligomers of Formula II wherein x is 0 and y is C=0, or wherein x is -N(R 8 )N(Rs)- and R8 is hydrogen; and y is C=0. [0159] Preferred are those polymers and oligomers of Formula II wherein A 1 and A 2 are independently optionally substituted o-, in-, or p-phenylene. Those oligomers wherein A 1 and A 2 are optionally substituted n--phenylene are especially preferred. Also preferred are polymers and oligomers of Formula II wherein one of Ai and A2 is o-, im-, or p-phenylene, and the other of A1 and A 2 is heteroarylene. Preferred heteroarylene groups include, but are not limited to, pyridinylene, pyrimidinylene, and pyrazinylene. [0160] Also preferred are polymers and oligomers of Formula II wherein A 1 and A 2 are independently optionally substituted arylene or optionally substituted heteroarylene, and (i) one of A1 and A 2 is substituted with one or more polar (PL) group(s) and one or more nonpolar (NPL) group(s) and the other of A 1 and A 2 is unsubstituted; or (ii) one of A 1 and A 2 is substituted with one or more polar (PL) group(s) and one or more nonpolar (NPL) group(s) and the other of A 1 and A 2 is substituted with one or more polar (PL) group(s). Polymers and oligomers in which either (i) one of A 1 and A 2 is substituted with one polar (PL) group and one nonpolar (NPL) group, and the other of A 1 and A 2 is unsubstituted, or (ii) one of A 1 and A 2 is substituted with one polar (PL) group and one nonpolar (NPL) group and the other of A 1 and A 2 is substituted with one or two polar (PL) group(s), are especially preferred. [0161] Thus, polymers and oligomers of Formula II are preferred in which Ai and A 2 are optionally substituted i-phenylene, wherein one of A1 and A 2 is substituted with one polar (PL) group and one nonpolar (NPL) group and the other of A 1 and A 2 is unsubstituted, WO 2004/082634 PCT/US2004/008155 - 56 [01621 In some aspects of the invention, preferred polymers and oligomers of Formula II are those wherein (i) R' is hydrogen, a polar group (PL), or a non polar group (NPL), and R 2 is -x-A 1 -x-R 1 , wherein A 1 is as defined above and is substituted with one or more polar (PL) group(s), one or more non-polar (NPL) group(s), or a combination of one or more polar (PL) group(s) and one or more non-polar (NPL) group(s), or (ii) R1 is hydrogen, a polar group (PL), or a non-polar group (NPL), and R2 is -x-A-x-R 1 , wherein A' is aryl or heteroaryl and is optionally substituted with one or more polar (PL) group(s), one or more non-polar (NPL) group(s), or a combination of one or more polar (PL) group(s) and one or more non-polar (NPL) group(s). [01631 More preferred are those oligomers of Formula II wherein R' is hydrogen, a polar group (PL), or a non-polar group (NPL), and R 2 is -x-A 1 -x

R

1 , wherein A 1 is as defined above and is substituted. with one or more polar (PL) group(s), one or more non-polar (NPL) group(s), or a combination of one or more polar (PL) group(s) and one or more non-polar (NPL) group(s). More preferred still are those oligomers wherein R' is hydrogen or a polar group (PL), and R 2 is -x-A 1 -x-Rl, where A 1 is substituted with one or more polar (PL) group(s) or a combination of one or more polar (PL) group(s) and one or more non-polar (NPL) group(s). Especially preferred are those oligomers wherein RI is a polar (PL) group and R 2 is -x-A1-x-R, where A 1 is substituted with one or two polar (PL) group(s) and one non-polar (NPL) group. [0164] In some aspects of the invention, preferred polymers and oligomers of Formula II are those wherein NPL is -B(OR 4

)

2 . Preferred values of R4 are hydrogen, C 1

-C

10 alkyl, C 3

-C

1 s branched alkyl, C 2

-C

1 o alkenyl, C 2

-C

1 O alkynyl,

C

3 -Cs cycloalkyl, C 6 -Cio aryl, and heteroaryl, any of which is optionally substituted with one or more Ci-C 6 alkyl or halo groups. [01651 In other aspects, preferred polymers and oligomers of Formula II include those wherein NPL is -( )qlNPL-UNPL-(CH2)pNPL- 3"')q2NPL-R4 and R 3 , R, R, R 4 ', UNmL, pNPL, qlNPL and q2NPL are as defined above.

WO 2004/082634 PCT/US2004/008155 -57 [0166] Preferred values for each of R 3 , R, and R are hydrogen, C 1

-C

6 alkyl, and C 1

-C

6 alkoxy. Hydrogen is an especially preferred value for R 3 , R", and R'. [01671 Preferred values of R 4 are hydrogen, C 1 -Cio alkyl, C 3

-C

18 branched alkyl, C 2

-C

10 alkenyl, C 2

-C

10 alkynyl, C 3

-C

8 cycloalkyl, C 6

-C

10 aryl, and heteroaryl, any of which is optionally substituted with one or more C 1

-C

6 alkyl or halo groups. Values of R 4 'that are more preferred are CI-Cio alkyl, C 3 -CIS branched alkyl, C 2

-C

10 alkenyl, C 2 -Cio alkynyl, and C 6

-C

10 aryl, especially phenyl. Especially preferred values of Rf are Cv-Cio alkyl and C 3

-C

18 branched alkyl. Suitable C 1

-C

10 alkyl and C 3

-C

18 branched alkyl groups are methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, and n-pentyl. [0168] Preferred values of UNPL are 0, S, S(=0), S(=0)2, NH, -C(=0)-, -C(=0)-N=N-NH-, -C(=0)-NH-N=N-, -N=N-NH-, -C(=N-N(R 3

)

2 )-, -C(=NqR3)-, -C(=0)O-, -C(=0)S-, -C(=S)-, -O-P(=O)20-, -R3O-, -R'S-, -S-C=N- and -C(=0)-NR 3 -0-, wherein groups with two chemically nonequivalent termini can adopt both possible orientations. [0169] Values of UNPL that are more preferred are 0, S, NH, -C(=0)-, -C(=0) N=N-NH-, -C(=0)-NH-N=N-, -N=N-NH-, -C(=N-N(R-3)2)-, -C('=NR3)-, -C(=0)O-, -RS- and -R 3 0-. An especially preferred value of UNPL is -C(=0)_. Preferred polymers and oligomers of Formula II also include those wherein UNPL UNP is absent. [01701 In some aspects of the invention, preferred polymers and oligomers of Formula II are those wherein UNPL is -0-P(=0) 2 0-. [0171] Preferred values of pNPL are 0 to 6; values of pNPL of 0 to 4 are especially preferred, with values of pNPL of 0, 1 or 2 most preferred. [0172] Preferred values of qlNPL and q2NPL are 0 or 1. Values of qlNPL and q2NPL of 0 or 1 are especially preferred, with a value of 0 being the most preferred for each of qlNPL and q2NPL. [01731 In preferred polymers and oligomers of Formula II, the -(CH2)pNPL alkylene chain in NPL is unsubstituted or substituted with one or more amino or hydroxy groups. More preferred are those oligomers of Formula II wherein WO 2004/082634 PCT/US2004/008155 - 58 the -(CH2)pNPL- alkylene chain in NPL is substituted with one or more amino groups. [0174] An especially preferred value of NPL for polymers and oligomers of Formula II is C-C 6 alkyl. Examples of preferred values for NPL are n-propyl, isopropyl, n-butyl, and tert-butyl. [0175] In some aspects of the invention, preferred polymers and oligomers of Formula II are those wherein PL is -(NR)giP-U ,-(CH2)pP-(NR")q2P -, and R, R 5 , R, V, UPL, pPL, qlPL and q2PL are as defined above. [0176] Preferred values for R5, R', and R 5 ' are hydrogen, C 1

-C

6 alkyl, and

C

1

-C

6 alkoxy. Hydrogen is an especially preferred value for each of R5, R5', and R"'. [0177] Preferred values of UPL are 0, S, S(=O), S(=0)2, NI, -C(=0)-, -C(=0)-N=N-NH-, -C(=0)-NH-N=N-, -N=N-NH-, -C(=N-N(R)2)-,

-C(=NR

5 )-, -C(=O)O-, -C(=0)S-, -C(=S)-, -0-P(=0) 2 0-, -RO-, -R 5 S-, -S-C=N- and -C(=0)-NR 5 -O-, wherein groups with two chemically nonequivalent ternini can adopt both possible orientations. Values of UPL that are more preferred are 0, S, NH, -C(=O)-, -C(=0)-N=N-NH-, -C(=0)-NH-N=N-, -N=N-NH-, -C(=N-N(R) 2 )-, -C(=NR 5 )-, -C(=O)O-, -RS and -R 5 0-. Especially preferred values of UPL are 0, S, and -C(=O). Preferred polymers and oligomers of Formula II are also those wherein U"L is absent. [0178] In some aspects of the invention, preferred polymers and oligomers of Formula II are those wherein UPL is -0-P(=0) 2 0-. [01791 Preferred values of V are nitro, cyano, amino, hydroxy, C 1

-C

6 alkoxy,

C

1

-C

6 alkylthio, C 1

-C

6 alkylamino, C 1

-C

6 dialkylamino, -NiH(CH 2 )pNH 2 wherein p is 1 to 4, -N(CH 2

CH

2

NH

2

)

2 , diazamino, amidino, guanidino, guanyl, semicarbazone, C 6

-C

10 aryl, heterocycle, and heteroaryl, any of -which is optionally substituted with one or more of amino, halo, cyano, nitro, hydroxy,

-NH(CH

2 )pNH2 wherein p is 1 to 4, -N(CH 2

CH

2 NI2) 2 , amidino, guanidino, guanyl, aminosulfonyl, aminoalkoxy, lower acylamino, or benzyloxycarbonyl. [0180] Suitable heteroaryl groups include indolyl, 3.H-indolyl, IH-isoindolyl, indazolyl, benzoxazolyl, pyridyl, and 2-aminopyridyl. Suitable heterocycle WO 2004/082634 PCT/US2004/008155 -59 groups include piperidinyl, piperazinyl, imidazolidinyl, pyrrolidinyl, pyrazolidinyl, and morpholinyl. [0181] Values of V that are more preferred are amino, C 1

-C

6 alkylamino,

C

1

-C

6 dialkylamino, -NH(CH 2 )pNH2 wherein p is I to 4, -N(CH 2

CH

2 NH2) 2 , diazamino, amidino, guanidino, guanyl, and semicarbazone, preferably any of which is optionally substituted with one or more of amino, halo, cyano, nitro, hydroxy, -N[H(CH 2 )pNH 2 wherein p is 1 to 4, -N(CH 2

CH

2

NH

2 )2, amidino, guanidino, guanyl, aminosulfonyl, aminoalkoxy, lower acylamino, or benzyloxycarbonyl. [01821 Especially preferred values of V are amino, C 1

-C

6 alkylamino,

-NH(CH

2 )pNH 2 wherein p is 1 to 4, -N(CH 2

CH

2 NH2) 2 , diazamino, amidino, and guanidino, preferably any of which is optionally substituted with one or more of amino, halo, cyano, nitro, hydroxy, -NH(CH 2 )pNH 2 wherein p is 1 to 4, -N(CH 2

CH

2 NH2) 2 , amidino, guanyl, guanidino, or aininoalkoxy. Values of V that are most preferred are amino and guanidino. [0183] Preferred values of pPL are 0 to 6; values of pPL of 0 to 4 are especially preferred, with values of pPL of 2 to 4 especially preferred. [0134] Preferred values of q1PL and q2PL are 0 or 1. Values of qlPL and q2PL of 0 or 1 are especially preferred, with a value of 0 being especially preferred for each of qlPL and q2PL. [0185] In preferred polymers and oligomers of Formula II, the -(C.H2)pPL alkylene chain in PL is optionally substituted with one or more amino or hydroxy groups. [0186] Preferred polymers of Formula 11 are those in which n is 1 to about 500. Especially preferred are those polymers of Formula 11 wherein in is 1 to about 100, or wherein in is 1 to about 50. [0187] Oligomers of Formula II that are preferred are those wherein m is I to about 30, or in is I to about 25; more preferred are those wherein in is 1 to about 20, or wherein m is 1 to about 10, or wherein m is 1 to about 5. Especially preferred are those oligomers of Formula II wherein m is 1, 2 or 3.

WO 2004/082634 PCT/US2004/008155 - 60 [01881 Thus, in some aspects, the invention is directed to a method of treating a microbial infection in an animal in need thereof, the method comprising administering to the animal an effective amount of a pharmaceutical composition comprising a polymer or oligomer of Formula II, wherein: x is NR8, y is C=O, and R is hydrogen or alkyl;

A

1 and A 2 are independently optionally substituted o-, mi-, or p-phenylene or pyrimidinylene, wherein A 1 and A 2 are independently optionally substituted with one or more polar (PL) group(s), one or more non polar (NPL) group(s), or a combination of one or more polar (PL) group(s) and one or more non-polar (NPL) group(s); R1 is hydrogen, a polar group (PL), or a non-polar group (NPL), and R 2 is -x

A

1 -x-Rl, wherein A 1 is as defined above and is optionally substituted with one or more polar (PL) group(s), one or more non-polar (NPL) groupss, or a combination of one or more polar (PL) group(s) and one or more non-polar (NPL) group(s); NPL is (NR )qiNPL-UNPL-(CH2)pNPL-(NR")q2NPL -R 4 , wherein:

R

3 , R, and R are independently selected from the group consisting of hydrogen, Ci-C 6 alIyl, and C 1

-C

6 alkoxy;

R

4 ' is selected from the group consisting of hydrogen, C 1 -Cio alkyl, C 3 C 18 branched alkyl, C 2

-C

1 0 alkenyl, C 2

-C

10 alkynyl, C 3

-C

8 cycloalkyl, C 6 -Cio aryl, and heteroaryl, any of which is optionally substituted with one or more C 1

-C

6 alkyl or halo groups; UNPL is absent or selected from the group consisting of 0, S, NlH, -C(=0)-, -C(=0)-N=N-NH-, -C(=O)-NH-N=N-, -N=N-NH-,

-C(=N-N(R

3

)

2 )-, -C(=NR 3 )-, -C(=0)O-, -R 3 S- and -R 3 0-, wherein groups with two chemically nonequivalent termini can adopt both possible orientations; the -(CH2)pNPL- alkylene chain is optionally substituted with one or more amino or hydroxy groups; pNPL is 0 to 6; WO 2004/082634 PCT/US2004/008155 -61 qlNPL and q2NPL are independently 0; PL is -(NRe)qlPL- PL-(CH2)pPL-( )q2PL-V, wherein:

R

5 , R 5 ', and R 5 " are independently selected from the group consisting of hydrogen, CI-C 6 alkyl, and C 1

-C

6 alkoxy; UPL is absent or selected from the group consisting of 0, S, NH, C(=0)-, -C(=0)-N=N-NH-, -C(=0)-NH-N=N-, -N=N-NH-,

-C(=N-N(R

5

)

2 )-, -C(=NR 5 )-, -C(=0)O-, -R 5 O-, and -R 5 S-, wherein groups with two chemically nonequivalent termini can adopt both possible orientations; V is selected from the group consisting of nitro, cyano, amino, hydroxy, C 1 -C6 alkoxy, C 1

-C

6 alkylthio, C 1

-C

6 alkylamino,

C

1

-C

6 dialkylamino, -NIH(CH 2 )pNH 2 wherein p is 1 to 4,

-N(CH

2

CH

2

NH

2

)

2 , diazamino, amidino, guanidino, guanyl, semicarbazone,

C

6 -Cio aryl, heterocycle, and heteroaryl, preferably any of which is optionally substituted with one or more of amino, halo, cyano, nitro, hydroxy, -NH(CH 2 )pNH2 'wherein p is 1 to 4, -N(CH 2

CH

2

NH

2

)

2 , amidino, guanidino, guanyl, aminosulfonyl, aminoalkoxy, lower acylamino, or benzyloxycarbonyl; the -(CH2)pPL- alkylene chain is optionally substituted with one or more amino or hydroxy groups; pPL is 0 to 6; qlPL and q2PL are 0; and m is I to 10. [01891 The invention is also directed to a method of treating a microbial infection in an animal in need thereof, the method comprising administering to the animal an effective amount of a pharmaceutical composition comprising an oligomer of Formula Ila: R-x-A-x-y-A 2 -y-x-A-x-R 2 (Ia) WO 2004/082634 PCT/US2004/008155 - 62 or an acceptable salt or solvate thereof, wherein: x is NR 5 , 0, S, or -N(R 5

)N(R

8 )-; and y is C=0, C=S, or O=S=O; wherein R8 is hydrogen or alkyl;

A

1 and A 2 are independently optionally substituted arylene or optionally substituted heteroarylene, wherein A 1 and A 2 are independently optionally substituted with one or more polar (PL) group(s), one or more non-polar (NPL) group(s), or a combination of one or more polar (PL) group(s) and one or more non-polar (NPL) group(s);

R

1 is a polar group (PL) or a non-polar group (NPL); and R 2 is R 1 ; NPL is a nonpolar group independently selected from the group consisting of

-B(OR

4

)

2 and -(NR")qlNPL-UNPL-(CH2)pNPL-13')q2NPL -R 4 , wherein:

R

3 , R 3 ', and R 3 are independently selected from the group consisting of hydrogen, alkyl, and alkoxy;

R

4 and R are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and heteroaryl, any of which is optionally substituted with one or more alkyl or halo groups; UNPL is absent or selected from the group consisting of 0, S, S(=0), S(=0)2, NR 3 , -C(=rO)-, -C(=0)-N=N-NR-, -C(=0)-NR 3 -N=N-, -N=N-NR-, -C(=N-N(R 3

)

2 )-, -C(=NR 3 )-, -C(=O)O-, -C(=0)S-, -C(=S)-, -O-P(=0) 2 0-, -R 3 0-, -R 3 S-, -S-C=N- and --C(=0)-NR 3 -0- , wherein groups with two chemically nonequivalent termini can adopt both possible orientations; the -(CH2)pNPL- alkylene chain is optionally substituted with one or more amino or hydroxy groups, or is unsaturated; pNPL is 0 to 8; q1NPL and q2NPL are independently 0, 1 or 2; PL is a polar group selected from the group consisting of halo, hydroxyethoxymethyl, methoxyethoxymethyl, polyoxyethylene, and -( )qlPL-UPL-(CH 2)pPL-(NR5')q2PL-V,wherein: WO 2004/082634 PCT/US2004/008155 - 63 R 5 , R 5 ', and R are independently selected from the group consisting of hydrogen, alkyl, and alkoxy; UPL is absent or selected from the group consisting of 0, S, S(=0), S(=0) 2 , NR 5 , -C(=0)-, -C(=0)-N=N-NR 5 -, -C(=0)-NR 5 -N=N-, -N=N-NR-, -C(=N-N(R')2)-, -C(=NR5)-, -C(=0)O-, -C(=0)S-, -C(=S)-,-O-P(=0) 2 0-, -R 5 0-, -RS-, -S-C=N- and -C(=0)-NR 5 -0- , wherein groups with two chemically nonequivalent termini can adopt both possible orientations; V is selected from the group consisting of nitro, cyano, amino, hydroxy, alkoxy, alkylthio, alkylamino, dialkylamino,

-NH(CH

2 )pNH 2 wherein p is I to 4, -N(CH 2

CH

2

NH

2

)

2 , diazamino, amidino, guanidino, guanyl, semicarbazone, aryl, heterocycle and heteroaryl, preferably any of which is optionally substituted with one or more of amino, halo, cyano, nitro, hydroxy, -NH(CH2)pNH 2 wherein p is I to 4,

-N(CH

2

CH

2

NH

2

)

2 , amidino, guanidino, guanyl, aminosulfonyl, aminoalkoxy, aminoalkythio, lower acylamino, or benzyloxycarbonyl; the -(CH2)pPL- alkylene chain is optionally substituted with one or more amino or hydroxy groups, or is unsaturated; pPL is 0 to 8; and qlPL and q2PL are independently 0, 1 or 2; and a pharmaceutically acceptable carrier or diluent. [01901 Preferred oligomers of Formula Ila are those wherein x is NR 8 and y is C=0. For example, oligomers of Formula Ila wherein x is NH and y is C=O are especially preferred. Also preferred are oligomers of Formula Ila wherein x is 0 and y is C=0, or wherein x is -N(R 5

)N(R

8 )- and R! is hydrogen, and y is C=0. [01911 Preferred are those oligomers of Formula Ila wherein A 1 and A 2 are independently optionally substituted o-, m-, or p-phenylene, especially m phenylene. Also preferred are oligomers of Formula Ia wherein one of A 1 WO 2004/082634 PCT/US2004/008155 - 64 and A 2 is o-, m-, or p-phenylene, and the other of A 1 and A 2 is heteroarylene. Preferred heteroarylene groups include, but are not limited to, pyridinylene, pyrimidinylene, and pyrazinylene. [01921 As for the polymers and oligomers of Formula II, preferred oligomers of Formula Ila are those wherein A 1 and A 2 are independently optionally substituted arylene or optionally substituted heteroarylene, and (i) one of A 1 and A 2 is substituted with one or more polar (PL) group(s) and one or more nonpolar (NPL) group(s) and the other of A 1 and A 2 is unsubstituted; or (ii) one of A1 and A 2 is substituted with one or more polar (PL) group(s) and one or more nonpolar (NPL) group(s) and the other of A1 and A 2 is substituted with one or more polar (PL) group(s). Especially preferred are oligomers in which either (i) one of A 1 and A 2 is substituted with one polar (PL) group and one nonpolar (NPL) group, and the other of A 1 and A 2 is unsubstituted, or (ii) one of A 1 and A 2 is substituted with one polar (PL) group and one nonpolar (NPL) group and the other of A 1 and A 2 is substituted with one or two polar (PL) group(s), are especially preferred. [01931 Preferred oligomers of Formula Ila are those in which R' and R 2 are either hydrogen or a polar (PL) group. [0194] Preferred values of R 3 , R", R', R 4 , W', NPL, U pNPL L, qINFL, q2NPL, PL, R', R5', R", V, UPL, pPL, qlPL and q2PL for the oligomers of Formula Ia are also the same as those listed for polymers and oligomers of Formula II above. [01951 In some aspects, the invention is directed to a method of treating a microbial infection in an animal in need thereof, the method comprising administering to the animal an effective amount of a pharmaceutical composition comprising a polymer or oligomer of Formula II': R x-A-x-y-B-y R 2thre or an acceptable salt or solvate thereof, WO 2004/082634 PCT/US2004/008155 - 65 wherein: x is NR 3 , 0, S, -C(R 7 R)NI, -C(R7R)O, -C(R'R)S, or -N(R 3 )(N=N)-; and y is C=0, C=S, O=S=0, -C(=0)C(=0)-, C(R 5

R

6 )C=O or C(R 5

R

6 )C=S; wherein R 3 is hydrogen or alkyl, and R7 and R 8 together are (CH 2 )p-, wherein p is as defined below; or x and y are taken together to be pyromellitic diimide; wherein R5 and R6 together are (CH 2

)

2 NR1 2

CH

2

)

2 , and R1 2 is hydrogen, -C(=N)CH 3 or

C(=NH)-NH

2 ; A and B are independently optionally substituted o-, n-, or p-phenylene or optionally substituted heteroarylene, wherein: A and B are independently optionally substituted with one or more polar (P) group(s), one or more non-polar (NP) group(s), or a combination of one or more polar (P) group(s) and one or more non-polar (NP) groupss; R, is (i) -B-y-R2 and R2 is -x-(CH 2 )p-W, wherein: x is as defined above; W is hydrogen, phenyl optionally substituted with up to three substituents selected from a group consisting of halogen, C 1

-C

4 alkyl, CI-C 4 alkoxy, acyl, and carboxyl, N-maleimide, or V as defined below; p is as defined below; and the -(CH 2 )p- chain is optionally substituted with one or more amino or hydroxyl groups, or the alkylene chain is unsaturated; or (ii) R 1 and R2 together are a single bond; or (iii) -y-(CH 2 )p-W or -U-(CH 2 )p-W, wherein: W is defined above; U is defined below; the -(CH 2 )p- alkylene chain is optionally substituted with one or more amino or hydroxyl groups, or the alkylene chain is unsaturated; P is as defined below; and R2 is -x-A-x-R'; or (iv) -y-B-y-R2 and R2 is -x-(CH 2 )p-W or -U-(CH 2 )p-W, wherein: W is defined above, U is defined below; and the -(CH- 2 )p- alkylene chain is optionally substituted with one or more amino or WO 2004/082634 PCT/US2004/008155 - 66 hydroxyl groups, or the alkylene chain is unsaturated; and p is as defined below; or (v) is H and R 2 is -x-A-x-R; NP is a nonpolar group independently selected from -B(OR 4

)

2 (wherein B in this instance represents a boron atom), R4, or -(NR3 )qU-(CH 2 )p-(N )q 2

-R

4 , wherein

R

3 is selected from the group consisting of hydrogen, alkyl, and alkoxy; R4 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and heteroaryl, any of which is optionally substituted with one or more alkyl, alkoxy, or halo groups; U is absent or selected from the group consisting of 0, S, S(=0), S(=0) 2 , NR 3 , -(C=0)-, -(C=0)-N=N-NR 3 -, -(C=O)-NR 3 -N=N-,

-N=N-NR

3 -, -C(=N-N(R 3

)

2 )-, -C(=NR 3 )-, -C(=0)O-, -C(=0)S-, -C(=S)-,-O-P(=0) 2 0- (wherein P in this instance represents a phosphorus atom), -R 3 -0-, -R 3 -S-, -S-C=N- and

-(C=O)-NR

3 -0-, wherein groups with tvo chemically nonequivalent termini can adopt both possible orientations; the -(CH 2 )p- alkylene chain is optionally substituted with one or more amino or hydroxyl groups, or the alkylene chain is unsaturated; p is independently 0 to 8; qI and q2 are independently 0 to 2; P is a polar group selected from the group consisting of halo, hydroxyethoxymethyl, methoxyethoxymethyl, polyoxyethylene, and -(NR 3 )qi U-(CH2)p-(NR 3 )q2-V, wherein; U and R? are as defined above; V is selected from the group consisting of nitro, cyano; thio, amino, hydroxyl, alkoxy, alkylthio, alkylamino, dialkylamino, NIH(CH 2 )pNH2,-N(CH 2

CH

2

NH

2

)

2 , diazamino, amidino, guanidino, guanyl, semicarbazone, alkoxycarbonyl, aryl, WO 2004/082634 PCT/US2004/008155 - 67 heterocycle and heteroaryl, any which is optionally substituted with one or more of amino, halo, cyano, nitro, hydroxyl, NH(CH 2 )pN1iI 2 , -N(CH 2

CH

2

NH

2

)

2 , alkylamino, dialkylamino, amidino, guanidino, guanyl, aminosulfonyl, aminoalkoxy, aminoalkylthio, lower acylamino, or benzyloxycarbonyl; the -(CH 2 )p- alkylene chain is optionally substituted with one or more amino or hydroxyl groups, or the alkylene chain is unsaturated; p, qi and q2 are as defined above; and m is 1 to about about 500; and a pharmaceutically acceptable carrier or diluent. [01961 In some aspects, the invention is also directed to a method of treating a microbial infection in an animal in need thereof, the method comprising administering to the animal an effective amount of a pharmaceutical composition comprising an oligomer of Formula Il', wherein: x is NR3 y is C=O; and R 3 is hydrogen or alkyl; A and B are independently optionally substituted o-, in-, or p-phenylene or optionally substituted pyrimidinyl, wherein: A and B are independently optionally substituted with one or more polar (P) group(s), one or more non-polar (NP) group(s), or a combination of one or more polar (P) group(s) and one or more non-polar (NP) group(s); R is (i) -y-(CH 2 )p-W or -U-(CH 2 )p -W, wherein: W is hydrogen, phenyl optionally substituted with up to three substituents selected from a group consisting of halogen, C 1

-C

4 alkyl, C 1

-C

4 alkoxy, acyl, and carboxyl, N-maleimide, or V as defined below; U is defined below; the -(CH 2 )p- alkylene chain is optionally substituted with one or more amino or hydroxyl groups; and R2 is -x-A-x-Rl or (ii) is H and R 2 is -x-A-x-Rl; WO 2004/082634 PCT/US2004/008155 -68 NP is -(NR 3 )qi-U-(CH2)p-(NR 3 )q2 -R 4 , wherein

R

4 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, and aryl, any of which is optionally substituted with one or more alkyl, alkoxy, or halo groups; U is absent, 0, S, or -(C=0)-; the -(CH 2 )p- alkylene chain is optionally substituted with one or more amino or hydroxyl groups; p is independently 0 to 6; q and q2 are each 0; P is(NR)qiU-(CH2)p-(NR 3 )q 2 -V, wherein; U and R3 are as defined above; V is selected from the group consisting of nitro, cyano, thio, amino, hydroxyl, alkoxy, alkylthio, alkylamino, dialkylamino,

-NH(CH

2 )pNIH 2 , -N(CH 2 CH2NH 2

)

2 , diazamino, amidino, guanidino, guanyl, semicarbazone, alkoxycarbonyl, aryl, heterocycle and heteroaryl, any of which is optionally substituted with one or more of amino, halo, cyano, nitro, hydroxyl, -TH(CH2)pNH2, -N(CH2CH 2

NH

2

)

2 , alkylamino, dialkylamino, amidino, guanidino, guanyl, aminosulfonyl, aminoalkoxy, aminoalkylthio, lower acylamino, or benzyloxycarbonyl; the -(CH 2 )p- alkylene chain is optionally substituted with one or more amino or hydroxyl groups; p is independently 0 to 6; qi and q2 are each 0; and m is I to 5; and a pharmaceutically acceptable carrier or diluent. [0197] In some aspects, in the polymer or oligomer of Formula II', X is NH, and y is C=O; A and B are n- or p-phenylene wherein (i) A is substituted at the 2-position with a polar (P) group and B is substituted at the 5-position with a WO 2004/082634 PCT/US2004/008155 - 69 nonpolar (NP) group, or (ii) A is substituted at the 2-position with a polar (P) group and at the 5-position with a nonpolar (NP) group and B is either substituted at the 2-position with a nonpolar (NP) group and at the 5-position with a polar (P) group or B is unsubstituted; NP is a nonpolar group independently selected from R 4 or -U-(CH2)p-R wherein R 4 is selected from a group consisting of methyl, ethyl, n propyl, iso-propyl, iso-butyl, sec-butyl, tert-butyl, iso-pentyl, and sec pentyl, and U and p are as defined below; P is a polar group U-(CH 2 )p-V wherein U is absent or selected fi-om a group consisting of 0 and S and V is selected from a group consisting of amino, lower alkyl amino, lower dialkylamino, imidazole, guanidine,

NH(CH

2 )pNH 2 , N(CH 2

CH

2

NH

2

)

2 ; piperidine, and 4-alkylpiperazine; p is independently 0 to 8; and m is I to about 500. [0198] In yet other aspects, in the polymer or oligomer of Formula II', A is an optionally substituted 1,3-diaminobenzene and B is an optionally substituted iso-phthalic acid. [01991 In some aspects, the invention is directed to a method of treating a microbial infection in an animal in need thereof, the method comprising administering to the animal an effective amount of a pharmaceutical composition comprising a polymer or oligomer of Formula XI: L (CH 2 )pV R U2 (XI) R4~ wherein

R

4 is selected from a group consisting of methyl, ethyl, n-propyl, iso propyl, n-butyl, iso-butyl, see-butyl, tert-butyl n-pentyl, iso pentyl, and sec-pentyl; WO 2004/082634 PCT/US2004/008155 - 70 U is 0 or S; V is amino, lower alkyl amino, lower dialkylamino, or guanidine; p is independently 0-8; and mn is 1 to about 30, or 1 to about 50; or an acceptable salt or solvate thereof; and a pharnaceutically acceptable carrier or diluent. [02001 In yet other aspects, the invention is directed to a method of treating a microbial infection in an animal in need thereof, the method comprising administering to the animal an effective amount of a pharmaceutical composition comprising a polymer or oligomer of Formula XVI: 0

R

2 0 R4 H H

L

0 RB/ I 0I R R m wherein: either R1 2 and R 14 are independently polar (P) groups and R 13 and R'1 are independently nonpolar (NP) groups substituted at one of the remaining unsubstituted carbon atoms, or R and R4 are independently nonpolar (NP)groups and R1 3 and R 15 are independently polar (P) groups; NP is a nonpolar group independently selected from R 4 or -U-R 4 where R4 is selected from a group consisting of methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, n-pentyl, iso-pentyl, and sec pentyl, and U is as defined below; P is a polar group U-(CH 2 )p-V wherein U is absent or selected from a group consisting of 0 and S, and V is selected from a group consisting of amino, lower alkyl amino, lower dialkylamino, imidazole, guanidine,

-NH(CH

2 )pNH 2 -, -N(CH 2

CH

2

NIH

2

)

2 -, piperidine, and 4 alkylpiperazine; U is 0 orS; WO 2004/082634 PCT/US2004/008155 -71 V is amino, lower alkyl amino, lower dialkylamino, and guanidine; p is independently 0 to 8; and m is 1 to about 30, or 1 to about 50; or an acceptable salt or solvate thereof; and a pharmaceutically acceptable carrier or diluent. [02011 In some aspects, the invention is directed to a method of treating a microbial infection in an animal in need thereof; the method comprising administering to the animal an effective amount of a pharmaceutical composition comprising a polymer or oligomer of Formula XX: R5 R 6 RS R 6 H H H R2, N N, (XX) 0

OR

7 RE

R

7 Rat m wherein j is independently 0 or 1, R and R 6 together are (CH 2

)

2

NH(CH

2

)

2 and R7 and R 8 together are (CH2)p wherein p is 4 to 6; m is I to about 30, or 1 to about 50; or an acceptable salt or solvate thereof: and a pharmaceutically acceptable carrier or diluent. [02021 In some aspects, the invention is directed to a method of treating a microbial infection in an animal in need thereof, the method comprising administering to the animal an effective amount of a pharmaceutical composition comprising a polymer or oligomer of Formula IV: Rl-[-x-Ar-x-z-y-A2-y-zI m-R2 (IV) or an acceptable salt or solvate thereof, wherein: x is NR', -NR 8

NR

8 -, C=0, or 0; y is NR, -R 8 Nk-, C=0, S, or 0; and R 8 is hydrogen or alkyl; z is C=0, C=S, O=S=0, -NReNR-, or -C(=0)C(=0)- WO 2004/082634 PCT/US2004/008155 -72

A

1 and A 2 are independently optionally substituted arylene or optionally substituted heteroarylene, wherein A 1 and A 2 are independently optionally substituted with one or more polar (PL) group(s), one or more non-polar (NPL) group(s), or a combination of one or more polar (PL) group(s) and one or more non-polar (NPL) group(s); R' is (i) hydrogen, a polar group (PL), or a non-polar group (NPL), and R 2 is -x-Ai-x-Rl, wherein A 1 is as defined above and is optionally substituted with one or more polar (PL) group(s), one or more non-polar (NPL) group(s), or a combination of one or more polar (PL) group(s) and one or more non-polar (NPL) group(s); or (ii) hydrogen, a polar group (PL), or a non-polar group (NPL), and R 2 is -x-A 1 -x-z-y-A 2 -y-RI, wherein A 1 and A 2 are as defined above, and each of which is optionally substituted with one or more polar (PL) group(s), one or more non-polar (NPL) group(s), or a combination of one or more polar (PL) group(s) and one or more non-polar (NPL) group(s); or (iii) hydrogen, a polar group (PL), or a non-polar group (NPL), and R 2 is -x-A -x-Rl, wherein A' is aryl or heteroaryl and is optionally substituted with one or more polar (PL) group(s), one or more non-polar (NPL) group(s), or a combination of one or more polar (PL) group(s) and one or more non-polar (NPL) group(s); or (iv) hydrogen, a polar group (PL), or a non-polar group (NPL), and R2 is -x-A1-x-z-y-A-y-R', wherein A 1 is as defined above, A' is aryl or heteroaryl, and each of A 1 and A' is optionally substituted with one or more polar (PL) group(s), one or more non-polar (NPL) group(s), or a combination of one or more WO 2004/082634 PCT/US2004/008155 -73 polar (PL) group(s) and one or more non-polar (NPL) group(s); or (v) -z-y-A' and R 2 is hydrogen, a polar group (PL), or a non-polar group (NPL), wherein A' is aryl or heteroaryl and is optionally substituted with one or more polar (PL) group(s), one or more non-polar (NPL) group(s), or a combination of one or more polar (PL) group(s) and one or more non-polar (NPL) group(s); or (vi) -z-y-A', and R 2 is -x-A", wherein A' and A" are independently aryl or heteroaryl, and each of A and A" is optionally substituted with one or more polar (PL) group(s), one or more non-polar (NPL) group(s), or a combination of one or more polar (PL) groups) and one or more non-polar (NPL) group(s); or (vii) R1 and R 2 are independently a polar group (PL) or a non-polar group (NPL); or (viii) R' and R 2 together form a single bond; NPL is a nonpolar group independently selected from the group consisting of

-B(OR

4

)

2 and -(NR)qlNPL-NPL(CH 2 )pNPI 3 ")q2NPL -R, wherein:

R

3 , R 3 , and R 3 " are independently selected from the group consisting of hydrogen, alkyl, and alkoxy;

R

4 and R 4 ' are independently selected from the group consisting of hydrogen, alkyl, alkenyl, allkynyl, cycloalkyl, aryl, and heteroaryl, any of which is optionally substituted with one or more alkyl or halo groups; UNPL is absent or selected from the group consisting of 0, S, S(=0), S(=0) 2 , NR 3 , -C(=O)-, -C(=0)-N=N-NR-, -C(=0)-NR 3 -N=N-,

-N=N-NR

3 -, -C(=N-N(R 3

)

2 )-, -C(=NR 3 )-, -C(=0)O-, -C(=0)S-, -C(=S)-, -0-P(=0) 2 0-, -R 3 0-, -R 3 S-, -S-C=N- and -C(=0)-NR3-O- , wherein groups with two chemically nonequivalent termini can adopt both possible orientations; WO 2004/082634 PCT/US2004/008155 - 74 the -(CH2)pNPL- alkylene chain is optionally substituted with one or more amino or hydroxy groups, or is unsaturated; pNPL is 0 to 8; qlNPL and q2NPL are independently 0, 1 or 2; PL is a polar group selected from the group consisting of halo, hydroxyethoxymethyl, methoxyethoxymethyl, polyoxyethylene, and -- (NR")g1PL-UPL-(CH2)pPL-(NR')q2PL-Y, wherein: Ri, R', and R" are independently selected from the group consisting of hydrogen, alkyl, and alkoxy; IL is absent or selected from the group consisting of 0, S, S(=0), S(=0) 2 , NRF, -C(=0)-, -C(=0)-N=N-NR-, -C(=0)-NR-N=N-,

-N=N-NR

5 -, -C(=N-N(R) 2 )-, -C(=NR 5 )-, -C(=0)O-, -C(=0)S-, -C(=S)-, -0-P(=0) 2 0-, -R 5 0-, -R 5 S-, -S-C=N- and -C(=0)-NR 0- , wherein groups with two chemically nonequivalent termini can adopt both possible orientations; V is selected from the group consisting of nitro, cyano, amino, hydroxy, alkoxy, alkylthio, alkylamino, dialkylamino,

-NH(CH

2 )pNH2 wherein p is 1 to 4, -N(CH 2

CH

2

NH

2

)

2 , diazamino, amidino, guanidino, guanyl, semicarbazone, aryl, heterocycle and heteroaryl, any of which is optionally substituted with one or more of amino, halo, cyano, nitro, hydroxy, -NiH(CH 2 )pNH 2 wherein p is 1 to 4,

-N(CH

2 CH2NH 2

)

2 , amidino, guanidino, guanyl, aminosulfonyl, aminoalkoxy, aminoalkythio, lower acylamino, or benzyloxycarbonyl; the -(CH2)pPL- alkylene chain is optionally substituted with one or more amino or hydroxy groups, or is unsaturated; pPL is 0 to 8; qIPL and q2PL are independently 0, 1 or 2; and m is 1 to about 500; and a pharmaceutically acceptable carrier or diluent.

WO 2004/082634 PCT/US2004/008155 - 75 [0203] Polymers and oligomers of Formula IV that are preferred for use in the disclosed method are those wherein x and y are independently NR8, C=0, or 0; z is C=O or -NR 8

NR

8 ; and R8 is hydrogen or Cu-C 6 alkyl. Especially preferred are those polymers and oligomers wherein x and y are each NR 8 , z is C=0, and R! is hydrogen. Also preferred are oligomers of Formula IV wherein x is NR 8 or 0, y is 0, and z is C=0, or wherein x and y are each C=0, and z is -N(R 8 )N(R8)-, especially wherein R 8 is hydrogen. [0204] Preferred are those polymers and oligomers of Formula IV wherein A 1 and A 2 are independently optionally substituted o-, m-, or p-phenylene. Those oligomers wherein A 1 and A 2 are optionally substituted im-phenylene are especially preferred. Also preferred are polymers and oligomers of Formula IV wherein one of A 1 and A 2 is o-, m-, or p-phenylene, and the other of A 1 and A 2 is heteroarylene. Preferred heteroaiylene groups include, but are not limited to, pyridinylene, pyrimidinylene, and pyrazinylene. [02051 Also preferred are polymers and oligomers of Formula IV wherein A, .and A 2 are independently optionally substituted arylene or optionally substituted heteroarylene, and (i) each of A 1 and A 2 is substituted with one or more polar (PL) group(s) and one or more nonpolar (TPL) group(s); or (ii) one of A and A 2 is substituted with one or more polar (PL) group(s) and the other of A 1 and A 2 is substituted with one or more nonpolar (NPL) group(s). Polymers and oligomers in which (i) each of A 1 and A 2 is substituted with one polar (PL) group and one nonpolar (NPL) group, or (ii) one of A 1 and A 2 is substituted with one or two polar (PL) group(s) and the other of A 1 and A 2 is substituted with one or two nonpolar (NPL) group(s), are especially preferred. In some aspects of the invention, preferred polymers and oligomers of Formula IV are those wherein (i) R is hydrogen, a polar group (PL), or a non polar group (NPL), and R 2 is -x-Ar-x-R 1 , wherein A 1 is as defined above and is optionally substituted with one or more polar (PL) group(s), one or more nonpolar (NPL) group(s), or a combination of one or more polar (PL) group(s) and one or more non-polar (NPL) group(s); or (iii) R' is hydrogen, a polar WO 2004/082634 PCT/US2004/008155 -76 group (PL), or a non-polar group (NPL), and R 2 is -x-A1-x-z-y-A 2 -y-R', wherein A 1 and A 2 are as defined above, and each of which is optionally substituted with one or more polar (PL) group(s), one or more nonpolar (NPL) group(s), or a combination of one or more polar (PL) group(s) and one or more non-polar (NPL) group(s). 10206] More preferred are those oligomers of Formula IV wherein R 1 is hydrogen, a polar group (PL), or a non-polar group (NPL), and R 2 is -x-A 1 -x

R

1 , wherein A 1 is as defined above and is substituted with one polar (PL) group and one non-polar (NPL) group; or those oligomers wherein R 1 is hydrogen, a polar group (PL), or a non-polar group (NPL), and R2 is -x-A 1 -x z-y-A 2 -y-R , wherein A 1 and A 2 are as defined above, and each of which is substituted with one polar (PL) group and one non-polar (NPL) group. [0207] In some aspects, preferred polymers and oligomers of Formula IV are those wherein NPL is -(NR 3 )qINPL-UNPL-(CH 2 )pNPLNR3")q 2

NPL-R

4 ', and R , R 3 , R 3 ', NPLpNPL qINPL and q2NPL are as defined above. [0208] Preferred values for each of R 3 , R', and R are hydrogen, C 1

-C

6 alkyl, and C1-C 6 alkoxy. Hydrogen is an especially preferred value for R 3 , R 3 , and R [0209] Preferred values of R 4 ' are hydrogen, C 1

-C

10 alkyl, C 3 -Ci 8 branched alkyl, C 2

-C

10 alkenyl, C 2

-C

10 alkynyl, C 3 -CS cycloalkyl, C 6

-C

10 aryl, and heteroaryl, any of which is optionally substituted with one or more C 1

-C

6 alkyl or halo groups. Values of R 4 that are more preferred are C 1

-C

1 0 alkyl, C 3

-C

1 8 branched alkyl, C 2

-C

10 alkenyl, C 2

-C

10 alkynyl, and C 6

-C

1 0 aryl, especially phenyl. Especially preferred values of R 4 ' are C 1

-C

10 alkyl and C 3

-C

1 8 branched alkyl. Suitable C 1

-C

10 alkyl and C 3

-C

1 8 branched alkyl groups are methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, and n-pentyl. [0210] Preferred values of UNPL are 0, S, NH, -C(=0)-, -C(=0)-N=N-NH-, -C(=O)-NH-N=N-, -N=N-NH-, -C(=N-N(R 3

)

2 )-, -C(=NR 3 )-, -C(=0)O-, -R 3

S

and -R 3 0-. [02111 Especially preferred polymers and oligomers of Formula IV are those wherein UNPL is absent.

WO 2004/082634 PCT/US2004/008155 -77 [0212] Preferred values of pNPL are 0 to 6; values of pNPL of 0 to 4 are especially preferred, with values of pNPL of 0, 1 or 2 most preferred. [0213] Preferred values of qlNPL and q2NPL are 0 or 1. Values of qlNPL and q2N7PL of 0 or 1 are especially preferred, with a value of 0 being the most preferred for each of qlNPL and q2NPL. [0214] In preferred polymers and oligomers of Formula IV, the -(CH2)pNPL alkylene chain in NPL is unsubstituted or substituted with one or more amino or hydroxy groups. More preferred are those oligomers of Formula IV wherein the -(CH2)pNpL- alkylene chain in NPL is substituted with one or more amino groups. [0215] An especially preferred value of NPL for polymers and oligomers of Formula IV is C 1

-C

6 alkyl. Examples of preferred values for NPL are n propyl, isopropyl, n-butyl, and tert-butyl. [0216] In some aspects of the invention, preferred polymers and oligomers of Formula IV are those wherein PL is -(NR)qlPL-UtL(CH2)pPL-(NR)q2PL -V, and R, R', R", V, UPL, pPL, qlPL and q2PL are as defined above. [0217] Preferred values for RI, RI, and R are hydrogen, C 1

-C

6 alkyl, and

C

1

-C

6 alkoxy. Hydrogen is an especially preferred value for each of :R, R", and R'. [0218] Preferred values of UPL are 0, S, NH, -C(=0)-, -C(=0)-N=N-NH-, -C(=0)-NH-N=N-, -N=N-NH-, -C(=N-N(R5) 2 )-, -C(=NR 5 )-, -C(=0)O-, -R 5

S

and -RO-. Especially preferred values of UPL are 0, S, and -CQ0). [02191 In some aspects of the invention, preferred polymers and oligomers of Formula IV are those wherein UPL is -O-P(=0) 2 0-. [0220] Preferred values of V are nitro, cyano, amino, 1, C 1

-C

6 alkoxy, C 1

-C

6 alkylthio, C 1

-C

6 alkylamino, C 1

-C

6 dialkylamino, -NH(CH 2 )pNH 2 wherein p is 1 to 4, -N(CH2CH 2

NH

2

)

2 , diazamino, amidino, guanidino, guanyl, semicarbazone, C 6 -Cio aryl, heterocycle, and heteroaryl, preferably any of which is optionally substituted with one or more of amino, halo, cyano, nitro, hydroxy, -NH(CH 2 )pNH 2 wherein p is 1 to 4, -N(CH 2

CH

2 NH2) 2 , amidino, WO 2004/082634 PCT/US2004/008155 -78 guanidino, guanyl, aminosulfonyl, aminoalkoxy, lower acylamino, or benzyloxycarbonyl. [0221] Suitable heteroaryl groups include indolyl, 3H-indolyl, IH-isoindolyl, indazolyl, benzoxazolyl, pyridyl, and 2-aminopyridyl. Suitable heterocycle groups include piperidinyl, piperazinyl, imidazolidinyl, pyrrolidinyl, pyrazolidinyl, and morpholinyl. [0222] Values of V that are more preferred are amino, C-C 6 alkylamino,

CI-C

6 dialkylamino, -NH(CH 2 )pNH 2 wherein p is I to 4, -N(CH 2

CH

2

NH

2

)

2 , diazamino, amidino, guanidino, guanyl, and semicarbazone, preferably any of which is optionally substituted with one or more of amino, halo, cyano, nitro, hydroxy, -NH(CH 2 )pNH 2 wherein p is 1 to 4, -N(CH 2

CH

2 NI-1 2

)

2 , amidino, guanidino, guanyl, aminosulfonyl, aminoalkoxy, lower acylamino, or benzyloxycarbonyl. [0223] Especially preferred values of V are amino, CI-C 6 alkylamino,

-NH(CH

2 )pNH 2 wherein p is 1 to 4, -N(CH2CH 2

NH

2

)

2 , diazamino, amidino, and guanidino, preferably any of which is optionally substituted with one or more of amino, halo, cyano, nitro, hydroxy, -NH(CH 2 )pNH 2 wherein p is I to 4, -N(CH2CH2NTH 2

)

2 , amidino, guanyl, guanidino, or aminoalkoxy. Values of V that are most preferred are amino and guanidino. [0224] Preferred values of pPL are 0 to 6; values of pPL of 0 to 4 are especially preferred, with values of pPL of 2 to 4 especially preferred. 102251 Preferred values of qPL and q2PL are 0 or 1. Values of qlPL and q2PL of 0 or 1 are especially preferred, with a value of 0 being especially preferred for each of q1PL and q2PL. [0226] In preferred polymers and oligomers of Fonmula IV, the -(CH2)pPL alkylene chain in PL is optionally substituted with one or more amino or hydroxy groups. [02271 Preferred polymers of Formula IV are those in which m is I to about 500. Especially preferred are those polymers of Formula IV wherein m is 1 to about 100, or wherein m is 1 to about 50.

WO 2004/082634 PCT/US2004/008155 - 79 [0228] Oligomers of Formula IV that are preferred are those wherein m is 1 to about 30, or m is 1 to about 25; more preferred are those wherein m is I to about 20, or wherein m is I to about 10, or wherein m is I to about 5. Especially preferred are those oligomers of Formula IV wherein m is 1, 2 or 3. The invention is also directed to a method of treating a microbial infection in an animal in need thereof, the method comprising administering to the animal an effective amount of a pharmaceutical composition comprising an oligomer of Formula IVa, Formula IVb, or Formula IVc:

R

1 -x-A-x-z-y-A 2 -y-R 2 (Iva) R1-x-A-x-z-y-A 2 -y-z-x-A-x-R2 (IVb)

R

1 -x-Arx-z-y-Ary-z-x-A-x-z-y-Ary-R 2 (lye) or an acceptable salt or solvate thereof, wherein: x is NtR, -NR.hR 8 -, C=0, or 0; y is NR 8 , -NR8NR'-, C=0, S, or 0; and R8 is hydrogen or alkyl; z is C=O, C=S, O=S=0, -NR 8 NR-, or -C(=0)C(=0)

A

1 and A 2 are independently optionally substituted arylene or optionally substituted heteroarylene, wherein A 1 and A 2 are independently optionally substituted with one or more polar (PL) group(s), one or more non-polar (NPL) group(s), or a combination of one or more polar (PL) group(s) and one or more non-polar (NPL) group(s); R' is hydrogen, a polar group (PL), or a non-polar group (NPL), and R 2 is R'; NPL is a nonpolar group independently selected from the group consisting of

-B(OR

4

)

2 and -(NR")qlNPL-UNPL-(CH2)pNPL~$N3")q2NPL -R 4 ', wherein:

R

3 , R 3 , and R3 are independently selected from the group consisting of hydrogen, alkyl, and alkoxy;

R

4 and R 4 ' are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and WO 2004/082634 PCT/US2004/008155 - 80 heteroaryl, any of which is optionally substituted with one or more alkyl or halo groups;

U

1 NPL is absent or selected from the group consisting of 0, S, S(=0), S(=0) 2 , NR 3 , -C(=0)-, -C(=0)-N=N-NR-, -C(=0)-NR3-N=N-, -N=N-NRW-, -C(=N-N(,R-)2)-, -C(=NRe)-, -C(=O)O-, -C(=0)S-, -C(=S)-, -O-P(=0) 2 0-, -R 3 O-, -R 3 S-, -S-C=N- and -C(=0)-NR 3 -0- , wherein groups with two chemically nonequivalent termini can adopt both possible orientations; the -(CIH2)pNPL- alkylene chain is optionally substituted with one or more amino or hydroxy groups, or is unsaturated; pNPL is 0 to 8; qlNPL and q2NPL are independently 0, 1 or 2; PL is a polar group selected from the group consisting of halo, hydroxyethoxymethyl, methoxyethoxymethyl, polyoxyethylene, and -(NR')q1-PLU-(CH2)p-(NR')q2nP-V, wherein:

R

5 , R ', and R 5 " are independently selected from the group consisting of hydrogen, alkyl, and alkoxy; UP is absent or selected from the group consisting of 0, S, S(=0), S(=0) 2 , NRS, -C(=0)-, -C(=0)-N=N-NR&-, -C(=0)-NR-N=N-, -N=N-NR'-, -C(=N-N(R5)2)-, -C(=NRW)-, -C(=0)O-, -C(=0)S-, -C(=S)-, -0-P(=0) 2 0-, -RO-, -RS-, -S-C=N- and -C(=0)-NR 5 -0- , wherein groups with two chemically nonequivalent termini can adopt both possible orientations; V is selected from the group consisting of nitro, cyano, amino, hydroxy, alkoxy, alkylthio, alkylamino, dialkylamino,

-NH(CH

2 )pNH 2 wherein p is I to 4, -N(CH 2

CH

2

NH

2

)

2 , diazamino, amidino, guanidino, guanyl, semicarbazone, aryl, heterocycle and heteroaryl, preferably any of which is optionally substituted with one or more of amino, halo, cyano, nitro, hydroxy, -NH(CH 2 )pNH 2 wherein p is I to 4, WO 2004/082634 PCT/US2004/008155 - 81 -N(CH 2

CH

2

NH

2

)

2 , amidino, guanidino, guanyl, aminosulfonyl, aminoalkoxy, aminoalkythio, lower acylamino, or benzyloxycarbonyl; the -(CH2)pPL- alkylene chain is optionally substituted with one or more amino or hydroxy groups, or is unsaturated; pPL is 0 to 8; q1.PL and q2PL are independently 0, 1 or 2; and a pharmaceutically acceptable carrier or diluent. [02291 Preferred values of A 1 , A 2 , R1, R2, R3, R, R', R , R4', NPL, UN pNPL, qNPL, q2NPL, PL, RI, R , R", V, U , pPL, qlPL and q2PL for the oligomers of Formula IVa, Fonnula IMb, and Formula IVe are also the same as those listed for polymers and oligomers of Formula 1V above. [02301 In some aspects, the invention is also directed to a method of treating a microbial infection in an animal in need thereof, the method comprising administering to the animal an effective amount of a pharmaceutical composition comprising a polymer or oligomer of Formula TV' or an acceptable salt or solvate thereof, wherein: x is NR 3 , -NR 3

NR

3 -, or C=O; y is NR 3 , -NR3NR 3 -, C=O; S, or 0; and R 3 is hydrogen or alkyl; z is C=0, C=S, O=S=0, -NR 3

NR

3 -, or-C(=O)C(=0)-; A and B are independently optionally substituted o-, m-, or p-phenylene or optionally substituted heteroarylene, wherein: A and B are independently optionally substituted with one or more polar (P) group(s), one or more non-polar (NP) group(s), or a combination of one or more polar (P) group(s) and one or more non-polar (NP) group(s); WO 2004/082634 PCT/US2004/008155 - 82 R' is (i) -B-y-R 2 and R2 is -x-(CH 2 )p-W, wherein: x is as defined above; W is hydrogen, pyridine, phenyl, said pyridine or phenyl optionally substituted with 1 or 2 substituents independently selected from the group consisting of halo, nitro, cyano, C 1

-C

6 alkoxy, C 1

-C

6 alkoxycarbonyl, and benzyoloxycarbonyl, carboxyl, N-maleimide, or V as defined below; the -(CH 2 )p alkylene chain is optionally substituted with one or more amino or hydroxyl groups, or the alkylene chain is unsaturated; and p is as defined below; or (ii) R' is H and R 2 is -x-(CH 2 )p-W; wherein: x is as defined above; W is as defined above; the -(CH 2 )p- alkylene chain is optionally substituted with one or more amino or hydroxyl groups, or the alkylene chain is un-saturated; and p is as defined below; or (iii) R' and R 2 together are a single bond; or (iv) -(CH 2 )p-W or -(CH 2 )p-U, wherein W is as defined above, U is as defined below, and the -(CH 2 )p- alkylene chain is optionally substituted with one or more amino or hydroxyl groups, or the alkylene chain is unsaturated, and p is as defined below; and R 2 is x-A-x-R; or (v) -(CH 2 )p-W or -(CH2),-U, wherein W is as defined above, U is as defined below, and the -(CH 2 )p- alkylene chain is optionally substituted with one or more amino or hydroxyl groups, or the alkylene chain is unsaturated, and p is as defined below; and R2 is -x-A-x-z-y-B-y-RI; or (vi) -z-y-B-y-R 2 and R2 is -(CH 2 )p-W or -(CH 2 )-U, wherein W is as defined above, U is as defined below, and the -(CH 2 )p- alkylene chain is optionally substituted with one or more amino or hydroxyl groups, or the alkylene chain is unsaturated, and p is as defined below; WO 2004/082634 PCT/US2004/008155 - 83 NP is a nonpolar group independently selected from -B(OR 4

)

2 (wherein B in this instance represents a boron atom), R4, or -(NR 3

)IU-(CH

2 )p-N 3 )q 2

-R

4 , wherein R3 is selected from the group consisting of hydrogen, alkyl, and alkoxy; R4 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and heteroaryl, any of which is optionally substituted with one or more alkyl, alkoxy, or halo groups; U is absent or selected from the group consisting of 0, S, S(=0), S(=0) 2 , NR, -(C=0)-, -(C=0)-N=N-NR 3 -, -(C=0)-NR 3 -N=N-,

-N=N-NR

3 -, -C(=N-N(R 3

)

2 )-, -C(=NR 3 )-,-C(=O)O-, -C(=0)S-, -C(=S)-, -0-P(=0) 2 0- (wherein P in this instance represents a phosphorus atom), -R3-0-, -R 3 -S-, -S-C=N- and -(C=0)-NR 3 -0- , herein groups with two chemically nonequivalent termini can adopt both possible orientations; the -(CH 2 )p- alkylene chain is optionally substituted with one or more amino or hydroxyl groups, or the alkylene chain is unsaturated; p is independently 0 to 8; q1 and q2 are independently 0 to 2; P is a polar group selected from. the group consisting of halo, hydroxyethoxymethyl, methoxyethoxymethyl, polyoxyethylene, and

-(NR

3 )q U-(CH 2 )p-(NR 3 )2-V, wherein; U and R 3 are as defined above; V is selected from the group consisting of nitro, cyano, thio, amino, hydroxyl, alkoxy, alkylthio, alkylamino, dialkylamino,

-NH(CH

2 )pNH 2 , -N(CH 2

CH

2

NH

2

)

2 , diazamino, amidino, guanidino, guanyl, semicarbazone, alkoxycarbonyl, aryl, heterocycle and heteroaryl, any of which is optionally substituted with one or more of amino, halo, cyano, nitro, hydroxyl, -NH(CH 2

)NH

2 , -N(CH 2

CH

2

NH

2

)

2 alkylamino, WO 2004/082634 PCT/US2004/008155 -84 dialkylamino, amidino, guanidino, guanyl, aminosulfonyl, aminoalkoxy,. aminoalkylthio, lower acylamino, or benzyloxycarbonyl; the -(CH 2 )p- alkylene chain is optionally substituted with one or more amino or hydroxyl groups, or the alkylene chain is unsaturated; p, ql and q2 are as defined above; and m is 1 to about about 500; and a pharmaceutically acceptable carrier or diluent. [02311 In some aspects, the invention is also directed to a method of treating a microbial infection in an animal in need thereof, the method comprising administering to the animal an effective amount of a pharmaceutical composition comprising a polymer or oligomer of Formula IV', wherein: x is NR ;y is NR 3 z is C=O; and R 3 is hydrogen or alkyl; A and B are independently optionally substituted o-, in-, or p-phenylene, wherein: A and B are independently optionally substituted with one or more polar (P) group(s), one or more non-polar (NP) group(s), or a combination of one or more polar (P) groups) and one or more non-polar (NP) group(s); R' is (i) -(CH 2 )p-W or -(CH 2 )p-U, wherein: W is hydrogen, pyridine, phenyl, said pyridine or phenyl optionally substituted with 1 or 2 substituents independently selected from the group consisting of halo, nitro, cyano, C-C 6 alkoxy, C 1

-C

6 alkoxycarbonyl, and benzyoloxycarbonyl, carboxyl, N-maleimide, or V as defined below; U is as defined below; the -(CH 2 )p- alkylene chain is optionally substituted with one or more amino or hydroxyl groups; p is as defined below; and R 2 is -x-A-x-Rl; or (ii) -(CH 2 )p-W or -(CHI 2 )p-U, wherein: W is as defined above; U is as defined below; and the -(CH 2 )p- alkylene chain is optionally WO 2004/082634 PCT/US2004/008155 -85 substituted with one or more amino or hydroxyl groups; p is as defined below; and R 2 is -x-A-x-z-y-B-y-Rl; NP is -(NR 3 ),i-U-(CH 2 )p-R 3 )q 2

-R

4 , wherein

R

4 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, and aryl, any of which is optionally substituted with one or more alkyl, alkoxy, or halo groups; U is absent, 0, S, or-(C=0)-; the -(CH 2 )p- alkylene chain is optionally substituted with one or more amino or hydroxyl groups; p is independently 0 to 6; qI and q2 are each 0; P is(NR 3 )qU-(CH 2 )p-(NR 3 )q2-V, wherein; U and R 3 are as defined above; V is selected from the group consisting of nitro, amino, hydroxyl, alkoxy, alkylthio, alkylamino, dialkylamino, -NH(CH2)pNH 2 ,

-N(CH

2

CH

2 NH2) 2 , diazamino, anidino, guanidino, guanyl, semicarbazone, alkoxycarbonyl, aryl, heterocycle and heteroaryl, any of which is optionally substituted with one. or more of amino, halo, -NH(CH 2 )pNH 2 , -N(CH 2

CH

2

NH

2

)

2 , alkylamino, dialkylamino, amidino, guanidino, guanyl, aminosulfonyl, aminoalkoxy, aminoalkylthio, lower acylamino, or benzyloxycarbonyl; the -(CH 2 )p- alkylene chain is optionally substituted with one or more amino or hydroxyl groups; p is independently 0 to 6; qI and q2 are each 0; and m is I to 5; and a pharmaceutically acceptable carrier or diluent. [02321 In other aspects, in the polymer or oligomer of Formula IV', x and y are NR, z is C=O or C=S, and R 3 is hydrogen; A and B are independently optionally substituted o-, m-, orp-phenylene; WO 2004/082634 PCT/US2004/008155 - 86 3NP is a nonpolar group independently selected from R 4 or -U-(H2)p-R4 wherein R 4 is selected from a group consisting of hydrogen, C 1

-C

4 alkyl, C 3

-C

1 2 branched alkyl, C 3 -Cs cycloalkyl, phenyl optionally substituted with one or more C 1

-C

4 alkyl groups and heteroaryl optionally substituted with one or more C 1

-C

4 alkyl groups, and U and p are as defined below; P is a polar group selected from II1a, hydroxyethoxymethyl, methoxyethoxymethyl or polyoxyethylene

-U--(CH

2 )-V iliaa) wherein U is 0, S, S(=0), S(=0) 2 , NH, or absent; V is selected from a group consisting of amino, hydroxyl, C 1

-C

6 alkylamino,

CI-C

6 dialkylamino, NH(CH 2 )pNH 2 , N(CH 2 CH2NH 2

)

2 , amidine, guanidine, semicarbazone, and imidazole, piperidine, piperazine, 4 alkylpiperazine and phenyl optionally substituted with an amino, C1-C 6 alkylamino, C 1

-C

6 dialkylamino or lower acylamino optionally substituted with one or more amino, lower alkylamino or lower dialkylamino; and the alkylene chain is optionally substituted with an amino or hydroxyl group; p is independently 0 to 8; and, m is 1 to about 500. [0233] In yet other aspects, in the polymer or oligomer of Formula IV', x and y are NH, z is C=0; A and B are in or p-phenylene and either (i) A is substituted at the 2-position with a polar (P) group and B is substituted at the 5-position with a nonpolar (NP) group, or (ii) A is substituted at the 5-position with a polar (P) group and B is substituted at the 2-position with a nonpolar (NP) group, or (iii) A and B are both substituted at the 2-position with a polar (P) group and at the 5-position with a nonpolar (NP) group, or WO 2004/082634 PCT/US2004/008155 - 87 (iv) A is substituted at the 2-position with a polar (P) group and at the 5-position with a nonpolar (NP) group and B is unsubstituted; NP is a nonpolar group independently selected from R 4 or -U-(CH2)p-R4 wherein R4 is selected from a group consisting of hydrogen, methyl, ethyl, n-propyl, iso-propyl, iso-butyl, sec-butyl, tert-butyl, iso-pentyl, and sec-pentyl, and U and p are as defined below; P is a polar group U-(CH 2 )p-V wherein U is absent or selected from a group consisting of 0 and S, and V is selected from a group consisting of amino, lower alkyl amino, lower dialkylamino, imidazole, guanidine,

NH(CH

2 )pNH 2 , N(CH 2

CH

2

NH

2

)

2 , piperidine, piperazine, and 4 alkylpiperazine; p is independently 0 to 8; and, m is I to about 500; or an acceptable salt or solvate thereof; and a pharmaceutically acceptable carrier or diluent. [02341 In some aspects, the invention is directed to a method of treating a microbial infection in an animal in need thereof, the method comprising administering to the animal an effective amount of a pharmaceutical composition comprising a polymer or oligomer of Formula XIV: (CH2)qV H H H2 SN N N NH R R 0 (XIV) R4 m R4 is selected from a group consisting of methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, n-pentyl, iso-pentyl, and see pentyl, and U and p are as defined below; U is absent, 0 or S, and V is selected from a group consisting of amino, lower alkyl amino, lower dialkylamino, imidazole, guanidine, WO 2004/082634 PCT/US2004/008155 -88 NiH(CH 2 )pNH 2 , N(CH 2

CH

2

NH

2

)

2 , piperidine, piperazine, and 4 alkylpiperazine; and, p is 0 to 8; m is 1 to about 30, or is 1 to about 50; or an acceptable salt or solvate thereof; and a pharmaceutically acceptable carrier or diluent. [0235] In yet other aspects, the invention is directed to a method of treating a microbial infection in an animal in need thereof, the method comprising administering to the animal an effective amount of a pharmaceutical composition comprising a polymer or oligomer of Formula XVII:

R

15 r-12 I HR H 0 H H 0 Rm wherein: either R1 2 and R 1 4 are independently polar (P) groups and R 13 and R15 are independently nonpolar (NP) groups substituted at one of the remaining unsubstituted carbon atoms, or R12 and R1 4 are independently nonpolar (NP) groups and R 13 and R 1 5 are independently polar (P) groups; NP is a nonpolar group independently selected from R 4 or -U-R4 wherein R 4 is selected from a the group consisting of methyl, ethyl, n-propyl, iso propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, n-pentyl, iso-pentyl, and sec-pentyl, and U and p are as defined below; P is a polar group U-(CH 2 )p-V wherein U is selected from a group consisting of 0 and S, and V is selected from a group consisting of amino, lower alkyl amino, lower dialkylamino, guanidine, pyridine, piperazine, and 4-alkylpiperazine; p is independently 0 to 8; and, WO 2004/082634 PCT/US2004/008155 -89 m is I to about 30, or 1 to about 50; or an acceptable salt or solvate thereof; and a pharmaceutically acceptable carrier or diluent. [02361 In, yet other aspects, the invention is directed to a method of treating a microbial infection in an animal in need thereof, the method comprising administering to the animal an effective amount of a pharmaceutical composition comprising a polymer or oligomer of Formula XVIII: NP NP 0 0 H 0Q H H 00 0 0 P P wherein: NP is a nonpolar group independently selected from R 4 or -(CH2)p-R4 wherein

R

4 is selected from a group consisting of hydrogen, methyl, ethyl, n propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, n-pentyl, iso-pentyl, and sec-pentyl, and p is as defined below; P is a polar group (CH2)p-V wherein V is selected from a group consisting of amino, lower alkyl amino, lower dialkylamino, imidazole, guanidine,

NH(CH

2 )pNH 2 , N(CH 2

CH

2

NH

2

)

2 , piperidine, piperazine, and 4 alkylpiperazine; p is independently 0 to 8; and, m is 1 to about 30, or 1 to about 50; or an acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier or diluent. [0237] The polymers and oligomers of the invention can be used to treat a microbial infection caused by any type of microorganism, including, but not limited to, bacteria, algae, fungi, yeast, mycoplasmas, mycobacterial, parasites and protozoa. The polymers and oligomers of the present invention are therefore effective in treating bacterial infections, fungal infections, viral WO 2004/082634 PCT/US2004/008155 - 90 infections, yeast infections, mycoplasmid infections, mycobacterial infections, or protozoal infections. [0238] The polymers and oligomers of the present invention have been shown to possess antiviral activity and can be used as antiviral agents. [0239] Thus, in some aspects, the invention is directed to a method of treating a viral infection in an animal in need thereof, the method comprising administering to the animal an effective amount of a pharmaceutical composition comprising a polymer of oligomer described above, for example, a polymer or oligomer of Formula I, Formula I', Formula II, Formula Ia, Formula II', Formula IV, Formula IVa, Formula IVb, Formula IVc, Formula IV', Formula VII, Formula IX, Fonnula XI, Formula XII, Formula XIII, Formula XIV, Formula XV, Formula XVI, Formula XVII, Formula XVIII, or Formula XX, as defined above. [0240] The polymers and oligomers of the present invention can also be used in methods of treating fungal infections. [02411 Immunocompromised individuals are at serious risk for developing systemic fungal infections and the high incidence of cancer and AIDS underscores the need for developing effective and safe antifungal therapies. Many of the existing antifungal drugs act on molecular targets involved in cell wall synthesis (Debono, M., and Gordee, R.S., Ann. Rev. MicrobioL 48:471 497 (1994)). However, many of these targets are also found in mammalian cells which can lead to unwanted side-effects, and current therapies are associated with serious clinical complications including hepatic and kidney toxicities. Furthermore, as with bacterial infections, drug-resistant fungi are emerging at an alarming rate (DeLucca, A.J., and Walsh, T.J., Antinicob. Agents Cliemother. 43:1-11 (1999)). Therefore, there is a strong need for the development of novel approaches for systemic and topical agents that can rapidly, effectively and safely control fungal infections while minimizing the potential for the development of resistance to their mechanism of action.

WO 2004/082634 PCT/US2004/008155 -91 [0242] The polymers and oligomers of the present invention have also been shown to possess antifungal activity and thus can be used as antifungal agents, for example, in a method of treating fungal infections in an animal. [02431 Thus, in some aspects, the invention is directed to a method of treating a fungal infection in an animal in need thereof, the method comprising administering to the animal an effective amount of a pharmaceutical composition comprising a polymer or oligomer described above, for example, a polymer or oligomer of Formula I, Formula I', Fonnula II, Formula Ila, Formula II', Formula IV, Formula IVa, Formula IVb, Formula IVe, Fonnula lV', Formula VII, Formula LX, Formula XI, Formula XII, Fonnula XIII, Formula XIV, Formula XV, Formula XVI, Formula XVII, Formula XVIII, or Formula XX, as defined above. [0244] The polymers and oligomers of the invention can also be used as antidotes for hemorrhagic complications associated with low molecular weight heparin therapy. [02451 Heparin has been commonly used as an anticoagulant and antithrombotic agent in the hospital setting. However, there are several pharmacokinetic parameters of standard heparin (SH) that complicate therapy. For example, the high serum protein-binding activity of SH precludes subcutaneous administration and its rapid and unpredictable plasma clearance necessitates constant monitoring of activated partial thromboplastin time to assess effectiveness (Turpie, A.G.G., An. Heart J. 135:S329-S335 (1998)). More recently, low molecular weight heparin derivatives (LMWH) have become the standard of care for the management of major vessel thrombotic conditions (Hirsh, J., and Levine, M.N., Blood. 79:1-17 (1992)). Nevertheless, LMWHs have gained popularity over standard heparin (SH) as antithrombotic agents because of their improved phannacokinetics and more predictable anticoagulant responses to weight-adjusted doses. LMWHs are formed by enzymatic or chemical cleavage of heparin and are effective factor Xa inhibitors because they contain the high affinity pentasaccharide sequence.

WO 2004/082634 PCT/US2004/008155 - 92 However, they are not effective thrombin inhibitors (Hirsh, J., and Levine, M.N., Blood. 79:1-17 (1992)). [0246] Both SIH and LMWH have a high net negative (anionic) charge. Hemorrhagic complications are associated with antithrombotic treatments with both agents and an overdose may result in serious bleeding. Protamine, by virtue of its positive charge, can neutralize the effects of the heparin but protamine therapy also has serious adverse, side-effects including hypotension, pulmonary hypertension and impairment of certain blood cells including platelets and lymphocytes (Wakefield, T.W., et al., J Surg. Res. 63:280-286 (1996)). Therefore, there is a strong need for the development of safe and effective antidotes for hemorrhagic complications associated with SH and LMWH antithrombotic therapies. [0247] The polymers and oligomers of the present invention have been shown to inhibit the anticoagulation effects of heparin, in particular, low molecular weight heparin, and can be used as antidotes for hemorrhagic complications associated with low molecular weight heparin therapy. [02481 Thus, in some aspects, the invention is directed to a method of providing an antidote to low / molecular weight heparin overdose in an animal in need thereof, the method comprising administering to the animal an effective amount of a pharmaceutical composition comprising a polymer or oligomer described above, for example, a polymer or oligomer of Formula I, Formula I', Formula II, Formula Ila, Formula II', Formula IV, Formula IVa, Formula IVb, Formula IVc, Formula IV', Formula VII, Formula IX, Formula XI, Formula XII, Formula XIII, Formula XIV, Fonnula XV, Formula XVI, Fonnula XVII, Formula XVIII, or Formula XX, as defined above. [02491 In some aspects of the invention, the polymers and oligomers of the present invention are useful as disinfectants. For example, coatings and paints adhesives are all exposed to microbial contamination and are used in locations where microbial growth is undesirable. Thus, the polymers and oligomers of the present invention are incorporated into polishes, paints, sprays, or WO 2004/082634 PCT/US2004/008155 - 93 detergents formulated for application to surfaces to inhibit the growth of a bacterial species thereon. These surfaces include, but are not limited to surfaces, such as, countertops, desks, chairs, laboratory benches, tables, floors, bed stands, tools or equipment, doorknobs, and windows. Polymers and oligomers of the present invention are also incorporated into soaps and hand lotions. The present cleansers, polishes, paints, sprays, soaps, or detergents contain a polymer or oligomer of the invention that provides a bacteriostatic property to them. They can optionally contain suitable solvent(s), carrier(s), thickeners, pigments, fragrances, deodorizers, emulsifiers, surfactants, wetting agents, waxes, or oils. For example, in some aspects of the invention, the polymers or oligomers are incorporated into a formulation for external use as a pharmaceutically acceptable skin cleanser, particularly for the surfaces of human hands. Cleansers, polishes, paints, sprays, soaps, hand lotions, and detergents are the like containing the antimicrobial polymers and oligomers of the present invention are useful in homes and institutions, particularly but not exclusively in hospital settings for the prevention of nosocomial infections. [0250] In other aspects of the invention, the polymers and oligomers of the invention are useful as preservatives and can be used in a method for killing or inhibiting the growth of a microbial species in a foodstuff and can be added to the foodstuff as a preservative. Foodstuffs that can be treated with a polymer or oligomer of the invention include, but are not limited to, non-acidic foods, such as mayonnaise or other egg products, potato products, and other vegetable or meat products. The polymer or oligomer for adding to the foodstuff can be part of any comestible formulation that can also include a suitable medium or carrier for convenient mixing or dissolving into a particular foodstuff. The medium or carrier is preferably one that will not interfere with the familiar flavor of the food of interest, such as are known by the artisan skilled in food processing techniques. [02511 In yet other aspects of the invention, the polymers and oligomers of the present invention provide a surface-mediated microbicide that only kills WO 2004/082634 PCT/US2004/008155 - 94 organisms in contact with the surface and are useful as surface-mediated disinfectants or preservatives. [0252] Any object that is exposed to or susceptible to bacterial or microbial contamination can be treated with the polymers and oligomers of the present invention to provide a microbial surface. To provide a microbial surface, a polymer or oligomer of the invention are attached to, applied on or incorporated into almost any substrate including but not limited to woods, paper, synthetic polymers (plastics), natural and synthetic fibers, natural and synthetic rubbers, cloth, glasses and ceramics by appropriate methods including covalent bonding, ionic interaction, coulombic interaction, hydrogen bonding or cross-linking. Examples of synthetic polymers include elastically deformable polymers which may be thermosetting or thermoplastic including, but not limited to polypropylene, polyethylene, polyvinyl chloride, polyethylene terephthalate, polyurethane, polyesters, such as polylactide, polyglycolide, rubbers such as polyisoprene, polybutadiene or latex, polytetrafluoroethylene, polysulfone and polyethylenesulfone polymers or copolymers. Examples of natural fibers include cotton, wool and linen. [0253] The incidence of infection from food-borne pathogens is a continuing concern and antimicrobial packaging material, utensils and surfaces would be valuable. In the health care and medical device areas the utility of antimicrobial instruments, packaging and surfaces are obvious. Products used internally or externally in humans or animal health including, but not limited to, surgical gloves, implanted devices, sutures, catheters, dialysis membranes, water filters and implements, all can harbor and transmit pathogens. [02541 Polymers and oligomers of the present invention are incorporated into any of these devices or implements to provide surface-medicated antimicrobial surfaces that will kill or inhibit the growth of organisms in contact with the surface. For example, the polymers and oligomers of the present invention can be incorporated into spinnable fibers for use in materials susceptible to bacterial contamination including, but not limited to, fabrics, surgical gowns, and carpets. Also, ophthalmic solutions and contact lenses easily become WO 2004/082634 PCT/US2004/008155 - 95 contaminated and cause ocular infections. Antimicrobial storage containers for contact lens and cleaning solutions incorporating polymers and oligomers of the present invention would thus be very valuable. [0255] Thus, in some aspects, the present invention is directed to a method of killing or inhibiting the growth of a microorganism, the method comprising contacting the microorganism with an effective amount of a polymer or oligomer described above, for example, a polymer or oligomer of Formula I, Formula I', Formula II, Formula Ila, Formula II', Formula IV, Formula IVa, Formula IVb, Formula IWe, Formula IV', Formula VII, Formula LX, Formula XI, Formula XII, Formula XIII, Formula XIV, Fonnula XV, Formula XVI, Formula XVII, Formula XVIII, or Formula XX, as defined above. [0256] In some aspects, the invention is directed to a polymer of Formula I, Formula I', Formula II, Formula II', Formula IV, Formula IV', Formula VII, Formula I.X, Formula XI, Formula XII, Formula XIII, Formula XIT, Formula XV, Formula XVI, Formula XVII, Formula XVIII, or Formula XX, as defined above, wherein m is 1 to about 500; or m is 1 to about 100; or m is 1 to about 50. [02571 In other aspects, the invention is directed to an oligomer of Formula I, Formula I', Formula II, Formula Ila, Formula II', Formula IV, Formula IVa, Formula IVb, Formula IVc, Formula IV', Formula VII, Formula IX, Formula XI, Fonnula XII, Formula XIII, Formula XIV, Formula XV, Formula XVI, Formula XVII, Formula XVIII, or Formula XX, as defined above, wherein m is 1 to about 30, or 1 to about 25, or 1 to about 20. In other aspects, in is I to about 10, or 1 to about 5, or 1 to about 3, 2 or 1. [0258] Thus, for example, the present invention is directed to an oligomer of Formula I: R-[-x-A 1 -y-x-A 2 -y-]m,-R 2 (I or an acceptable salt or solvate thereof, WO 2004/082634 PCT/US2004/008155 - 96 wherein: x is NR, y is C=O, and R8 is hydrogen;

A

1 is optionally substituted o-, m-, or p-phenylene and A 2 is -(CH2)q-, wherein q is 1, wherein one of A 1 and A 2 is substituted with one or two polar (PL) group(s), and the other of A 1 and A 2 is substituted with one or two non-polar (NPL) group(s); or

A

2 is optionally substituted o-, m-, or p-phenylene and A 1 is -(CH2)q-, wherein q is 1, wherein one of A 1 and A 2 is substituted with one or two polar (PL) group(s), and the other of A 1 and A 2 is substituted with one or two non-polar (NPL) group(s); R1 and R 2 are independently hydrogen, a polar (PL) group, or a non-polar (NPL) group; NPL is -(NRt)qlNPL-UNPL-(CH 2 )pNPL- 3")q2NPL -R', wherein:

R

4 ' is selected from the group consisting of C 1

-C

10 alkyl, C 3

-C

18 branched alkyl, C 2

-C

10 alkenyl, C 2

-C

10 alkynyl, and C 6 -Cio aryl, any of which is optionally substituted with one or more alkyl or halo groups; UNPL is absent or selected from the group consisting of NH, -C(=O)-, 0 and S; the -(CH2)pNPL- alkylene chain is optionally substituted with one or more amino groups; pNPL is 0 to 8; qlNPL and q2NPL are 0; PL is-(NR)qPLJPL-(CH 2 )pPL-(NR5)q 2 PL-V, wherein: UPL is absent or selected from the group consisting of 0, S, NH, and -C(=0); V is selected from the group consisting of amino, C 1

-C

6 alkylamino,

-NH(CH

2 )pNH 2 wherein p is I to 4, -N(CH 2

CH

2

NH

2

)

2 , diazamino, amidino, and guanidino, any of which is optionally substituted with one or more of amino, halo, cyano, nitro, hydroxy, -NH(CH 2 )pNH 2 wherein p is I to 4, WO 2004/082634 PCT/US2004/008155 -97

-N(CH

2

CH

2

NH

2

)

2 , amidino, guanyl, guanidino, or aminoalkoxy; the -(CH2)ppL- alkylene chain is optionally substituted with one or more amino groups; pPL is 0 to 8; qlPL and q2PL are 0; and {02591 m is 4 or 5. [0260] In other aspects, the invention is directed to an oligomer of Formula Ila:

R

1 -x-A-x-y-A 2 -y-x-A-x-R 2 (Ila) or an acceptable salt or solvate thereof, wherein: x is NR 8 , 0, S, or -N(R 8

)N(R

8 )-; and y is C=0, C=S, or O=S=0; wherein R 8 is hydrogen or alkyl;

A

1 and A 2 are independently optionally substituted arylene or optionally substituted heteroarylene, wherein A 1 and A 2 are independently optionally substituted with one or more polar (PL) groupss, one or more non-polar (NPL) group(s), or a combination of one or more polar (PL) group(s) and one or more non-polar (NPL) groupss; R' is a polar group (PL) or a non-polar group (NPL); and R 2 is R 1 ; NPL is a nonpolar group independently selected from the group consisting of

-B(OR

4

)

2 and -- (NR')qlNPL-UNPL-(CH2)pNPL- 3")q2NPL -R 4 ', wherein:

R

3 , R, and R 3 " are independently selected from the group consisting of hydrogen, alkyl, and alkoxy;

R

4 and R 4 ' are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and heteroaryl, any of which is optionally substituted with one or more alkyl or halo groups; UNPL is absent or selected from the group consisting of 0, S, S(=0), S(=0) 2 , NR 3 , -C(=0)-, -C(=0)-N=N-NR 3 -, -C(=0)-NR 3

-N=N-,

WO 2004/082634 PCT/US2004/008155 - 98 -N=N-NR 3 -, -C(=N-N(R93))-,

-C(=NR

3 )-, -C(=O)O-, -C(=O)S-, -C(=S)-, -O-P(=0) 2 0-, -RO-, -R 3 S-, -S-C=N- and -C(=O)-NR-O- , wherein groups with two chemically nonequivalent termini can adopt both possible orientations; the -(CH2)pNPL- alkylene chain is optionally substituted with one or more amino or hydroxy groups, or is unsaturated; pNPL is 0 to 8; qlNPL and q2NPL are independently 0, 1 or 2; PL is a polar group selected from the group consisting of halo, hydroxyethoxymethyl, methoxyethoxymethyl, polyoxyethylene, and -(NR)qiPL-JPL-(CH 2 )pPLNR 5 ')q 2 PL-V, wherein: R', R 5 , and R"' are independently selected from the group consisting of hydrogen, alkyl, and alkoxy; UPL is absent or selected from the group consisting of 0, S, S(=0), S(=0)2, NR, -C(=0)-, -C(=0)-N=N-NR 5 -, -C(=0)-NR 5 -N=T-, -N=N-NR-, -C(=N-N(R5)2)-, -C(=NR')-, -C(=0)O-, -C(=0)S-, -C(=S)-, -0-P(=0)20-, -R 5 O-, -R 5 S-, -S-C=N- and -C(=0)-NR 5 -0- , wherein groups with tvo chemically nonequivalent termini can adopt both possible orientations; V is selected from the group consisting of nitro, cyano, amino, hydroxy, alkoxy, alkylthio, alkylamino, dialkylamino, -NH(CH2)pNH 2 wherein p is I to 4, -N(CH 2

CH

2 NH2) 2 , diazamino, amidino, guanidino, guanyl, semicarbazone, aryl, heterocycle and heteroaryl, any of which is optionally substituted with one or more of amino, halo, cyano, nitro, hydroxy, -NH(CH 2 )pNH 2 wherein p is 1 to 4,

-N(CH

2

CH

2

NH

2

)

2 , amidino, guanidino, guanyl, aminosulfonyl, aminoalkoxy, aminoalkythio, lower acylamino, or benzyloxycarbonyl; the -(CH2)ppL- alkylene chain is optionally substituted with one or more amino or hydroxy groups, or is unsaturated; WO 2004/082634 PCT/US2004/008155 - 99 pPL is 0 to 8; and q1PL and q2PL are independently 0, 1 or 2. [02611 Examples of oligomers of the present invention, including oligomers for use in the disclosed methods of the invention, include, but are not limited to, the following compounds: WO 2004/082634 PCT/US2004/008155 -1.00 NH42 '.N f tV't~ ) A H HNH NI LH 11 f 0 ) Vf wikf tI A 0 NH t WO 2004/082634 PCT/L1S2004/008155 - 101 I~~ty~~ffz~ flyN~ kyNHz N, 7y H~~~~~N~S

N

1 1 NI ~ Ht J 4 NIl NH Htt sfA m bx 14 Ist> f' o. KM 0 0k-0 90kM 1)40 WO 2004/082634 PCT/L1S2004/008155 - 102 ThAt -,ti yrY M "1 WO 2004/082634 PCT/L1S2004/008155 - 103 M4z R C ' sf N it C)0 WO 2004/082634 PCT/L1S2004/008155 -104 14 2 NNH NHH2 HZN 1 Man, f f~tij WO 2004/082634 PCT/US2004/008155 -105 2IY K Nt H2K yNB 1 NHA' wtyrn f I th ol f tNH NNH, 0 u : HA1 RMNHZ NN [02 62 i some aspects of the invention, the polymers and oligomers, of the present invention are derivatives referred to as prodrugs. The expression "prodrug" denotes a derivative of a known direct acting drug, which derivative has enhanced delivery characteristics and therapeutic value as compared to the drug, and is transformed into the active drug by an enzymatic or chemical process. [0263] When any variable occurs more than one time in any constituent or in any of the polymers or oligomers recited for any of the general Formulae above (for example, Formulae 1, II, or IV), its definition on each occurrence is WO 2004/082634 PCT/US2004/008155 - 106 independent of its definition at every other occurrence. Also, combinations of substituents and/or variables are permissible only if such combinations result in stable compounds. [0264] It is understood that the present invention encompasses the use of stereoisomers, diastereomers and optical isomers of the polymers and oligomers of the present invention, as well as mixtures thereof, for treating microbial infections, killing or inhibiting the growth of a microorganism, and providing an antidote to low molecular weight heparin overdose in an animal. Additionally, it is understood that stereoisomers, diastereomers and optical isomers of the polymers and oligomers of the present invention, and mixtures thereof, are within the scope of the invention. By way of non-limiting example, the mixture may be a racemate or the mixture may comprise unequal proportions of one particular stereoisomer over the other. Additionally, the polymers and oligomers of the present invention may be provided as a substantially pure stereoisomers, diastereomers and optical isomers. [02651 In another aspect of the invention, the polymers and oligomers of the present invention may be provided in the form of an acceptable salt (i.e., a pharmaceutically acceptable salt) for treating microbial infections, killing or inhibiting the growth of a microorganism, and providing an antidote to low molecular weight heparin overdose in an animal. Polymer or oligomer salts may be provided for pharmaceutical use, or as an intermediate in preparing the pharmaceutically desired form of the polymer or oligomer. One polymer or oligomer salt that may be considered to be acceptable is the hydrochloride acid addition salt. Hydrochloride acid addition salts are often acceptable salts when the pharmaceutically active agent has an amine group that can be protonated. Since a polymer or oligomer of the invention may be polyionic, such as a polyamine, the acceptable polymer or oligomer salt may be provided in the form of a poly(amine hydrochloride). [0266] Polyamides and polyesters that are useful for the present invention can be prepared by typical condensation polymerization and addition polymerization processes. See, for example, G. Odian, Principles of WO 2004/082634 PCT/US2004/008155 -107 Polymerization, John Wiley & Sons, Third Edition (1991), M. Steven, Polymer Chemistry, Oxford University Press (1999). Most commonly the polyamides are prepared by (a) thermal dehydration of amine salts of carboxylic acids, (b) reaction of acid chlorides with amines and (c) aminolysis of esters. Methods (a) ahd (c) are of limited use in polymerizations of aniline derivatives which are generally prepared utilizing acid chlorides. The skilled chemist, however, will recognize that there are many alternative active acylating agents, for example phosphoryl anhydrides, active esters or azides, which may replace an acid chloride and which, depending of the particular polymer being prepared, may be superior to an acid chloride. The acid chloride route is probably the most versatile and baa been used extensively for the synthesis of aromatic polyamides H Ir Homopolymers derived flom substituted aminobenzoic acid derivatives can also prepared in a stepwise fashion. A stepwise process comprises coupling an N-protected amino acid to an amine (or hydroxy group) and subsequently removing the amine-protecting group and repeating the process. These techniques have been highly refined for synthesis of specific peptides, allow for the synthesis of specific sequences, and both solid-phase and solution techniques for peptide synthesis are directly applicable to the present invention. An alternative embodiment of the present invention is the corresponding polysulfonamides that can be prepared in analogous fashion by substituting sulfonyl chlorides for carboxylic acid chlorides. [02671 The most common method for the preparation of polyureas is the reaction of diamines with diisocyanates. (Yamaguchi, I. et al., Polyi. Bull. 44:247 (2000)) This exothermic reaction can be carried out by solution techniques or by interfacial techniques. One skilled in organic and polymer chemistry will appreciate that the diisocyanate can be replaced with a variety WO 2004/082634 PCT/US2004/008155 - 108 of other bis-acylating agents e.g., phosgene or N, N'-(diimidazolyl)carbonyl, with similar results. Polyurethanes are prepared by comparable techniques using a diisocyanate and a dialcohol or by reaction of a diamine with a bis chloroformate. [0268] The syntheses of appropriately substituted monomers are straightforward. Numerous pathways are available to incorporate polar and nonpolar side chains. Phenolic groups on the monomer can be alkylated. Alkylation of the commercially available phenol will be accomplished with standard Williamson ether synthesis for the non-polar side chain with ethyl bromide as the alkylating agent. Polar sidechains can be introduced with bifunctional alkylating agents such as BOC-NH(CH 2

)

2 Br. Alternatively, the phenol group can be alkylated to install the desired polar side chain function by employing the M.itsonobu reaction with BOC-NIH(CH 2

)

2 -OH, triphenyl phosphine, and diethyl acetylenedicarboxylate. Standard conditions for reduction of the nitro groups and hydrolysis of the ester afford the amino acid. With the aniline and benzoic acid in hand, coupling can be effected under a variety of conditions. Alternatively, the hydroxy group of the (di)nitrophenol can be converted to a leaving group and a functionality introduced under nucleophilic aromatic substitution conditions (see FIG 8, for example). Other potential scaffolds that can be prepared with similar sequences are methyl 2 nitro-4-hydroxybenzoate and methyl 2-hydroxy-4-nitrobenzoate. [02691 The polymers and oligomers of the present invention are designed using computer-aided computational techniques, such as de novo design techniques, to embody the amphiphilic properties believed to be important for activity. In general, de novo design of oligomers is done by defining a three dimensional framework of the backbone assembled from a repeating sequence of monomers using molecular dynamics and quantum force field calculations. Next, side groups are computationally grafted onto the backbone to maximize diversity and maintain drug-like properties. The best combinations of functional groups are then computationally selected to produce a cationic, anphiphilic structures. Representative compounds are synthesized from this WO 2004/082634 PCT/US2004/008155 - 109 selected library to verify structures and test their biological activity. Importantly, novel molecular dynamic and coarse grain modeling programs have been developed for this approach because existing force fields developed for biological molecules, such as peptides, were unreliable in these oligomer applications (Car, R., and Parrinello, M., Phys. Rev. Lett., 55:2471-2474 (1985); Siepmann, J.L, and Frenkel, D., Mol. Phys. 75:59-70 (1992); Martin, M.G., and Siepmann, J.L, J. Phys. Clhem. B 103:4508-4517 (1999); Brooks, B.R., et al., J Comp. Chem. 4:187-217 (1983)). Several chemical structural series of oligomers and polymers have been prepared. See, for example, WO 02/100295 A2, the entire contents of which are incorporated. herein by reference. The polymers and oligomers of the present invention are prepared in a similar manner (see belov). [0270] The general approach is as follows: 1) A polymer backbone that should fold into a given, well-defined three-dimensional structure is defined. Extensive theoretical studies are carried out to demonstrate that the polymers are able to adopt the desired secondary conformation. Model compounds (short oligomers) are prepared for structural analysis of folding by X-ray crystallography. 2) The backbone of the polymer is then decorated with appropriate functional groups to endow the oligomer or polymer with the desired facial amphiphilic character. 3) The desired oligomers and polymers are synthesized, and their biological activities are measured. 4) Biophysical studies are carried out to confirm that the polymers are binding to membranes in the desired conformation and that the mechanism of action is as expected from the design. 5) Based on the findings, structures are redesigned to optimize the potency and selectivity of the compounds, and steps 2-4 are re-iterated. [0271] The goal of this approach is to capture the structural and biological properties of antimicrobial peptides within the framework of traditional polymers that can be prepared by inexpensive condensation reactions.

WO 2004/082634 PCT/US2004/008155 -110 [0272] While the synthesis of a variety of polymer backbones is well understood, computer-aided computational techniques can provide valuable insight and guidance in the selection of potential antimicrobial polymers. The goal of these computations is to identify potential low energy conformations which have a geometrical repeat that matches a convenient sequence repeat of less than 6 monomer units. For example in a-amino acid oligomers, the geometrical repeat of the P-sheet is 2.0 residues. Once these repeating scaffolds are identified and the frequency of the repeat is calculated; polar and nonpolar substituents can be incorporated into the monomers to confer amphiphilic properties into the molecule. [0273] High level ab initio calculations are one technique which will identify accessible low energy conformations. Unfortunately, these techniques, while extremely powerful, are not practical with molecules the size of the present invention, Molecular Dynamics simulations provide an alternative that can be adapted efficiently to molecules envisioned in the present invention. Key elements in determining conformational energies are strong electrostatic interactions (i.e., intramolecular hydrogen bonding) between adjacent or more distant monomers and rigidification caused by the backbone torsions or by bulky functional groups. In order to simulate these interactions in molecular mechanics calculations the empirical parameters, i.e., a force field, must be determined for representative polymer backbones. Density functional theory (DFT) can. be used to carry out ab initio calculations on small model compounds that share the basic structural connectivity of the polymer backbones and which will generate required torsional potentials. The procedure to carry out these computations is: 1. Select simple model compounds that share similar torsional patterns with the target polymer backbones. 2. For each compound, perform a full geometric optimization at the BLYP/6-31 G(d) level of theory (multiple initial configurations ensure the global minimum is obtained).

WO 2004/082634 PCT/US2004/008155 - 111 3. Calculate the single-point energy at the most stable geometry obtained in step 2 above, using B3LYP/6-311G++(dp) or plane wave CPMD. 4. Constrain a relevant torsion to a set angle and repeat steps 2 and 3. 5. Repeat step 4 for several angles; the torsional energy is obtained by subtracting the non-bonded interactions. 6. Fit energies versus torsion angle to a cosine series whose coefficients are the force field parameters. [0274] Molecular dynamic and coarse grain modeling programs can be used for the above design approach. See, for example, U.S. Patent Appl. No. 10/446,171, filed May 28, 2003, and U.S. Patent Appl. No. 10/459,698, filed June 12, 2003. The contents of U.S. Appl. No. 10/446,171 and U.S. Apple. No. 10/459,698 are fully incorporated by reference herein. [0275] After verifying the suitability of the force field by comparing computed predictions of the structure and thermodynamic properties to molecules that have similar torsional patterns and for which experimental data are available, the fitted torsions are then combined with bond stretching, bending, one-four, van der Waals, and electrostatic potentials borrowed from the CHARMM (Brooks, B.R., et al., J. Comp. Chem. 4:187-217 (1983)) and TraPPE (Martin, M.G., and Siepmann, J.., J. Phys. Chen. B 103:4508-4517 (1999); Wick, C.D., et al., J. Phys. Chein. B 104:3093-3104 (2000)) molecular dynamics force fields. To identify conformations that can adopt periodic folding patterns with polar groups and apolar groups lined up on the opposite sides, initial structures can be obtained with the Gaussian package (Frisch, M., et al., Gaussian 98 (revision A.7) Gaussian Inc., Pittsburgh, PA 1998). Then, the parallelized plane-wave Car-Parrinello CP-MD (Car, R., and Parrinello, M., Phys. Rev. Lett. 55:2471-2474 (1985)) program, (cf R6thlisberger, U., et al., J. Chen. Phys. 3692-3700 (1996)) is used to obtain energies at the minimum and constrained geometries. The conformations of the polymers without side-chains can be investigated in the gas phase. Both MD and MC methods will be used to sample the conformations. The former is useful for WO 2004/082634 PCT/US2004/008155 -112 global motions of the polymer. With biasing techniques (Siepmann, J.L, and Frenkel, D., Mol. Phys. 75:59-70 (1992); Martin, M.G., and Siepmann, J.L, J Phys. Chem. B 103:4508-4517 (1999); Vlugt, T.J.H., et al. Mol. Phys. 94:727 733 (1998)) the latter allows efficient sampling for polymers with multiple local minimum configurations that are separated by relatively large barriers. [0276] The potential conformations are examined for positions to attach pendant groups that will impart amphiphilic character to the secondary structure, Polymers selected from the gas phase studies with suitable backbone conformations and with side-chains at the optimal positions to introduce amphiphilicity will be further evaluated in a model interfacial system, n-hexane/water, chosen because it is simple and cheap for calculations while it mimics well the lipid/water bilayer environment. Polymer secondary structures that require inter-polymer interactions can be identified by repeating the above-mentioned calculations using a periodically repeated series of unit cells of various symmetries (so called variable cell molecular dynamics or Monte Carlo technique) with or without solvent. The results of these calculations will guide the selection of candidates for synthesis. [0277] An embodiment of the present is a computation technique to identify polymer backbones which can produce facially amphiphilic polymers by: (1) selecting a polymer backbones or scaffolds suitable for regiospecific introduction of polar (P) and nonpolar (NP) groups; (2) determining parameters for molecular mechanics force field utilizing ab initio quantum mechanical calculations; (3) calculating energetically accessible conformations of the backbone using molecular dynamics or molecular mechanics calculations; (4) identifying energetically accessible conformations of the backbone wherein the periodicity of a geometrical/conformational repeat matches a sequence repeat; (5) synthesizing monomers with polar and nonpolar substituents; (6) synthesizing an antimicrobial polymer containing the monomers by solution or solid-phase synthesis.

WO 2004/082634 PCT/US2004/008155 - 113 [0278] An example of the design, synthesis, and testing of arylamide polymers and oligomers, a subgroup of polymers and oligomers disclosed in the present invention, is presented in Tew, G.N., et al., Proc. NatL Acad. Sci. USA 99:5110-5114 (2002), the contents of which are fully incorporated by reference herein (Tew, G.N., et al., Proc. Natl. Acad. Sci. USA 99:5110-5114 (2002)). See also Example 12 below. [0279] Oligomers of the present invention are synthesized by solid-phase synthetic procedures well know to those of skill in the art. See, for example, Tew et al. (Tew, G.N., et al., Proc. NatL. Acad. Sci. USA 99:5110-5114 (2002)). See also Barany, G., et al., Int. J. Pept. Prot, Res. 30:705-739 (1987); Solid-phase Synthesis: A Practical Guide, Kates, S.A., and Albericio, F., eds., Marcel Dekker, New York (2000); and Dorwald, F.Z., Organic Synthesis on Solid Phase: Supports, Linkers, Reactions, 2nd Ed., Wiley-VCH, Weinheim (2002). [0280] The polymers and oligomers of the invention are synthesized in a range of molecular weights. Molecular weights for the polymers and oligomers range from about 300 Daltons to about 1,000,000 Daltons. Preferred polymers of the present invention have average molecular weights that range from about 400 Daltons to about 120,000 Daltons (about 2 to about 500 monomer units). Especially preferred polymers have average weights that range from about 1,000 Daltons to about 25,000 Daltons (about 5 to about 100 monomer units). Oligomers of the present invention have molecular weights that range from about 300 Daltons to about 6,000 Daltons (about 2 to about 25 monomer units), with preferred oligomers having molecular weights that range from about 300 Daltons to about 2,500 Daltons (about 2 to about 10 monomer units). [0281] One of skill in the art will recognize that the synthetic processes for producing polymers and oligomers of the invention can be modified to produce different ranges in molecular weight. The polymer chemist will readily appreciate that the chain length of polymers can be varied by techniques know in the polymer art. Advancements in solid-phase and solution WO 2004/082634 PCT/US2004/008155 -114 phase synthesis of amino acid oligomers have made available techniques to prepare homogeneous oligomers with defined sequence and size and these techniques can be adapted to the present invention. [0282] The polymers and oligomers of the invention are tested for antimicrobial activity by methods well known to those of skill in the art. See, for example, Tew, G.N., et al. (Tew, G.N., et al., Proc. Nal, Acad. Sci. USA 99:5110-5114 (2002)). Antimicrobial testing can be carried out using the micro-broth dilution technique with E. coli, or, if desired, another bacterial strain, such as, for example, B. subtilis, P. aeruginosa, K. pneumoniae, S. typhimuriun, N. gonorrhoeae, B. megateriun, S. aureus, E. feacalis, M. luteus ,or S. pyogenes. Other specific bacterial strains that can be screened include ampicillin and streptomycin-resistant E. coli D31, vancomycin-resistant Enterococcus faeciuni A436, and methicillin-resistant S. aureus 5332. Any polymer or oligomer found to be active can be purified to homogeneity and re tested to obtain an accurate IC 50 . Secondary screens include Iebsiella pneunoniae Kpl, and Salmonella ty.phimuriuin S5, and Pseudomionus aeruginosa 10. Traditionally, the micro-broth dilution technique only evaluates a single data point between 18-24 hours; however, the measurements can be extended to 24 hr to monitor cell growth through the entire growth phase. These experiments are performed in LB medium (which is a rich medium typically used to grow cells for protein expression) and represent a critical initial screen for activity. Since salt concentration, proteins, and other solutes can affect the activities of antibiotics, materials that show no activity in rich medium can be re-tested in minimal medium. (M9) to determine if rich medium is limiting activity. No relationship between the media and the activity has been observed which is consistent with the mode of action this is believed to be through general membrane disruption. [0283] Standard assays can be performed to determine whether a polymer or oligomer is bacteriostatic or bactericidal. Such assays are well known to those of skill in the art and are performed, for example, by incubating E. coli cells overnight with the polymer or oligomer being tested, and then plating the WO 2004/082634 PCT/US2004/008155 - 115 mixture on agar plates according to procedures well known to those of skill in the art. See, for example, Tew, G.N., et al. (Tew, G.N., et al., Proc. Natl. Acad. Sci. USA 99:5110-5114 (2002)), and Liu, D., and DeGrado, W. F. (Liu, D., and DeGrado,W.F., J Amer. Chem. Soc. 123:7553-7559 (2001)). 102841 Assays for determining the antiviral and antifungal activity of polymers and oligomer are also well known to those of skill in the art. For examples of antiviral assays, see Belaid et al., (Belaid, A., et al., J Med. Virol. 66:229-234 (2002)), Egal et al., (Egal, M., et al., Int. J. Antimicrob. Agents 13:57-60 (1999)), Andersen et al., (Andersen, J.H., et al., Antiviral Rs. 51:141-149 (2001)), and Bastian, A., and Schafer, H. (Bastian, A., and Schafer, H., Regul. Pept. 15:157-161 (2001)). See also Cole, A.M., et al., Proc. Natl. Acad. Sci USA 99:1813-1818 (2002). For examples of antifungal assays, see Edwards, J.R., et al., Antimficrobial Agents Chemotherapy 33:215 222 (1989), and Broekaert, W.F., et al., FEAS Mlicrobiol. Lett. 69:55-60 (1990). The entire contents of each of these documents is fully incorporated herein by reference. [02851 Assays for measuring the cytotoxic selectivity for polymers and oligomers toward bacteria and eukaryotic cells are well known to those of skill in the art. For example, cytotoxic selectivity can be assessed by determining the hemolytic activity of the polymer or oligomer. Hemolytic activity assays are performed by measuring the degree of hemolysis of human erythrocytes following incubation in the presence of the polymer or oligomer and determining HC50 values. HC50 values represent the concentration of compound that results in 50% hemoglobin release. See, for example, Liu, D., and DeGrado, W.F. (Liu, D., and DeGrado,W.F., J. Amer. Chem. Soc. 123:7553-7559 (2001)), and references cited therein. See also Javadpour, M.M., et al., J. Med. Chem. 39:3107-3113 (1996). [0286] Vesicle leakage assays can also be used to confirm that a polymer or oligomer interact with and disrupt phospholipid bilayers, a model for cellular membranes. Vesicle leakage assays are well known to those of skill, in the art.

WO 2004/082634 PCT/US2004/008155 -116 See, for example, Tew, G. N., et al. (Tew, G.N., et al., Proc. Natl. Acad. Sci. USA 99:5110-5114 (2002)), and references cited therein. [0287] Assays for determining the heparin-neutralizing activity of a polymer or oligomer are well known to those of skill in the art and are commonly performed using either an activated partial thromboplastin time assay (for example, by measuring the delay in clotting times for activated plasma in the presence of a fixed concentration of heparin, in the absence and presence of a test compound) or a Factor X assay. See, for example, Kandrotas (Kandrotas, R.J., Clin. Pharmacokinet. 22:359-374 (1992)), Wakefield et al. (Wakefield, T.W., et al., J. Surg. Res. 63:280-286 (1996)), and Diness, V., and Ostergaard, P.B. (Diness, V.O., and Ostergaard, P.B., Thromb. Haemost. 56:318-322 (1986)), and references cited therein. See also Wong, P.C., et al, J. Pharm. Exp. Therap. 292:351-357 (2000), and Ryn-McKenna, J.V., et al., Thromb. Haemiost. 63:271-274 (1990). 102831 The polymers and oligomers of the present invention can be used to kill or inhibit the growth of any of the following microbes or mixtures of the following microbes, or, alternatively, can be administered to treat local and/or systemic microbial infections or illnesses caused by the following microbes or mixtures of the following microbes: Gram-positive cocci, for example Staphylococci (Staph. aureus, Staph. epiderinidis) and Streptococci (Strept. agalactiae, Strept. faecalis, Strept. pneumoniae, Strept. pyogenes); Gram negative cocci (Neisseria gonorrhoeae and Yersinia pestis) and Gram negative rods such as Enterobacteriaceae, for example Escherichia coli, Hazophilus influenzae, Citrobacter (Citrob. freundii, Citrob. divernis), Salmonella and Shigella, and Francisella (Francisella tularensis); Gram positive rods such as Bacillus (Bacillus anthracis, Bacillus thuringenesis); furthermore Klebsiella (Klebs. pneumoniae, Klebs. oxytoca), Enterobacter (Ent. aerogenes, Ent. agglomerans), Hafnia, Serratia (Serr. marcescens), Proteus (Pr. mirabilis, Pr. rettgeri, Pr. vulgaris), Providencia, Yersinia, and the genus Acinetobacter. Furthermore, the anti-microbial spectrum of the polymers and oligomers of the invention covers the genus Pseudomonas (Ps.

WO 2004/082634 PCT/US2004/008155 - 117 aeruginosa, Ps. maltophilia) and strictly anaerobic bacteria such as, for example, Bacteroides fragilis, representatives of the genus Peptococcus, Peptostreptococcus and the genus Clostridium; furthermore Mycoplasmas (M. pneumoniae, M. hominis, Ureaplasma urealyticum) as well as Mycobacteria, for example Mycobacterium tuberculosis. This list of microbes is purely illustrative and is in no way to be interpreted as restrictive. [0289] Examples of microbial infections or illness that can be treated by administration of the polymers and oligomers of the invention include, but are not limited to, microbial infections or illnesses in humans such as, for example, otitis, pharyngitis, pneumonia, peritonitis, pyelonephritis, cystitis, endocarditis, systemic infections, bronchitis (acute and chronic), septic infections, illnesses of the upper airways, diffuse panbronchiolitis, pulmonary emphysema, dysentery, enteritis, liver abscesses, urethritis, prostatitis, epididymitis, gastrointestinal infections, bone and joint infections, cystic fibrosis, skin infections, postoperative wound infections, abscesses, phlegmon, wound infections, infected bums, burns, infections in the mouth, infections after dental operations, osteomyelitis, septic arthritis, cholecystitis, peritonitis with appendicitis, cholangitis, intraabdominal abscesses, pancreatitis, sinusitis, mastoiditis, mastitis, tonsileitis, typhoid, meningitis and infections of the nervous system, salpingitis, endometritis, genital infections, pelveoperitonitis and eye infections. [0290] Examples of viral infections that can be treated by administration of the polymers and oligomers of the invention include, but are not limited to, viral infections caused by human immunodeficiency virus (HIV-1, HIV-2), hepatitis virus (e.g., hepatitis A, hepatitis 13, hepatitis C, hepatitis D, and hepatitis E viruses), herpesviruses (e.g., herpes simplex virus types 1 and 2, varicella-zoster virus, cytomegalovirus, Epstein Barr virus, and human herpes viruses types 6, 7, and 8), influenza virus, respiratory syncytial virus (RSV), vaccinia virus, and adenoviruses. This list is purely illustrative and is in no way to be interpreted as restrictive.

WO 2004/082634 PCT/US2004/008155 - 118 [02911 Examples of fungal infections or illnesses that can be treated by administration of the polymers and oligomers of the present invention include, but are not limited to, fungal infections caused by Chytridiomycetes, Hyphochrytridiomycetes, Plasmodiophoromycetes, Oomycetes, Zygomycetes, Ascomycetes, and Basidiomycetes. Fungal infections which can be inhibited or treated with compositions of the polymers and oligomers provided herein include, but are not limited to: Candidiasis, including, but not limited to, onchomycosis, chronic mucocutaneous candidiasis, oral candidiasis, epiglottistis, esophagitis, gastrointestinal infections, genitourinary infections, for example, caused by any Candida species, including, but not limited to, Candida albicans, Candida tropicalis, Candida (Torulopsis) glabrata, Candida parapsilosis, Candida lusitaneae, Candida rugosa and Candida pseudotropicalis; Aspergillosis, including, but not limited to, granulocytopenia caused, for example, by, Aspergillus spp. Including, but not limited, to Aspergillus fminigatus, Aspergillus favus, Aspergillus niger and Aspergillus terreus; Zygomycosis, including, but not limited to, pulmonary, sinus and rhinocerebral infections caused by, for example, zygomycetes such as Mucor, Rhizopus spp., Absidia, Rhizomucor, Cunningamella, Saksenaea, Basidobolus and Conidobolus; Cryptococcosis, including, but not limited, to infections of the central nervous system, e.g., meningitis, and infections of the respiratory tract caused by, for example, Cryptococcus neoformnans; Trichosporonosis caused by, for example, Trichosporon beigeli; Pseudallescheriasis caused by, for example, Pseudallescheria boydii; Fusarium infection caused by, for example, Fusarium such as Fusarium solani, Fusariumn noniliforme and Fusarium prohferartum; and other infections such as those caused by, for example, Penicillium spp. (generalized subcutaneous abscesses), Trichophyton spp., for example, Trichophyton mnentagrophytes and Trichophyton rubrun, Stachybotrys spp., for example, S. chartarumn, Drechslera, Bipolaris, Exserohilum spp., Paecilonyces lilacinum, Exophila jeansemnei (cutaneous nodules), Malassezia furfur (folliculitis), Alternaria (cutaneous nodular lesions), Aureobasidium pullulans (splenic and disseminated infection), WO 2004/082634 PCT/US2004/008155 -119 Rhodotorula spp. (disseminated infection), Chaetomium spp. (empyema), Torulopsis candida (fungemia), Curvularia spp. (nasopharnygeal infection), Cuminghamella spp. (pneumonia), H. Capsulatum, B. dermatitidis, Coccidioides inmitis, Sporothrix schencckii and Paracoccidioides brasiliensis, Geotrichuin candidum (disseminated infection). The polymers and oligomers of the present invention can also be used to kill or inhibit the growth of any of the fungi listed above. This list is purely illustrative and is in no way to be interpreted as restrictive. [0292] The polymer or oligomer can be administered to a human subject. Thus, in some aspects of the invention, the polymer or oligomer is administered to a human. [0293] The methods disclosed above also have veterinary applications and can be used to treat a wide variety of non-human vertebrates. Thus, in other aspects of the invention, the polymer or oligomer is administered in the above methods to non-human vertebrates, such as wild, domestic, or farm animals, including, but not limited to, cattle, sheep, goats, pigs, dogs, cats, and poultry such as chicken, turkeys, quail, pigeons, ornamental birds and the like. [02941 The following are examples of microbial infections in non-human vertebrates that can be treated by administering a polymer or oligomer of the invention: Pig: coli diarrhoea, enterotoxaemia, sepsis, dysentery, salmonellosis, metritis-mastitis-agalactiae syndrome, mastitis; ruminants (cattle, sheep, goat): diarrhoea, sepsis, bronchopneumonia, salmonellosis, pasteurellosis, mycoplasmosis, genital infections; horse: bronchopneumonias, joint ill, puerperal and post-puerperal infections, salmonellosis; dog and cat: bronchopneumonia, diarrhoea, dermatitis, otitis, urinary tract infections, prostatitis; poultry (chicken, turkey, quail, pigeon, ornamental birds and others): mycoplasmosis, E. coli infections, chronic respiratory tract illnesses, salmonellosis, pasteurellosis, psittacosis. This list is purely illustrative and is in no way to be interpreted as restrictive. [0295] For those applications in which the polymers and oligomers of the present invention are used as disinfectants and/or preservatives, e.g., in WO 2004/082634 PCT/US2004/008155 -120 cleansers, polishers, paints, sprays, soaps, or detergents, the polymers and oligomers are incorporated into the cleanser, polisher, paint, spray, soap, or detergent formulation, optionally in combination with suitable solvent(s), carrier(s), thickeners, pigments, fragrances, deodorizers, emulsifiers, surfactants, wetting agents, waxes, or oils. If the polymer or oligomer is to be used as a preservative in a foodstuff, the polymer or oligomer can be added to the foodstuff as part of any comestible formulation that can also include a suitable medium or carrier for convenient mixing or dissolving into the foodstuff. The amount of polymer or oligomer added to or incorporated into the cleanser, polisher, soap, etc. formulation or into the foodstuff will be an amount sufficient to kill or inhibit the growth of the desired microbial species and can easily be determined by one of skill in the art. [0296] For those applications in which the polymers and oligomers of the invention are used as surface-mediated microbicides, e.g., in some applications as disinfectants and as preservatives (e.g., including, but not limited to, medical devices such as catheters, bandages, and implanted devices, or food containers and food handling implements), the polymers and oligomers may be attached to, applied on or incorporated into almost any substrate including, but not limited to, woods, paper, synthetic polymers (plastics), natural and synthetic fibers, natural and synthetic rubbers, cloth, glasses and ceramics by appropriate methods, including covalent bonding, ionic interaction, coulombic interaction, hydrogen bonding or cross-linking. [0297] Procedures for attaching, applying, and incorporating the polymers and oligomers of the invention into appropriate materials and substrates are disclosed in WIPO Publ. No. WO 02/100295, the contents of which are fully incorporated herein by reference. Appropriate substrates and materials are also disclosed in WO 02/100295. [0298] The following examples are illustrative, but not limiting, of the methods and compositions of the present invention. Other suitable modifications and adaptations of the variety of conditions and parameters WO 2004/082634 PCT/US2004/008155 - 121 normally encountered and obvious to those skilled in the art are within the spirit and scope of the invention. [0299] The polymers and oligomers of the present invention are administered in the conventional manner by any route where they are active. Administration can be systemic, topical, or oral. For example, administration can be, but is not limited to, parenteral, subcutaneous, intravenous, intramuscular, intraperitoneal, transdermal, oral, buccal, or ocular routes, or intravaginally, by inhalation, by depot injections, or by implants. Thus, modes of administration for the polymers and oligomers (either alone or in combination with other pharmaceuticals) can be, but are not limited to, sublingual, injectable (including short-acting, depot, implant and pellet forms injected subcutaneously or intramuscularly), or by use of vaginal creams, suppositories, pessaries, vaginal rings, rectal suppositories, intrauterine devices, and transdermal forms such as patches and creams. [03001 Specific modes of administration will depend on the indication (e., whether the polymer or oligomer is administered to treat a microbial infection, or to provide an antidote for hemorrhagic conditions associated with heparin therapy). The mode of administration can depend on the pathogen or microbe to be targeted. The selection of the specific route of administration and the dose regimen is to be adjusted or titrated by the clinician according to methods known to the clinician in order to obtain the optimal clinical response. The amount of polymer or oligomer to be administered is that amount which is therapeutically effective. The dosage to be administered will depend on the characteristics of the subject being treated, e.g., the particular animal treated, age, weight, health, types of concurrent treatment, if any, and frequency of treatments, and can be easily determined by one of skill in the art (e.g., by the clinician). [0301] The pharmaceutical fornulations containing the polymers and oligomers and a suitable carrier can be solid dosage forms which include, but are not limited to, tablets, capsules, cachets, pellets, pills, powders and granules; topical dosage forms which include, but are not limited to, solutions, WO 2004/082634 PCT/US2004/008155 - 122 powders, fluid emulsions, fluid suspensions, semi-solids, ointments, pastes, creams, gels and jellies, and foams; and parenteral dosage forms which include, but are not limited to, solutions, suspensions, emulsions, and dry powder; comprising an effective amount of a polymer or oligomer as taught in this invention. It is also known in the art that the active ingredients can be contained in such formulations with pharmaceutically acceptable diluents, fillers, disintegrants, binders, lubricants, surfactants, hydrophobic vehicles, water soluble vehicles, emulsifiers, buffers, humectants, moisturizers, solubilizers, preservatives and the like. The means and methods for administration are known in the art and an artisan can refer to various pharmacologic references for guidance. For example, Modern Pharmaceutics, Banker & Rhodes, Marcel Dekker, Inc. (1979); and Goodman & Gilnan's The Pharmaceutical Basis of Therapeutics, 6th Edition, MacMillan Publishing Co., New York (1980) can be consulted. 103021 The polymers and oligomers can be formulated for parenteral administration by injection, e.g., by bolus injection or continuous infusion. The polymers and oligomers can be administered by continuous infusion subcutaneously over a period of about 15 minutes to about 24 hours. Formulations for injection can be presented in unit dosage form, e.g., in ampoules or in multi-dose containers, with an added preservative. The compositions can take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and can contain formulatory agents such as suspending, stabilizing and/or dispersing agents. [0303] For oral administration, the polymers and oligomers can be formulated readily by combining these compounds with pharmaceutically acceptable carriers well known in the art. Such carriers enable the compounds of the invention to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions and the like, for oral ingestion by a patient to be treated. Pharmaceutical preparations for oral use can be obtained by adding a solid excipient, optionally grinding the resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain WO 2004/082634 PCT/US2004/008155 - 123 tablets or dragee cores. Suitable excipients include, but are not limited to, fillers such as sugars, including, but not limited to, lactose, sucrose, mannitol, and sorbitol; cellulose preparations such as, but not limited to, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose, and polyvinylpyrrolidone (PVP). If desired, disintegrating agents can be added, such as, but not limited to, the cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate. [0304] Dragee cores can be provided with suitable coatings. For this purpose, concentrated sugar solutions can be used, which can optionally contain gum arabic, tale, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. Dyestuffs or pigments can be added to the tablets or dragee coatings for identification or to characterize different combinations of active compound doses. [0305] Pharmaceutical preparations which can be used orally include, but are not limited to, push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. The push-fit capsules can contain the active ingredients in admixture with filler such as, e.g., lactose, binders such as, e.g., starches, and/or lubricants such as, e.g., tale or magnesium stearate and, optionally, stabilizers. In soft capsules, the active compounds can be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols. In addition, stabilizers can be added. All formulations for oral administration should be in dosages suitable for such administration. [03061 For buccal administration, the polymer and oligomer compositions can take the form of, e.g., tablets or lozenges formulated in a conventional manner. [0307] For administration by inhalation, the polymers and oligomers for use according to the present invention are conveniently delivered in the form of an aerosol spray presentation from. pressurized packs or a nebulizer, with the use of a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, WO 2004/082634 PCT/US2004/008155 -124.

dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case of a pressurized aerosol the dosage unit can be determined by providing a valve to deliver a metered amount. Capsules and cartridges of, e.g., gelatin for use in an inhaler or insufflator can be formulated containing a powder mix of the compound and a suitable powder base such as lactose or starch. [0308] The polymers and oligomers can also be formulated in rectal compositions such as suppositories or retention enemas, e.g., containing conventional suppository bases such as cocoa butter or other glycerides. [0309] In addition to the formulations described previously, the polymers and oligomers can also be formulated as a depot preparation. Such long acting formulations can be administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection. [03101 Depot injections can be administered at about 1 to about 6 months or longer intervals. Thus, for example, the compounds can be formulated with suitable polymeric or hydrophobic materials (for ex ample as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt. [03111 In transdernal administration, the polymers and oligomers, for example, can be applied to a plaster, or can be applied by transdermal, therapeutic systems that are consequently supplied to the organism. [0312] The pharmaceutical compositions of the polymers and oligomers also can comprise suitable solid or gel phase carriers or excipients. Examples of such carriers or excipients include but are not limited to calcium carbonate, calcium phosphate, various sugars, starches, cellulose derivatives, gelatin, and polymers such as, e.g., polyethylene glycols. [0313] The polymers and oligomers can also be administered in combination with other active ingredients, such as, for example, adjuvants, protease inhibitors, or other compatible drugs or compounds where such combination is seen to be desirable or advantageous in achieving the desired effects of the methods described herein (e.g., controlling infection caused by harmful microorganisms, or treating hemorrhagic complications associated with WO 2004/082634 PCT/US2004/008155 - 125 heparin therapy.). For example, the polymers and oligomers of the present invention can be administered with other antibiotics, including, but not limited to, vancomycin, ciprofloxacin, merapenem, oxicillin, and amikacin. [0314] The following examples will serve to further typify the nature of this invention but should not be construed as a limitation in the scope thereof, which scope is defined solely by the appended claims. EXAMPLE 1 Synthesis of a Polyarnide Polyner The following protocol, illustrated in FIG. 8, was used to synthesize polyamide polymer XIa (FIG. 8). 2,6-Dinitro-4-t-butyl-phenyl(4-methyl)-benzenesulfonate (11) [0315] 2, 6-dinitro-4-t-butyl-phenol (80 mmol; 10) and tosyl chloride (80 mmol) were dissolved in 300 ml CH 2 Cl 2 . Diisopropylethylamine (DIEA, 80 mmol) was added to the solution. The mixture was stirred at room temperature for 2 hours. The solution was washed with 10% citric acid, saturated aqueous NaCl (sat. NaCI), and dried with MgSO 4 . The solvent was removed under reduced pressure, and the product was obtained as a bright yellow solid in quantitative yield. 'Hl NMR (500MHz, CDC 3 ): 6 = 8.12(s,2H), 7.80(d,2H), 7.40(d,2H), 2.51(s,3H), 1.41(s, 911). ESI-MS: m/z: 417.2 (M+Na*) 2,6-Dinitro-4-t-butyl-l-( 2 -t-butoxycarbonylaminoethyl)sulfanylbenzene (12). [0316] Compound 11 (13 minol), 2-Boc-aminoethanthiol (16 mmol) and DIEA (13 mmol) were dissolved in 50 ml chloroform. The solution was stirred under nitrogen for 12 hours. The solution was washed with 0.5 M NaOH, 10% citric acid, sat. Na 2

CO

3 and sat. NaCl, and dried with MgSO 4 . The solution volume was reduced to 15 ml by rotary evaporation. After addition of 80 ml hexane the product crystallized as a bright yellow solid in. 94% yield. 'H WO 2004/082634 PCT/US2004/008155 -126 NMR (500 MHz, CDCl 3 ): 8 7.81(s,2H), 4.87(s,IH), 3.31(t,2H), 310(t,2H), 1.44(s,9H), 1.39(s,9H). ESI-MS: m/z: 422.4(M+Na+). 2,6-Diamino-4-t-butyl-1-(2-t-butoxycarbonylaminoethyl)sulfanylbenzene (13) [0317] Dinitro compound 12 (20 mmol) and sodium acetate (200 mmol) were added to 50 ml EtOH. The mixture was heated to 78 'C, and the solid dissolved completely. Stannous chloride dihydrate (200 mmol) was added to the solution, and the reaction mixture was stirred at 7 'C for 35 minutes. After removal of solvent under reduced pressure, the residue was dissolved in 800 ml EtOAc, and washed with 40% KCO 3 . The organic phase was dried, evaporated and the residue column chromatographed (SiO 2 ) and eluted with a gradient of CH2Cl2/MeOH from 100:1 to 95:5 to produce 13 in 93% yield. 1 H NMR. (500 MHz, CDCl 3 ): S 6.21(s,2H), 5.41(s,1H), 4.35(br,4H), 3.21(t,2H), 2.75(t,2H), 1.35 (s,9H), 1.24(s,9H). ESI-MS: m/z:34,0.5(MVH*) General method of polymerization [03181 Diamine 13 (0.1 mmol) was dissolved in 3 ml DMF. Isophthaloyl dichloride (0.1 mmol), triethylamine (0.2 mmol)) and NN dimethylethylenediamine (0.2/n nnnol) were added while stirring. The mixture was stirred under nitrogen for 18 hours. After the volume of solvent was reduced to 1 ml, water was added to precipitate the polymer. The polymer was collected and dried under vacuum. The Boc group was removed by treatment with trifluoroacetic acid (TFA, 3 ml) for 1 hour. The deprotected polymer was dried under vacuum overnight. EXAMPLE 2 Solid phase Synthesis of Polyamide Oligomers [03191 The following protocol, illustrated in FIG. 8, was used to synthesize polyamide oligomers XIb and Xle (FIG. 8).

WO 2004/082634 PCT/US2004/008155 -127 [0320] Fmoc-PAL-PEG-resin (0.1 mmol) was swelled in DMF; then the Fmoc was removed with 20% piperidine in DMF for 20 min. The oligomer was then built up by alternately coupling 10 equivalents of isophthalic acid or diamine 13. In each case the couplings were carried out in DMF using 10 equivalents each of 2-(IH-benzotriazole-1-yl)-1,1,3,3,-tetramethyluroniurm hexafluorophosphate (HBTU) and N-hydroxybenzotriazole hydrate (HOBt), and 20 equivalents of DIEA for 24 hours at room temperature. The oligomers were cleaved from the resin by treatment with TFA/anisole (95:5) for 1 hour. Pure oligomers were obtained by HPLC on a reverse phase C4 column, with a linear gradient from 30% to 80% solvent B in 50 minutes (solvent A, 0.1% TFA in water; solvent B, acetonitrile/water/TFA 900:99:1). MALDI-TOF MS: compound 2: 756.5 (M +H+), compound 3: ll25.6.(M+H t ). EX MPLE 3 General Method for Amide Polymerization [0321] An oven-dried flask is charged with diamine dissolved in dimethylsulfoxide (DMSO). To this solution is added an equimolar quantity of the diacid chloride which is freshly prepared by stirring the dicarboxylic acid with excess thionyl chloride for 2 hr prior to addition to the diamine solution. A catalytic amount of 4-dimethylaminopyridine and four-fold molar excess of triethylamine are added to the stirring mixture. The reaction is stirred at room temperature overnight wider positive N 2 pressure. The DMSO solution is poured into water and the solid polymer is recovered by filtration. The degree of polymerization is controlled by the addition of various molar amounts of a monofunctional amine. The molar amount of the monofunctional amine is determined by the Flory equation (G. Odian, Principles of Polymerization, John Wiley & Sons, Third Edition (1991) p.78-82).

WO 2004/082634 PCT/US2004/008155 - 128 EXAMPLE 4 General Method for Polyurea Polymerization [03221 A dried flask is charged with equal molar ratios of the diamine and the diisocyanate in DMSO. The reaction is stirred at room temperature overnight under positive N 2 pressure. The reaction is poured into water or other and the solid polymer is recovered by filtration. The degree of polymerization is controlled by the addition of various molar amounts of a monofunctional amine. The molar amount of the monofunctional amine is determined by the Flory equation. EXAMPLE 5 Antimicrobial Assays [0323] Antimicrobial assays are carried out in suspension using BHI medium inoculated with bacteria (106 CFU/ml) in a 96-well format. A stock solution of the polymers was prepared in DMSO/water and used to prepare a ten fold dilution series. Minimal inhibitory concentrations (MIC) were obtained by incubating the compounds with the bacteria for 18 hours at 37'C, and measuring cell growth by monitoring at 590 mn. Antibacterial data for various polyamide and polyurea oligomers and polymers are presented in FIG. 8 and FIG. 9. EXAMPLE 6 Hemolytic Activity [03241 The toxicity to mammalian cells of polymers and oligomers of the present invention was evaluated using human blood obtained from healthy WO 2004/082634 PCT/US2004/008155 -129 volunteers, anticoagulated with 0.1 volume of sodium citrate. The general procedure is as follows: Washed erythrocytes are suspended in either HEPES buffer, pH 7.4, containing 1 mM Mg2* and 1 mM Ca2* or in heated and unheated autologous serum obtained from clotted blood. Red cell agglutination is evaluated microscopically and red cell lysis is evaluated by measuring the amount of released hemoglobin spectroscopically. The effect of polymers on platelet function is studied by adding increasing concentrations of polymer to citrate-anticoagulated platelet-rich plasma. Platelet aggregation and secretion are then evaluated in a lumi-aggregometer (Chrono-Log). EXAMPLE 7 Struture-Activity Relationships for a Series of Arylamide Polyamide Oligomers [03251 A series of arylamide oligomers were designed, synthesized, and assayed for their ability to selectively lyse bacterial cells. Structure-activity relationships for antimicrobial efficacy and selectivity were then determined for the series of oligomers. [0326] The aiylamide oligomers were designed, synthesized, and tested for antimicrobial activity using the procedures as described above. The oligomers were also assayed for their ability to lyse mammalian cells by measuring hemolysis of human erythrocytes following one hour incubation in the presence of compound (Liu, D., and DeGrado,W.F., J. Amer. Chem. Soc., 123:7553-7559 (2001). HC 50 values represent the concentration of compound that results in 50% hemoglobin release. The assay results are presented in Table 1.

WO 2004/082634 PCT/US2004/008155 -130 Table 1. Arylamidce structure - activity rtelationships Oligomer Compound MW MIC E. HG 5 0 No. COiE RBC ___ __ ___ __ ___ __ __---------- ___ __ __ g___ (J~/M ) (pgg/ml) 1 '-6000 7,5--15 1 50 H H N, N, /10 2 '-6000 125 >200 N N A 0 A H 2 3 -6000 >200 H H NN ~A A~)10 r4 ~ -6000 >500 >500 NH HHF N N 0 WO 2004/082634 PCT/US2004/008155 - 131 5 779 25 >200 0 0 0 6 921 6 715 HNH2 NH2 [0327] Many of the compounds synthesized initially were highly efficacious against bacteria but also had high hemolytic activity. However, it was found that selectivity could be improved while maintaining potent antimicrobial activity by decreasing the repeat length and modulating the positive charge through end-group substitutions (Table 1). Beginning with an arylamide oligomer having a repeat length of n=10 (Molecular Weight (MW) approximately 6000 Daltons), the tert-butyl analogue (compound 1) had relatively potent activity against E-coli but significant hemolytic activity. A reduction in hydrophobicity of the R group (compounds 2 and 3) or neutralization of the positive charge (compound 4) significantly reduced activity against both . coli and erythrocytes. By reducing the chain length to n = 2 (MW 779 Daltons) and increasing the positive charge at the end-groups (compound 5), moderate antimicrobial activity was restored without significant hemolytic activity. A further modification of the positive charge at the end-groups (n= 2, MW 921 Daltons) resulted in a highly potent and selective oligomer (compound 6).

WO 2004/082634 PCT/US2004/008155 -132 EXAMPLE 8 Structure-Activity Relationships for a Series of Salicylamide Polyamide Oligomers [0328] A series of salicylamide oligomers were designed, synthesized, and assayed for their ability to selectively lyse bacterial cells. Structure-activity relationships for antimicrobial efficacy and selectivity were then determined for the series of oligomers. [0329] The salicylamide oligomers were designed, synthesized, and tested for antimicrobial activity as described above. The oligomers were also assayed for their ability to lyse mammalian cells by measuring hemolysis of human erythrocytes following one hour incubation in the presence of compound (Liu, D., and DeGrado, W.F., J. Amer. Chen. Soc. 123:7553-7559 (2001)). HCo values represent the concentration of compound that results in 50% hemoglobin release. The assay results are presented in Table 2. [0330] The structure-activity relationship for compounds in this salicylamide series showed the strong effect of chain length on antimicrobial activity and hydrophobicity of the end group on hemolytic activity (Table 2). For the salicylamide compounds having a leucine apolar group on the salicylic acid (compounds 1-3), a minimum chain length of 4 was required for antimicrobial activity. This chain length dependence may reflect a limit size requirement that is needed for accessing and disrupting the bacterial cell membrane. For similar salicylamides having a leucine apolar group (compounds 4-9), modification of the charge on the polar endgroup did not significantly affect antimicrobial activity but has a strong impact on hemolytic activity. The structure-activity relationship was used to design and synthesize two highly potent salicylamide compounds having no appreciable hemolytic activity (Compounds 6 and 7, Table 2).

WO 2004/082634 PCT/US2004/008155 -133 Table 2. Salicylamide structure-activity relationships Oligomer n X Com- MW MIC: E- HC50 pound coli RBC _____ pg/ml p gm l/mlI 2 1 599 >60 >200 N N 3 2 890 >500 >200 0 4 NH 3 1181 30 ->200 00 H 0 4 Leu 4 20 >200 HX N NH2 5 Leu 5 20 >200 H o 4 Leu 6 12 >200 NXN H O N H2 5 Leu 7 12 >200 H 4 Leu 8 12 35 N H 5 Leu 9 12 8 H2N N EXAMPLE 9 Antiviral Activity of Oligoners [03311 Three oligomers were synthesized as described above and tested for their ability to inhibit HIV replication in cell culture (Table 3, FIG. 12, and FIG. 13). Two viruses were used in the infection assays; NLHX or YU2 that use CXCR4 or CCR5 as co-receptors, respectively. U87/CD4/CCR5 or U87/CD4/CXCR4 cells were seeded in 48-well plates at 3 x 104 cells/well on the day prior to infection. Culture supernatants were removed from cells and replaced with pseudotyped luciferase reporter virus alone or pseudotyped WO 2004/082634 PCT/US2004/008155 -134 luciferase reporter virus and defensin-like compound at indicated final concentrations. Virus and compound were removed from cells approximately 16 hours post-infection, the cells were washed and then culture media was replenished. Cells were lysed and assayed for luciferase activity 3 days post infection. Results are presented as a percent of luciferase activity observed in the absence of compound. [03321 The results in Figure 12 demonstrate that Compound 1 (DL-III-71) inhibits the infection of the CCR5 tropic virus but has little effect on CXCR4 tropic virus infection. The inhibition observed at 200 ug/ml on both viruses is likely a non-specific effect due to apparent cytotoxicity of the compound. Compound 2 (DL-IV-1) has little inhibitory effect on infection of the CXCR4 tropic virus but inhibits the infection of the CCR5 tropic virus by 50% at the highest dose tested (Figure 13). No cytotoxicity was observed at any dose. [03331 Compound 3 (Compound E, FIG. 14) was tested against 3 viruses: NLHX, YU2 and VSV-2, a non-HIV based virus pseudotype (FIG. 14). A similar level of inhibition was observed with all three Env types indicating that Compound 3 blocks HIT infection and is not specific for HIV. No cytotoxicity w as evident at any concentration tested. 103341 These results demonstrate that the amnphiphilic oligomers effectively block HIV infection and their inhibitory properties for viral infection are not limited to HIV or HIV subtypes.

WO 2004/082634 PCT/US2004/008155 - 135 Table 3. Compound Structure No. HRR1 N NH2 R1 1N H 0 R21 R (DL-I-71) o n24 (NHC R2 E= H N s R1 2 H H H H - H H~ RI. NH NH R2 H2 3H H I H RI1 RI= f1~~~~~ R1 - ~ 0 R2= H0 EXAMPLE 10 Antifungal Activity of Oligoners (03351 Several different genera of fungi were tested for their sensitivity to a set of salicylamide and arylamide oligomers. Both non-filamentous (yeast) and filamentous fungi were tested and specific fungi that are associated with various types of human infections were chosen for the screen (Table 4). Five oligomers (3 arylamides and 2 salicylamides) which inhibit the growth of bacteria were tested for their antifungal activities (Table 5). The antifungal assays were done to determine the minimal inhibitory concentrations that WO 2004/082634 PCT/US2004/008155 -136 resulted in complete inhibition of growth (MIC 1 oo). All growth assays were done in a total of 1 ml volumes and growth was assessed by turbidity measurements. Other assay conditions are described in Table 6. Moderate inhibitory activity against Candida albicans and Trichophyton mentagrophytes was observed for all of the compounds tested (MIC = 100 ug/ml) and the growth of Aspergillus fumigatus was moderately inhibited by oligomers 2, 4, and 5 (Table 7). However, all of the tested oligomers were very active against Cryptococcus neoformans with 4 of the 5 compounds exhibiting highly potent growth inhibitory activity (<1 ug/ml). Surprisingly, the MIC values for C. neoforians were significantly more potent than the MICs for E. coli for 4 of the 5 compounds tested. These data indicate that the amphiphilic oligomers synthesized for antibacterial properties also possess significant antifungal activities which could be developed for both pharmaceutical and material applications.

WO 2004/082634 PCT/US2004/008155 -137 Table 4. Organism Clinical Features Yeast Candida albicans Mucosal infections (skin, GI, urinary tract, reproductive organs) ATCC 10231 Filamentous fungi Aipergillus Allergic disease, sinusitis bronchoputnonary infections and systemic wnigatus infections in immune-compromised individuals ATCC 1028 Cptococcus Opportunistic pathogen causing systemic infections in ininune neojormans compromised individuals ATCC 24067 Ttichopbyton Skin infections (dermatophytosis) mentagropytes ATCC 9533 Trichophyton Chronic infections of the skin and nails, most widely distributed Ivbrwa dermatophyte ATCC 10218 Control E. cob Verify compound integrity and actiAty, verify assay conditions ATCC 25922 WO 2004/082634 PCT/US2004/008155 - 138 Table 5. Oligomer Structure

NH

2 R2NH2 f2 2 H H H H NH= Rl -N N, N, N IN 2 0 0 R2 =H 2H R2 - NH 2 HH IH H R N N .- - N N, R1 R2 =H0 -- NHI 00 R I H 0RI= HT- N~ YN jaNH 2 o 0 4 2N 0 H N~ N NH-1 H0 Ic 0n4R2= -NH IRNnH4 WO 2004/082634 PCT/US2004/008155 - 139 Table 6. Method Candida [Aspergillus Cgptococcus TDicophyton Trichophyton E coi Conditions albicans fumgatus neoformans mientagrophytes rubmm (ATCC25922) Culture Fluid Potatoe Fluid Potatoe Fluid Nutrient Medium Sabouraud Dextrose Sabouraud Dextrose Sabouraud Broth Medium Broth Medium Broth Medium Incubation 20 hours 2 days 2 days 3 days 3 days 20 hours Time Incubation 37 0 C 28 C 37 C 28 C 28)C 37 "C Temp. Table 7. MICIO (ug/ml) Oligomer Caidida Aspeigillus Cgptococcus Tichophy'ton Ttichophyton, E. Coi albicans fii;gaus neofomians mentagtophytes mbmm (ATCC2592) 1 100 >100 0.3 100 >100 30 2 100 100 <0.1 100 >100 3 3 100 >100 30 100 >100 30 4 100 100 1 100 >100 100 5 100 100 1 100 >100 10 Control Amphotericin 0.1 1 0.1 0.3 1 Gentamycin E lT 3 WO 2004/082634 PCT/US2004/008155 -140 EXAMPLE 11 Ability of Oligomers to Inhibit the Anticoagulation Effects of Low Molecular Weight Heparin [03361 Several of the amphiphilic polymers and oligomers that were synthesized for antimicrobial applications were tested for their ability to inhibit the anticoagulation effects of heparin. The structures for compounds that were tested in the collaboration appear in FIG. 15. It was assumed that heparin-neutralizing activity would largely be dependent on the charge and charge distribution characteristics of the compounds rather than oil their hydrophobic qualities. [0337] Table 8 sunmmarizes the effects of increasing concentrations of the oligomers on the delay in clotting times of activated plasma caused by a fixed concentration of heparin. Many of the oligomers when tested at a concentration of 4. ug/ml significantly antagonized the delay in clotting time induced by 1 unit (0.2 ug/ml) of heparin (compounds 2, 3, 11-19). [03381 Dose-response data were collected for several of the compounds and heparin activity was antagonized at concentrations as low as 1.5 ug/ml of oligomer but not at 0.4 ug/ml. The near stoichiometric level of antagonism indicates high affinity binding between the oligomer and heparin molecules. [03391 Antagonism of the delay in clotting time caused by low molecular weight heparin (LMWH) was also investigated (Table 9). Compounds 2, 4, 11, 18 and 19 (boxed in Figure 16) when tested at 4.4 ug/ml significantly antagonized the delay in plasma clotting caused by LMWH (Innohep, 4.6 ug/ml final concentration). As with heparin, the near stoichiometric level of antagonism indicates a high affinity association between the effective oligomers and LMWII. A reduction in concentration of oligomer to 1.5 ug/ml resulted in a loss of the heparin-antagonizing activity. An indication of activity WO 2004/082634 PCT/US2004/008155 - 141 for compound 19 at 0.4 ug/mi is suspect because of the lack of a consistent dose-response effect. This initial survey has resulted in the identification of multiple oligomeric compounds of diverse structure (salicylamides, hydrazides and calixarenes) that potently inhibit the anticlotting activities of heparin and, most importantly, LMWH. [03401 An arylamide oligomer was tested for its LMWH-antagonizing activity by measuring clotting time in whole blood. This compound, Pmx10073 (Figure 17), is similar to the antimicrobial arylamides and was designed to antagonize LMWHM. Pmx10073 has a high positive-charge density but lacks the hydrophobic side chains present on the arylamide series of compounds shown to be important for antibacterial activity. A dose-response for antagonism of the delay in clotting time induced by 3 different concentrations of LMWH (LeoPhann, 1 ug/ml) is shown in Figure 18. Potent antagonism of LMWIH activity is observed at all three concentrations of LMWH. Furthermore, the concentration of Pmx10073 which causes a 50% inhibition of LMWH activity is approximately 1.5 ug/ml in the presence of I or 2 ug/ml LMWH and shifts to 3 ug/ml in the presence of 4 ug/ml LMWH. This stoichiometric response is clearly indicative of a high affinity association between Pmx 10073 and LMWH. [0341] With regard to the results of the previous studies, the results with Pmx10073 further demonstrate LMWH-antagonizing activity of yet another structural class of oligomers arylamides) and confirms activity against LMVWH produced by another manufacturer. One distinction is that the studies with Pmx10073 were done in whole blood. This is important in consideration of phannaceutical applications because it indicates that potential serun protein binding by the compound is not an issue that could impact biological activity in vivo. The utility for pharmaceutical applications is further supported by selectivity experiments. The concentrations of compound that are cytotoxic for mammalian cells were detennined and compared to efficacious concentrations. In hemolysis studies, using human red blood cells, 50% RBC lysis occurred at Pmx10073 concentrations of approximately 3100 ug/ml, a WO 2004/082634 PCT/US2004/008155 -142 selectivity margin ([50% antagonism of LMWH effects on clotting time]/[50% RBC lysis]) of over 1000 fold. This superior safety index argues that in vivo efficacy can be achieved at concentrations that are far below cytotoxic levels. These data strongly support the development of amphiphilic oligomers and their derivatives as antidotes for hemorrhagic complications associated with LMWH treatment.

WO 2004/082634 PCT/US2004/008155 - 143 Table 8: Effects of Oligomers on Clotting Times of Activated Plasma in the Presence of Heparin. Heparin I unit, 0.2 ugl1) Qiigomner (44.4 ugml)Q Trial #1 Trial #2 Trial #3 Trial #4 Average SD SE None 180.0 205.1 263.2 266.2 228.6 42.9 21.5 #1 153.6 15W6 136.1 151.6 150.0 9.7 4.9 #2 46.6 31.8 351 33.2 36.7 6.8 3.4 #3 38,7 34. 38.6 35.6 30.A 2.3 1.1 #4 31.6 29.6 29A 26.1 29,2 2.3. 11 #5 351 35.1 33.6 33.2 34.3 1.0 0,5 .. #6 36 297 33.9 29. 1. #7 27.1 32.6 30.6 31.1 30.4 2.3 12 8 366 34. 34.6 34.1 35, 1.1 0.6 #9 31.7 33.8 33,8 33.1 33.1 1.0 0.5 #10 40.7 35.6 36 . 33. 30.J 330 i6 #11 78.6 .71.6 61.6 60.1 68.0 8.7 4.4 Oligomer #1 170.0 104.2 221 192,1 263 W 2 6T,6 F02 672 816 TV! i.L _ 339 3 72:2 75.1 a12 92.6 9.3 9,0 45 _ '1T55_' 152 3 1_02.6 1 OS_ 18.0 9.0 14 1K2.5 149J 202.6 4 0 20.6 1IZ 6 i45.1 142.0 197.6 279.1 191.J 63.0 32.0 #1 1616 149.2 169.6 221.1 1729 334 16.7 #8 216. 1991 2432 >350 219.0 /0 >360 >350 O 113A 314.6 .450 >450 ii 45A 22 30A 59.7 4 .3 9 #12 702 83.1 901 100J O60 118 6A #13 1.2 882 94.1 1062 92.4 10. 6.3 #14 . h!14 40. 342, 31.8 35.5 4.5 2.6 #15 37.6 342 35. 31.7 34.7 2.4 1.2 #16 53.1 55.6 54.4 1.6 1.3 #HT 2566 222 23.9 2A 1.7 #18 57.6 57 #19 29.0 267 J 27.9 1.6 12 OlIgomer (A 1-m-l) ......... .. __ __ _ _ . - #14 42. - 39A 40.9 2.5 1.8 #16 397 j 42.7 412 2.1 1.5 #17 43.1 43.1 #19 432 37,1 40.2 4,3 3.1 Oligomor #14 306 >400 >400 #16 >400 >400 #17 >400 >400 #19 >400 >400 WO 2004/082634 PCT/US2004/008155 - 144 Table 9: Effects of Oligomers on Clotting Times of Activated Plasm~a in the Presence LMWKH 115~ *#4 42 L 8II.2 #0 12407 = :2: =.--i_____ WO 2004/082634 PCT/US2004/008155 - 145 EXAMPLE 12 Synthesis and Antibacterial Properties of a Second Series of Arylamide Oligomers [0342] A series of arylamide oligomers were designed, synthesized, and their antibacterial activities and selectivity determined. Antibacterial assays, hemolysis assays, and vesicle leakage experiments were carried out as described above, and as in Tew, G.N., et al., Proc. Natl. Acad. Sci. USA 99:5110 (2002) and Liu, D. et al., Angew. Chem. Int. Ed. Engl. 43:1158-1162 (2004). [0343] Triarylamide 1 (FIG. 18, 1, and compound 1 in Example 6) was selected as a template for optimizing the selectivity of a second arylamide series of antimicrobial oligomers. Various amino acid side chains were introduced into triarylamide 1 to produce compounds 2-12. Amino acid side chains were chosen because their amino groups would introduce an additional positively charged center, while theit sidechains would provide a ready source of diversity. Compounds 2 through 12 were synthesized by following the procedures outlined below and tested using antibacterial and hemolysis assoays. The results are presented in FIG. 18 and FIG. 19. [03441 Compounds 2-4, which have increasingly hydrophobic substituents, showed good activity against both Gram-negative and Gram-positive bacteria (MIC = 6 to 12 tg/ml versus both E. coli and S. aureus; FIG. 18). However, these compounds also showed toxicity towards human red cells, which increased as a function of the hydrophobicity of the sidechain. In contrast, the introduction of more polar substituents in compounds 5 through 8 led to oligomers with significantly lower toxicity towards erythrocytes. Compound 8, which features the dibasic Arg substituent, was the most active of the series. This compound displayed antibacterial activity similar to the potent magainin analogue MSI-78, and significantly greater selectivity. Given these results, an additional polar, positively charged, aminoalkyl substituent was introduced WO 2004/082634 PCT/US2004/008155 - 146 from. the central isophthaloyl group. This substitution enhanced the selectivity of the compounds without greatly altering their potency, irrespective of the amino acid component (FIG. 19). Indeed, the Arg-containing analogue, compound 12, did not lyse red cells at concentrations as high as 800 pM. [03451 To confirm the mechanism of action of this series of compounds, compound 8 to induce leakage of a fluorescent dye, calcein, from large unilamellar vesicles (LUV) composed of 90% stearolylolcoyl phosphatidycholine (SOPC) and 10% stearolyloleoyl-phosphatidylserine (SOPS) was determined. Lysis occurred in a concentration-dependent manner, beginning at concentrations as low as 0.625 tg/ml. With concentrations of oligomer near the MIC for inhibition of bacterial growth, the vesicle leakage was close to 90% at 300s. [03461 Because the amino acid sidechain appeared to influence the selectivity of the compounds, the relationship between the selectivity ratio (the ratio of the MIC for a given bacteria versus the IC 50 for lysing human erythrocytes) and the hydrophobicity for each compound was determined. Hydrophobicity was determined by estimating the n-octanol/water partitioning coefficient, Kow, a common measure of the hydrophobicity of a molecule. (See, for example, J. Sangster, Octanol- Water Partitioning Coefficients: Fundamentals and Physical Chemistry, John Wiley & Sons, Chichester, 1997; and C. Hansch, A. Leo, Exploring QSAR. Vol.1: Fundamentals and Applications In Chenistry and Biology, American Chemical Society, Washington, 1995). The atom/fragment approach was used to estimate Kom (W. M. Meylan, P. H. Howard, Perspectives in Drug Discovery and Design 2000, 19, 67). It was found that the logarithm of the selectivity ratio varied linearly with log Kow, [0347] Hydrophobic moment distributions were obtained for a few selected compounds from extensive molecular dynamics simulations of the arylamides. (See Liu, D. et al., Angew. Chem. Int. Ed. Engl. 43:1158-1162 (2004)). Inspection of the plots of the hydrophobic moment distributions for three of the compounds (not shown) revealed that the conformational ensemble for the Arg case (Compound 8) had the largest hydrophobic moment and therefore the WO 2004/082634 PCT/US2004/008155 - 147 most amphiphilic conformations. Visual inspection of configurations obtained from molecular dynamics simulations for compounds 2 and 8 revealed that the benzene rings on the two sides that the Arg groups of compound 8 were attached to were roughly perpendicular to the interface, with the t-butyl groups sliding into the n-octane phase and the polar side chains exposed into the water phase, a conformation that maximizes both polar and non-polar interactions. [0348] By varying the appending group so as to adjust the overall charge, hydrophobicity and hydrophobic moment, aiylamide oligomers with both good activity and selectivity were obtained. [0349] The oligomers in this Example were synthesized according to the following synthetic schemes and protocols.

WO 2004/082634 PCT/L1S2004/0081 55 - 148 13 144 is 4 & rtjJj0 VE1 WO 2004/082634 PCT/L1S2004/008155 -149 MADn, pl% 4Y THP MCC 17 MA lion I~ m l0* hJMPOH -I-i 71* >up WO 2004/082634 PCT/US2004/008155 -150 Schemae4 ee [0350] 2,6-Dinitro-4-t-b utyl-phenyl(4-methyl)-benzen esulfon ate (13). 2, 6 di-nitro-4-t-butyl-phenol (80 mimol) and tosyl chloride (80 mmiol) were dissolved in 300 ml CH2,C12. Diisopropylethylamine (DIEA, 80 mmol) was added to the solution. The mixture was stirred at room temperature for 2 hours. The solution was washed with 10% citric acid, saturated aqueous NaCl, and dried with MgSO4. The solvent was removed under reduced pressure, and the product was obtained as a bright yellow solid in quantitative yield. 1H NMR (500MHz, CDCL3): 8 = 8.12 (s, 2H), 7,80 (d, 2H), 7.40 (d, 2H), 2,51(s, 3H), 1.41(s, 9H). ESI-MS: m/z (M+Na+): 417.07 called) , 417.2 (found). [03511 2,6-Dinitro-4-t-butyl-1-(2-t-butoxycarbonylaminoethyl)-sulfanyl benzene (14). Compound 1 (13 mmol), 2-Boc-am-inoethanthiol (16 mm-ol) and WO 2004/082634 PCT/US2004/008155 -151 DIEA(13 mmol) were dissolved in 50 ml chloroform. The solution was stirred under nitrogen for 12 hours. The solution was washed with 0.5 M NaOH, 10% citric acid, sat. Na 2

CO

3 and sat. NaCl, and dried with MgSO 4 . The solution volume was reduced to 15 ml by rotary evaporation. The product crystallized as a bright yellow solid after addition of 80 m1 hexane. Yield: 94%. 1 H N

T

MR (500 MHz, CDCL 3 ): 8 = 7.81(s, 2H), 4.87(s, 1H), 3.31(t, 2F), 3.10(t, 2H), 1.44 (s, 9ff), I .39(s, 9B:). ESI-MS: m/z(M+Na+): 422.45 (calcd), 422.4 (found). [0352] 2,6-Diamino-4-t-butyl-1-(2-t-butoxycarbonylaminoethyl)sulfanyl benzene(15). Dinitro compound 2(20 mmol) and sodium acetate (200 mmol) were added to 50 ml EtOH. The mixture was heated to 78 *C, and the solid dissolved completely. SnCl 2 - 2H20 (200 mnol) was added to the solution, and the reaction mixture was stirred at 78 C for 35 minutes. After removal of solvent under reduced pressure, the residue was dissolved in 800 ml EtOAc, and washed with 40% KCO 3 . The solvent was reduced by rotary evaporation, and the product was purified by column chromatography (silica gel,

CH

2

C

2 /MeOH 100:1 to 95:5). Yield: 93%. 'H. NIR (500 MHz, CDCl 3 ): 8 = 6.21(s, 2H), 5.41(s, 1H), 4.35(br, 4H), 3.21(t, 2H), 2;75(t, 2H), 1.35(s, 9H1), 1.24(s, 9H). ESI-MS: m/z (MH): 340.51(calcd), 340.5(found). Synthesis of diamine 16 and 1 [0353] Diamine 15 (5 rnnnol) was dissolved in 50 mL CH 2 CL2 with DIEA. (10 mmol). Isophthaloyl dichloride (2.3 mmol) was dissolved in 10 mL

CH

2 Cl 2 /DMF (4:1) and was added dropwise to the diamine solution under argon, The addition was finished in one hour. The mixture was stirred overnight. Solvent was removed using a rotovap. The product was purified by column chromatograph (silica gel, Hexane/EtOAc 2:1 to 1:1).Yield 60%. 1H NMR (500 MHz, CDC 3 ): - = 9.69 (s, 211), 8.57 (s, 111), 8.19 (d, 2H), 8.18 (s, 2H), 7.70 (t, 1H), 6.61 (s, 2H), 5.22 (b, 2H), 4.47 (b, 4H), 3.25 (in, 4H), 2.83 (t, 4H), 1.34 (s, 36H). MALDI-MS: m/z (MNa*): 832.08 (calcd), 831.26(found). The Boc group of 16 was removed by treatment with WO 2004/082634 PCT/US2004/008155 - 152 50%TFA/CH 2

CL

2 to give compound 1. MALDI MS: m/z (MW) 608.86 (calcd), 609.26 (found). [03541 Dimethyl 5-(((2-((t-butyloxy)carbonyl)amino)ethoxy)benzene-1,3 dicarboxylate (17). (See D. L. Boger, et aL, Bioorg. Med. Chen. 1998, 6, 1347-1378). [0355] To a solution of dimethyl 5-hydroxy isophthalate(5g, 23.33nimol), PPh 3 (6.73g, 25.66mmo1), and t-butyl N-(2-hydroxyethyl)carbamate (4.05m1, 25.66mmol) in dry THF(60ml) was added diethyl azodicarboxylate(11 .64m1, 25.66mmol; 40% in toluene) dropwise at 0*C, The resulting mixture was warmed to room temperature and stirred for 24hrs. The solvent was evaporated and the residue was dissolved with EtOAc. The organic layer was washed with H20, saturated NaCI(aq) and dried with Na2SO 4 . The solution was filtered and concentrated. The residue was purified by column chromatography (pet. Ether/Et 2 O 5:3) to give compound 17 (5,41g, 71%). 1H NMVIR(500MHz, CDC 3 ) :8 1.43(s, 9H), 3.54(m, 2H), 3.92(s, 61H), 4.08(t, 21H), 5.01(s, 1H), 7.71(s, 2H), 8.26(s, IH). Electrospray ionization-MS: m/z (M+Na ): 376.1372 called) , 376.1363 (found). [0356] 5-(((2(t-butyloxy)carbonyl)amino)ethoxy)benzene- 1,3-dicarboxylic acid (18). [03571 To a solution of compound 17(1.66g, 4.70mmol) in MeOH/THF(10ml:10ml) was added 2N LiOH(9.28m1, 18.80ml). The resulting mixture was stirred for 24hrs. The MeOH and THF was removed under reduced pressure. The aqueous solution was diluted with H20(20ml) and cooled down to 0 0 C and acidified to pH3 with 3N HCI. The white precipitate was filtered and washed with H20. Compound 18(l.46g, 96%) was obtained without further purification (TLC indicated it is pure compound). 'H NMR.(500MHz, DMSO-d 6 ): 8 1.37(s, 9H), 3.32(m, 2H), 4.08(t, 2H), 6.98(t, 1H), 7.64(s, 2H), 8.07(s,1H), 13.23(s, 2H). Electrospray ionization-MS: m/z (MNa*): 348.1059 called) , 348.1062 (found).

WO 2004/082634 PCT/US2004/008155 - 153 Synthesis of diamine 19 and 9. [0358] To a solution of diacid compound 18 (200mg, 0.615mmol) in dry THF(10ml) was added pyridine(149p1, 1.845mmol) and DMF(catalytic amount), The resulting mixture was cooled down to 0 0 C and then oxalyl chloride(164pl, 1.845mmol) was added dropwise. After stirring for 45mm at room temperature, the solvent, excess oxalyl chloride, and pyridine were removed under vacuum to give the crude acyl chloride which was directly used in the following without further purification. To a solution of diamine compound(630mg, 1.845mmol), Et 3 N(5 14111, 3.69mmol), and DMAP(7.5mg,0062mmol) in dry CH 2

CI

2 (10ml) was added the crude acyl chloride in CH 2

C

2 (20ml) dropwise for 2hrs. After a total of 7hrs, the solvent was removed and then the residue was dissolved in EtOAc and washed with saturated NaHC0 3 (aq) and saturated NaCl(aq). After drying on Na 2

SO

4 , the organic layer was filtered and concentrated under reduced pressure. The residue was purified by column chromatography(Hexane/EtOAc 2:1) to give diamine 19 (369mg, 62%). 1H NIMR (500MHz, DMSO-d 6 ) :6 1.25-1.29(36H), 1.38(s, 9H), 2.63(t, 4H), 3.00(br d, 4H), 3.38(m, 4H), 4.15(t, 4H), 5.50(s, 4H), 6.70(s, 21), 6.85(s, 2H), 7.05(s, 1H), 7.27(s, 2H), 7.70(s, 211), 8.10(s, 1H), 9.84(s, 2H). Electrospray ionization-MS: m/z (MNa*) 990.4809 (calcd), 990.4828 (found). The Boc group of 19 was removed by treatment with 50%TFA/CH 2 Cl 2 to give compound 9. Electrospray ionization-MS: m/z (MH) 667.3417 called) , 668.3447 (found). General method to synthesize amino acid appended arylamides (2-8, 11, 12). (See D.T.S. Rijkers, et al., Tetrahedron 1995, 51, 11235-11250) [0359] Boc amino acids (Boc protecting group for both a-amino and side chain amino groups) were used for the synthesis except arginine. Fmoc D-Arg (pbf) was used for synthesis of 8 and 12. Diamine 16 or 19 (2mmol) and protected amino acid (8 mmol) were dissolved in 30 mL anhydrous pyridine and was cooled down to -30 C with dry ice/acetone. POCL 3 (8mmol) was WO 2004/082634 PCT/US2004/008155 -154 added dropwise to the solution in 0.5 hour. The mixture was stirred for another 0.5 hour before the reaction was quenched with 50 mL ice water. The product was extracted with EtOAc (50 ml x 1, 30 ml x 3), washed with 10% citric acid (50 mL x 1), sat. NaHCO 3 (50 mL x 3) and sat. NaCl (50 mL x 1). The protected product was purified by column chromatograph (silica gel, CH2Cl 2 /MeOH 100:1 to 98:2). Boc and pbf groups were removed by treatment of 20 ml TFA/TIS (95:5) for one hour. Fmoc group was removed by 30 mL 20% piperidine for one hour. The product was concentrated to an oil. Water (0.1% HCI, 100 mL) was added to the oil. The aqueous solution was washed with ether (50 mL x 4) and dried on a lyophilizer. Further purification was carried out on HPLC. Yield 60%. MALDI-MS: m/z (MW): 2:835.18 (calcd), 835.33(found); 3:903.21 (calcd), 903.38 (found); 4:981,28 (calcd), 981.44(found); 5:779.07 (calcd), 779.26 (found); 6:831.15 called) , 831,35 (found); 7:865.21 (caled), 865.44 (found); 8:921.23 called) , 921.91(found); 11:962.48 called) , 962.48 (found); 12:980.54 (calcd), 980.54 (found). Synthesis of 10 [0360] To a solution of arylamide compound 19 (37mg, 0.038nnol) and DMAP(cat.) in dry CH 2 C1 2 (3ml) was added pyridine(31pl, 0.38mmol). The resulting mixture was cooled down to 0 C and treated with acetic anhydride(36pl, 0.38mmol) and then warmed to room temperature. After stirring for 12hrs, the solvent was removed under reduced pressure. The residue was dissolved with EtOAc and washed with 10% citric acid(aq), saturated NaHJCO 3 (aq), and saturated NaCl(aq). After drying on Na 2

SO

4 , the organic layer was filtered and concentrated under reduced pressure. The residue was purified by column chromatography(Hexane/EtOAc 1:1.5 to 1:2) to give diacetylated compound(31mg, 78%). [03611 The Boc group of diacetylated compound was removed by treatment with 50%TFA/CH 2

CI

2 to give compound 10. Electrospray ionization-MS: m/z (MH): 752.3628 (calcd), 752.3661 (found).

WO 2004/082634 PCT/US2004/008155 - 155 [03621 Having now fully described this invention, it will be understood to those of ordinary skill in the art that the same can be performed within a wide and equivalent range of conditions, formulations, and other parameters without affecting the scope of the invention or any embodiment thereof. All documents, e.g., scientific publications, patents, patent applications and patent publications recited herein are hereby incorporated by reference in their entirety to the same extent as if each individual document was specifically and individually indicated to be incorporated by reference in its entirety. Where the document cited only provides the first page of the document, the entire document is intended, including the remaining pages of the document.

Claims (65)

1. A method of treating a microbial infection in an animal in need thereof, said method comprising administering to the animal an effective amount of a pharmaceutical composition comprising an oligomer of Formula I: R 1 [x-A 1 -y-x-A2-Y-1m-R 2 (I) or an acceptable salt or solvate thereof, wherein: x is NR', -N(R 8 )N(R 8 )-, 0, or S; y is C=O, C=S, O=S=0, or -C(=0)C(=0) and R8 is hydrogen or alkyl; A 1 and A 2 are independently optionally substituted arylene or optionally substituted heteroarylene, wherein: (i) A 1 and A 2 are independently optionally substituted with one or more polar (PL) group(s), one or more non-polar (NPL) group(s), or a combination of one or more polar (PL) group(s) and one or more non-polar (NPL) group(s); or (ii) A 1 is optionally substituted arylene or optionally substituted heteroarylene and A 2 is a C 3 to C 8 cycloalkyl or -(CH2)q-, wherein q is 1 to 7, wherein A 1 and A 2 are independently optionally substituted with one or more polar (PL) group(s), one or more non-polar (NPL) group(s), or a combination of one or more polar (PL) group(s) and one or more non-polar (NPL) group(s); or (iii) A 2 is optionally substituted arylene or optionally substituted heteroarylene, and A 1 is a C 3 to C 8 cycloalkyl or -(CH2)q-, wherein q is 1 to 7, wherein A 1 and A 2 are independently optionally substituted with one or more polar (PL) group(s), WO 2004/082634 PCT/US2004/008155 - 157 one or more non-polar (NPL) group(s), or a combination of one or more polar (PL) group(s) and one or more non-polar (NPL) group(s); R' is (i) hydrogen, a polar (PL) group, or a non-polar (NPL) group, and R 2 is -x-A1-y-R", wherein R" is hydrogen, a polar (PL) group, or a non-polar (NPL) group; or (ii) R 1 and R 2 are independently hydrogen, a polar (PL) group, or a non-polar (NPL) group; or (iii) R 1 and R 2 together are a single bond; NPL is a nonpolar group independently selected from the group consisting of -B(OR 4 ) 2 and -(NRI)qlNPL-UNPL-(CH2)pNPL-3")q2NPL -R4', wherein: R 3 , R 3 , and R 3 " are independently selected from the group consisting of hydrogen, alkyl, and alkoxy; R 4 and R 4 ' are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and heteroaryl, any of which is optionally substituted with one or more alkyl or halo groups; UNPL is absent or selected from the group consisting of 0, S, S(=0), S(=0) 2 , NR 3 , -C(=0)-, -C(=O)-N=N-NR 3 -, -C(=0)-NR 3 -N=N-, -N=N-NR 3 -, -C(=N-N(R 3 ) 2 )-, -C(=NR 3 )-, -C(=0)O-, -C(=0)S-, -C(=S)-, -0-P(=0) 2 0-, -R 3 0-, -R 3 S-, -S-C=N- and -C(=0) NR 3 -O- , wherein groups with two chemically nonequivalent tennini can adopt both possible orientations; the -(CH2)pNPL- alkylene chain is optionally substituted with one or more amino or hydroxy groups, or is unsaturated; pNPL is 0 to 8; q1NPL and q2NPL are independently 0, 1 or 2; PL is a polar group selected from the group consisting of halo, hydroxyethoxymethyl, methoxyethoxymethyl, polyoxyethylene, and -(NR )qlPL-UPL-(CH2)pPL- 5')q2PL-V,wherein: WO 2004/082634 PCT/US2004/008155 - 158 R 5 , R5', and R 5 " are independently selected from the group consisting of hydrogen, alkyl, and alkoxy; UPL is absent or selected from the group consisting of 0, S, S(=0), S(=0) 2 , NR 5 , -C(=0)-, -C(=0)-N=N-NR 5 -, -C(=O)-NR 5 -N=N-, -N=N-NR 5 -, -C(=N-N(R)2)-, -C(=NR 5 )-, -C(=O)O-, -C(=O)S-, -C(=S)-, -0-P(=0) 2 0-, -R50-, -RiS-, -S-C=N- and -C(=0) NR 5 -0-, wherein groups with two chemically nonequivalent termini can adopt both possible orientations; V is selected from the group consisting of nitro, cyano, amino, hydroxy, alkoxy, alkylthio, alkylamino, dialkylamino, -NH(CH 2 )pNH 2 wherein p is 1 to 4, -N(CH 2 CH 2 NH 2 ) 2 , diazamino, amidino, guanidino, guanyl, semicarbazone, aryl, heterocycle and heteroaryl, any of which is optionally substituted with one or more of amino, halo, cyano, nitro, hydroxy, -NH(CH 2 )pNH 2 wherein p is 1 to 4, -N(CH 2 CH 2 NH 2 ) 2 , amidino, guanidino, guanyl, aminosulfonyl, aminoalkoxy, aminoalkythio, lower acylamino, or benzyloxycarbonyl; the -(CH2)pPL- alkylene chain is optionally substituted with one or more amino or hydroxy groups, or is unsaturated; pPL is 0 to 8; qlPL and q2PL are independently 0, 1 or 2; and m is 1 to about 20; and a pharmaceutically acceptable carrier or diluent.

2. The method of claim 1, wherein x is NR 8 and y is C=0.

3. The method of claim 1, wherein A 1 is substituted arylene, A 2 is -(CH2)q, and q is 1 or 2, and wherein one of A 1 and A 2 is substituted with one or more polar (PL) group(s), and the other of A 1 and A 2 is substituted with one or more non-polar (NPL) group(s). WO 2004/082634 PCT/US2004/008155 -159

4. The method of claim 3, wherein A 1 is substituted m-phenylene and q is 1, and wherein one of A 1 and A 2 is substituted with one polar (PL) group, and the other of A 1 and A 2 is substituted with one non-polar (NPL) group.

5. The method of claim 1, wherein A 2 is substituted arylene, A 1 is -(CH2)q-, and q is 1 or 2, and wherein one of A 1 andr A 2 is substituted with one or more polar (PL) group(s), and the other of A 1 and A 2 is substituted with one or more non-polar (NPL) group(s).

6. The method of claim 5, wherein A 2 is substituted m-phenylene and q is 1, and wherein one of A 1 and A 2 is substituted with one polar (PL) group, and the other of A 1 and A 2 is substituted with one non-polar (NPL) group.

7. The method of claim 1, wherein: x is NR 8 , y is C=O, and R 8 is hydrogen; A 1 is optionally substituted o-, m-, or p-phenylene and A 2 is -(CH2)q-, wherein q is 1, and wherein one of A 1 and A 2 is substituted with one or two polar (PL) group(s), and the other of A 1 and A 2 is substituted with one or two non-polar (NPL) group(s); or A 2 is optionally substituted o-, n-, or p-phenylene and A 1 is -(CH2)q-, wherein q is 1, and wherein one of A 1 and A 2 is substituted with one or two polar (PL) group(s), and the other of A 1 and A 2 is substituted with one or two non-polar (NPL) group(s); R' and R 2 are independently hydrogen, a polar (PL) group, or a non-polar (NPL) group; NPL is -(R)q1NPL-UNPL-(CH2)pNPL- 3")q2NPL -R 4 ', wherein: R 4 ' is selected from the group consisting of C 1 -C 10 alkyl, C 3 -C 18 branched alkyl, C 2 -Cio alkenyl, C 2 -C 10 alkynyl, and C 6 -C 10 aryl, any of which is optionally substituted with one or more alkyl or halo groups; WO 2004/082634 PCT/US2004/008155 -160 UNPL is absent or selected from the group consisting of NH, -C(=O)-, 0 and S; the -(CH2)pNpL- alkylene chain is optionally substituted with one or more amino groups; pNPL is 0 to 8; qlNPL and q2NPL are 0; PL is-(NR)qiPL-UPL-(CH 2 )pPL-(NR 5 )q 2 PL-V, wherein: UPL is absent or selected from the group consisting of 0, S, NH, and -C(=0); V is selected from the group consisting of amino, C 1 -C 6 alkylamino, -NH(CH 2 )pNH 2 wherein p is 1 to 4, -N(CH 2 CH 2 NH 2 ) 2 , diazamino, amidino, and guanidino; the -(CH 2 )ppL- alkylene chain is optionally substituted with one or more amino groups; pPL is 0 to 8; qlPL and q2PL are 0; and m is 4 or 5.

8. The method of claim 7, wherein A 1 is optionally substituted mn phenylene, A 2 is -(CH2)q-, q is 1, and wherein one of A 1 and A 2 is substituted with one polar (PL) group, and the other of A 1 and A 2 is substituted with one non-polar (NPL) group.

9. The method of claim 7, wherein A 2 is optionally substituted n phenylene, A 1 is -(CH2)q-, q is 1, and wherein one of A 1 and A 2 is substituted with one polar (PL) group, and the other of A 1 and A 2 is substituted with one non-polar (NPL) group.

10. The method of claim 9, wherein A 1 substituted with one non-polar (NPL) group, and A 2 is substituted with one polar (NPL) group. WO 2004/082634 PCT/US2004/008155 -161

11. The method of claim 1, wherein the oligomer is one of H H 0 H 0 H H2N I N I H HNH 2 0 z 0 l- 0 1- 0H 0 0 00 NH 2 NH 2 NH 2 NH 2 0 H 0 H 0 H0 H 2 N N N N N N N N NH 2 I H~ H 0 H H 0 o 0 H 0 H 00 H0H0 N NH N NH N NH N NH NH 2 NH 2 NH 2 NH 2

12. The method of claim 1, wherein the microbial infection is a bacterial infection, a fungal infection, or a viral infection.

13. A method of killing or inhibiting the growth of a microorganism, said method comprising contacting the microorganism with an effective amount of an oligomer of claim 1.

14. The method of claim 13, wherein the microorganism is a bacterial cell, a fungus, or a virus.

15. A method of providing an antidote to low molecular weight heparin overdose in an animal, said method comprising administering to the animal an effective amount of a pharmaceutical composition comprising an oligomer of claim 1.

16. A method of treating a microbial infection in an animal in need thereof, said method comprising administering to the animal an effective WO 2004/082634 PCT/US2004/008155 -162 amount of a pharmaceutical composition comprising an oligomer of Formula II: R'-[-x-A 1 -x-y-A 2 -y-]m-R2 or an acceptable salt or solvate thereof, wherein: x is NR, 0, S, -N(R 8 )N(R)-, -N(R 8 )-(N=N)-, -(N=N)-N(R)-, -C(R 7 R')NR 8 -, -C(RR')O-, or -C(R 7 R 7 ')S-; and y is C=0, C=S, O=S=0, -C(=0)C(=0)-, C(R 6 R 6 )C=O or C(R 6 R6')C=S; or x and y are taken together to be pyromellitic diimide; wherein R 8 is hydrogen or alkyl; R7 and R 7 ' are independently hydrogen or alkyl, or R 7 and RT together are -(CH 2 )p-, wherein p is 4 to 8; and R 6 and R 6 ' are independently hydrogen or alkyl, or R 6 and R 6 ' together are (CH 2 ) 2 NR1 2 (CH 2 ) 2 , wherein R 12 is hydrogen, -C(=NDCH 3 or C(=NH)-NH 2 ; A 1 and A 2 are independently optionally substituted arylene or optionally substituted heteroarylene, wherein A 1 and A 2 are independently optionally substituted with one or more polar (PL) group(s), one or more non-polar (NPL) group(s), or a combination of one or more polar (PL) group(s) and one or more non-polar (NPL) group(s); R 1 is (i) hydrogen, a polar group (PL), or a non-polar group (NPL), and R 2 is -x-A 1 -x-R', wherein A 1 is as defined above and is optionally substituted with one or more polar (PL) group(s), one or more non-polar (NPL) group(s), or a combination of one or more polar (PL) group(s) and one or more non-polar (NPL) group(s); or (ii) hydrogen, a polar group (PL), or a non-polar group (NPL), and R2 is -x-A'-x-Rl, wherein A' is aryl or heteroaryl and is optionally substituted with one or more polar (PL) group(s), one or more WO 2004/082634 PCT/US2004/008155 - 163 non-polar (NPL) group(s), or a combination of one or more polar (PL) group(s) and one or more non-polar (NPL) group(s); (iii) -y-A 2 -y-R2, and R 2 is hydrogen, a polar group (PL), or a non-polar group (NPL); or (iv) -y-A' and R 2 is -x-A', wherein A' is aryl or heteroaryl and is optionally substituted with one or more polar (PL) group(s), one or more non-polar (NPL) group(s), or a combination of one or more polar (PL) group(s) and one or more non-polar (NPL) group(s); or (v) R 1 and R 2 are independently a polar group (PL) or a non-polar group (NPL); or (vi) R 1 and R 2 together form a single bond; NPL is a nonpolar group independently selected from the group consisting of -B(OR 4 ) 2 and -(NR)qlNPL-UNPL (CH2)pNPL- 3")q2NPL -R 4 ', wherein: R 3 , R 3 ', and R 3 " are independently selected from the group consisting of hydrogen, alkyl, and alkoxy; R 4 and R 4 ' are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and heteroaryl, any of which is optionally substituted with one or more alkyl or halo groups; UNPL is absent or selected from the group consisting of 0, S, S(=0), S(=0) 2 , NR 3 , -C(=0)-, -C(=0)-N=N-NR 3 -, -C(=O)-NR 3 -N=N-, -N=N-NR 3 -, -C(=N-N(R) 2 )-, -C(=NR 3 )-, -C(=O)O-, -C(=0)S-, -C(=S)-, -0-P(=0) 2 0-, -R 3 0-, -R 3 S-, -S-C=N- and -C(=O)-NR 3 -0- , wherein groups with two chemically nonequivalent termini can adopt both possible orientations; the -(CH2)pNPL- alkylene chain is optionally substituted with one or more amino or hydroxy groups, or is unsaturated; pNPL is 0 to 8; qlNPL and q2NPL are independently 0, 1 or 2; WO 2004/082634 PCT/US2004/008155 -164 PL is a polar group selected from the group consisting of halo, hydroxyethoxymethyl, methoxyethoxymethyl, polyoxyethylene, and -- N )qlPL-UPL-(CH2)pPL_ ')q2PL-V, wherein: R 5 , R 5 , and R 5 " are independently selected from the group consisting of hydrogen, alkyl, and alkoxy; UPL is absent or selected from the group consisting of 0, S, S(=0), S(=0) 2 , NR', -C(=0)-, -C(=O)-N=N-NR 5 -, -C(=O)-NR 5 -N=N-, -N=N-NRs-, -CQ=N-N(R 5 ) 2 )-, -C(=NR 5 )-, -C(=0)O-, -C(=0)S-, -C(=S)-, -0-P(=0) 2 0-, -R 5 O-, -R 5 S-, -S-C=N- and -C(=0)-NR5-0- , wherein groups with two chemically nonequivalent termini can adopt both possible orientations; V is selected from the group consisting of nitro, cyano, amino, hydroxy, alkoxy, alkylthio, alkylamino, dialkylamino, -NH(CH 2 )pNH 2 wherein p is 1 to 4, -N(CH 2 CH 2 NH 2 ) 2 , diazamino, amidino, guanidino, guanyl, semicarbazone, aryl, heterocycle and heteroaryl, any of which is optionally substituted with one or more of amino, halo, cyano, nitro, hydroxy, -NH(CH 2 )pNH 2 wherein p is 1 to 4, -N(CH 2 CH 2 NH 2 ) 2 , amidino, guanidino, guanyl, aminosulfonyl, aminoalkoxy, aminoalkythio, lower acylamino, or benzyloxycarbonyl; the -(CH2)pPL- alkylene chain is optionally substituted with one or more amino or hydroxy groups, or is unsaturated; pPL is 0 to 8; qlPL and q2PL are independently 0, 1 or 2; and m is 1 to about 20; and a pharmaceutically acceptable carrier or diluent.

17. The method of claim 16, wherein: x is NR8, y is C=O, and R 8 is hydrogen or alkyl; WO 2004/082634 PCT/US2004/008155 - 165 A 1 and A 2 are independently optionally substituted o-, M-, or p-phenylene or pyrimidinylene, wherein A 1 and A 2 are independently optionally substituted with one or more polar (PL) group(s), one or more non polar (NPL) group(s), or a combination of one or more polar (PL) group(s) and one or more non-polar (NPL) group(s); R 1 is hydrogen, a polar group (PL), or a non-polar group (NPL), and R 2 is -x A 1 -x-Rl, wherein A 1 is as defined above and is optionally substituted with one or more polar (PL) group(s), one or more non-polar (NPL) group(s), or a combination of one or more polar (PL) group(s) and one or more non-polar (NPL) group(s); NPL is -(NR 3 )q lNPLUNPL-(CH 2 )pNPL-3(NR")q 2 NPL -R 4 ', wherein: R 3 , R 3 ', and R 3 "' are independently selected from the group consisting of hydrogen, C 1 -C 6 alkyl, and C 1 -C 6 alkoxy; R 4 ' is selected from the group consisting of hydrogen, C 1 -C 10 alkyl, C 3 C 18 branched alkyl, C 2 -C 10 alkenyl, C 2 -C 10 alkynyl, C 3 -C 8 cycloalkyl, C 6 -C 10 aryl, and heteroaryl, any of which is optionally substituted with one or more C 1 -C 6 alkyl or halo groups; UNPL is absent or selected from the group consisting of 0, S, NH, C(=0)-, -C(=0)-N=N-NH-, -C(=O)-NH-N=N-, -N=N-NH-, C(=N-N(R 3 ) 2 )-, -C(=NR 3 )-, -C(=0)O-, -R 3 S- and -R 3 0-, wherein groups with two chemically nonequivalent termini can adopt both possible orientations; the -(CH2)pNPL- alkylene chain is optionally substituted with one or more amino or hydroxy groups; pNPL is 0 to 6; qlNPL and q2NPL are 0; PL is -(NR)qlPL-UPL-(CH2)pPL-(NR )q2PL-V, wherein: R 5 , R 5 , and R 5 " are independently selected from the group consisting of hydrogen, C 1 -C 6 alkyl, and C 1 -C 6 alkoxy; WO 2004/082634 PCT/US2004/008155 - 166 UPL is absent or selected from the group consisting of 0, S, NH, C(=0)-, -C(=0)-N=N-NH-, -C(=0)-NH-N=N-, -N=N-NH-, -C(=N-N(R) 2 )-, -C(=NR 5 )-, -C(=0)O-, -RO-, and -R 5 S-, wherein groups with two chemically nonequivalent termini can adopt both possible orientations; V is selected from the group consisting of nitro, cyano, amino, hydroxy, C 1 -C 6 alkoxy, C 1 -C 6 alkylthio, CI-C 6 alkylamino, C 1 -C 6 dialkylamino, -NH(CH 2 )pNH 2 wherein p is 1 to 4, -N(CH 2 CH 2 NH 2 ) 2 , diazamino, amidino, guanidino, guanyl, semicarbazone, C 6 -C 10 aryl, heterocycle, and heteroaryl; the -(CH2)ppL- alkylene chain is optionally substituted with one or more amino or hydroxy groups; pPL is 0 to 6; q1PL and q2PL are 0; and m is I to 10.

18. The method of claim 16, wherein x is 0 and y is C=0.

19. The method of claim 16, wherein x is -N(R 8 )N(R 5 )-, y is C=0, and R' is hydrogen.

20. The method of claim 16, wherein A1 and A 2 are independently optionally substituted o-, in-, orp-phenylene.

21. The method of 20, wherein A 1 and A 2 are independently optionally substituted n-phenylene.

22. The method of claim 16, wherein one of A 1 and A 2 is o-, in-, or p phenylene, and the other of A 1 and A 2 is heteroarylene. WO 2004/082634 PCT/US2004/008155 - 167

23. The method of claim 22, wherein one of A 1 and A 2 is n-phenylene, and the other of A 1 and A 2 is pyrimidinylene.

24. The method of claim 16, wherein A 1 and A 2 are independently optionally substituted arylene or optionally substituted heteroarylene, and one of A 1 and A 2 is substituted with one or more polar (PL) group(s) and one or more nonpolar (NPL) group(s) and the other of A 1 and A 2 is unsubstituted.

25. The method of claim 24, wherein A 1 and A 2 are optionally substituted m-phenylene, and one of A 1 and A 2 is substituted with one polar (PL) group and one nonpolar (NPL) group and the other of A 1 and A 2 is unsubstituted.

26. The method of claim 16, wherein R 1 is hydrogen, a polar group (PL), or a non-polar group (NPL), and R 2 is -x-A 1 -x-Rl, wherein A, is as defined in claim 16 and is substituted with one or more polar (PL) group(s), one or more non-polar (NPL) group(s), or a combination of one or more polar (PL) group(s) and one or more non-polar (NPL) group(s).

27. The method of claim 26, wherein R 1 is a polar (PL) group and R 2 is -x-A 1 -x-R, where A 1 is substituted with one or two polar (PL) group(s) and one non-polar (NPL) group.

28. The method of claim 16, wherein: NPL is -(NRI)qlNPL-UNPL~(CH2)pNPL- 3")q2NPL-R4', and R 3 , R 3 ', R 3 "', R 4 ' UNPL, pNPL, qlNPL and q2NPL are as defined in claim 16.

29. The method of claim 28, wherein R 3 , R?, and R 3 " are independently hydrogen, C 1 -C 6 alkyl, or C 1 -C 6 alkoxy.

30. The method of claim 29, wherein R 3 , R3', and R 3 are hydrogen. WO 2004/082634 PCT/US2004/008155 - 168

31. The method of claim 28, wherein R 4 ' is C 1 -C 10 alkyl, C 3 -C 1 8 branched alkyl, C 2 -C 10 alkenyl, C 2 -C 10 alkynyl, or C 6 -C 10 aryl.

32. The method of claim 31, wherein R4' is phenyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, or n-pentyl.

33. The method of claim 28, wherein UNPL is 0, S, NH, -C(=O)-, -C(=0)-N=N-N-H-, -C(=0)-NH-N=N-, -N=N-NH-, -C(=N-N(R3)2 -C(=NR 3 )-, -C(=0)O-, -R 3 S- or -R 3 0-.

34. The method of claim 33, wherein UNPL is -C(0)-.

35. The method of claim 33, wherein UNPL is absent.

36. The method of claim 16, wherein NPL is n-propyl, isopropyl, n-butyl, or tert-butyl.

37. The method of claim 28, wherein: pNPL is 0 to 2; and qlNPL and q2NPL are independently 0 or 1.

38. The method of claim 28, wherein the -(CH2)pNpL- alkylene chain in NPL is substituted with one or more amino groups.

39. The method of claim 16, wherein: PL is -- (NR')qlPL-UPL -(CH2)pPL-(NR")q2PL -V, and R', R", R 5 ", V, UPL, pPL, qPL and q2PL are as defined in claim 16.

40. The method of claim 39, wherein R 5 , R 5 , and R5" are independently hydrogen, C 1 -C 6 alkyl, or C 1 -C 6 alkoxy. WO 2004/082634 PCT/US2004/008155 -169

41. The method of claim 39, wherein UPL is 0, S, NI, -C(=O)-, -C(=0)-N=N-NH-, -C(=0)-NH-N=N-, -N=N-NH-, -C(=N-N(R5)2)-, -C(=NRi)-, -C(=0)O-, -R 5 S- or -R 5 0-.

42. The method of claim 41, wherein UPL is 0, S, -C(=0), or is absent.

43. The method of claim 39, wherein V is amino, C 1 -C 6 alkylamino, -NH(CH 2 )pNH 2 wherein p is 1 to 4, -N(CH 2 CH 2 NH 2 ) 2 , diazamino, amidino, or guanidino.

44. The method of claim 39, wherein pPL is 2 to 4, and qlPL and q2PL are 0.

45. The method of claim 39, wherein the -(CH2)ppL- alkylene chain in PL is substituted with one or more amino groups.

46. The method of claim 16, wherein m is I to about 5.

47. The method of claim 16, wherein m is 1, 2 or 3.

48. The method of claim 16, wherein: x is NR, y is C=0, and R 8 is hydrogen; A 1 and A 2 are independently optionally substituted m-phenylene, wherein (i) one of A 1 and A 2 is substituted with one polar (PL) group and one nonpolar (NPL) group and the other of A 1 and A 2 is unsubstituted; or (ii) one of A 1 and A 2 is substituted with one polar (PL) group and one nonpolar (NPL) group and the other of A 1 and A 2 is substituted with one or two polar (PL) group(s); R 1 is hydrogen or a polar group (PL), and R 2 is -x-A 1 -x-Rl, wherein A 1 is as defined above and is optionally substituted with one or more polar (PL) group(s), one or more non-polar (NPL) group(s), or a WO 2004/082634 PCT/US2004/008155 -170 combination of one or more polar (PL) group(s) and one or more non polar (NPL) group(s); NPL is --(NR)qiNPL-UNPL-(CH 2 )pNPL-NR3")q 2 NPL -R 4 ', wherein: R3, R 3 ', and R 3 " are independently selected from the group consisting of hydrogen, C 1 -C 6 alkyl, and C 1 -C 6 alkoxy; R 4 is selected from the group consisting of hydrogen, C 1 -C 10 alkyl, C 3 C 18 branched alkyl, C 2 -C 10 alkenyl, C 2 -C 10 alkynyl, C 3 -C9 cycloalkyl, C 6 -C 10 aryl, and heteroaryl, any of which is optionally substituted with one or more C 1 -C 6 alkyl or halo groups; UNPL is absent or selected from the group consisting of 0, S, NH, C(=0)-, -R 3 S- and -R30-, wherein groups with two chemically nonequivalent termini can adopt both possible orientations; the -(CH2)pNPL- alkylene chain is optionally substituted with one or more amino groups; pNPL is 0 to 6; qlNPL and q2NPL are 0; PL is -R')qiPLUPL(CH 2 )pPL-(NR')q 2 PL-, wherein: R 5 , R 5 , and R 5 are independently selected from the group consisting of hydrogen, C 1 -C 6 alkyl, and C 1 -C 6 alkoxy; UPL is absent or selected from the group consisting of 0, S, NH, C(=0)-, -RO-, and -RS-, wherein groups with two chemically nonequivalent termini can adopt both possible orientations; V is selected from the group consisting of amino, hydroxy, C 1 -C 6 alkylamino, -NH(CH 2 )pNH 2 wherein p is 1 to 4, -N(CH 2 CH 2 NH 2 ) 2 , diazamino, amidino, and guanidino; the -(CH2)ppL- alkylene chain is optionally substituted with one or more amino groups; pPL is 0 to 6; q1PL and q2PL are 0; and m is 1, 2 or 3. WO 2004/082634 PCT/US2004/008155 - 171

49. A method of treating a microbial infection in an animal in need thereof, said method comprising administering to the animal an effective amount of a pharmaceutical composition comprising an oligomer of Formula Ila: R 1 -x-A 1 -x-y-A 2 -y-x- A 1 -x-R 2 (IIa) or an acceptable salt or solvate thereof, wherein: x is NR 8 , O, S, or -N(Rs)N(R)-; and y is C=0, C=S, or O=S=0; wherein R 8 is hydrogen or alkyl; A 1 and A 2 are independently optionally substituted arylene or optionally substituted heteroarylene, wherein Ai and A 2 are independently optionally substituted with one or more polar (PL) group(s), one or more non-polar (NPL) group(s), or a combination of one or more polar (PL) group(s) and one or more non-polar (NPL) group(s); R' is a polar group (PL) or a non-polar group (NPL); and R 2 is R'; NPL is a nonpolar group independently selected from the group consisting of -B(OR 4 ) 2 and -(NR 3 )qlNPL-UNPL-(CH 2 )pNPL-N 3 ")q 2 NPL -R 4 ', wherein: R 3 , R', and R" are independently selected from the group consisting of hydrogen, alkyl, and alkoxy; R 4 and R 4 ' are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and heteroaryl, any of which is optionally substituted with one or more alkyl or halo groups; UNPL is absent or selected from the group consisting of 0, S, S(=0), S(=0) 2 , NR 3 , -C(=0)-, -C(=0)-N=N-NR 3 -, -C(=0)-NR 3 -N=N-, -N=N-NR 3 -, -C(=N-N(R 3 ) 2 )-, -C(=NIR 3 )-, -C(=O)O-, -C(=0)S-, -C(=S)-, -0-P(=0) 2 0-, -R 3 0-, -R 3 S-, -S-C=N- and -C(=)-NR3-0-, wherein groups with two chemically nonequivalent termini can adopt both possible orientations; WO 2004/082634 PCT/US2004/008155 -172 the -(CH2)pNPL- alkylene chain is optionally substituted with one or more amino or hydroxy groups, or is unsaturated; pNPL is 0 to 8; qlNPL and q2NPL are independently 0, 1 or 2; PL is a polar group selected from the group consisting of halo, hydroxyethoxymethyl, methoxyethoxymethyl, polyoxyethylene, and -NR 5 ')qlPL-UPL-(CH 2 )pPL-(NR)q 2 PL-V, wherein: R 5 , R5', and R 5 " are independently selected from the group consisting of hydrogen, alkyl, and alkoxy; UPL is absent or selected from the group consisting of 0, S, S(=0), S(=0) 2 , NR, -C(=0)-, -C(=O)-N=N-NR 5 -, -C(=O)-NR 5 -N=N-, -N=N-NR 5 -, -C(=N-N(R 5 ) 2 )-, -C(=NR 5 )-, -C(=O)O-, -C(=0)S-, -C(=S)-, -0-P(=0) 2 0-, -RO-, -R5S-, -S-C=N- and -C(=0)-NR 5 -0-, wherein groups with two chemically nonequivalent termini can adopt both possible orientations; V is selected from the group consisting of nitro, cyano, amino, hydroxy, alkoxy, alkylthio, alkylamino, dialkylamino, -NH(CH 2 )pNH 2 wherein p is 1 to 4, -N(CH 2 CH 2 NH 2 ) 2 , diazamino, amidino, guanidino, guanyl, semicarbazone, aryl, heterocycle and heteroaryl, any of which is optionally substituted with one or more of amino, halo, cyano, nitro, hydroxy, -NH(CH 2 )pNH 2 wherein p is 1 to 4, -N(CH 2 CH 2 NH 2 ) 2 , amidino, guanidino, guanyl, aminosulfonyl, aminoalkoxy, aminoalkythio, lower acylamino, or benzyloxycarbonyl; the -(CH2)pPL- alkylene chain is optionally substituted with one or more amino or hydroxy groups, or is unsaturated; pPL is 0 to 8; and qlPL and q2PL are independently 0, 1 or 2; and a pharmaceutically acceptable carrier or diluent. WO 2004/082634 PCT/US2004/008155 - 173

50. The method of claim 49, wherein the oligomer is selected from the group consisting of: HN NH HN NH2 H2N NH NH2 HN yNH 2 HN NH HN NH H2N N N NH2 H2N N A N NH, - 0 0 0 0 H2N NH2 H H I H H H2N N N Y . N N NH2 0 - 0 0 0 HN NH 2 H H H IH SH H H2N N N N I . N N NYNH2 NH 0 0 0 0 NH H 2 N NH HN NH2 N NH HHH HH H H H2N N N N -- '. NNN N NH2 NH 0 0 0 0 NH H2N NH H2N N S H S NNH2 0 0 - 0 H2N NH 2 H NH,2 H S H H S H NH, H H2N N NN,,N S N N NH2 NH 0 0 0 0 NH WO 2004/082634 PCT/US2004/008155 -174 H 2 N NH 2 H 2 N NA N NH 2 0 0 H 2 N NH 2 N2 H H H H NH 2 ~,, N N N N o0~ 0 0 K u HH 2 N sfNH 2 N2 H H I H H NH .. Il ol N N ' N N T o o 0 0 . 0 H 2 N NH 2 NH 2 S -~S HN NH H H H 2 HN ~ NNH 0 - 0 0 0 H 2 N NH 2 H H H H HNN N ' N N Y H H2N NH2 HN S S NH OH HH HH N ~N N N 0 0 0 K-0 WO 2004/082634 PCT/US2004/008155 -175 NH, NH 2 H 2 N N H NH 2 HNYNH 2 NH 2 NH 2 HNyNH 2 O 0 HN NH H 2 N N .- N ~NH 2 H H H 2 N N N -; N NH2 O O HNyNH 2 HN2NH 2 HN NH 2 HNyNH 2 HN NH 2 HN NH2 HN NH 2 NH NH H H HN HyH NHN HN NH HN NH H I H H S H H O H H 2 N N; ,- N NH 2 H 2 N y N N N N y NH2 ./ 0 0 NH / 0 0 NH WO 2004/082634 PCT/US2004/008155 -176 HN NH 2 HN NH 2 HN NH 2 NH 2 HN yNH 2 NH NH NH NH H I H H I H H 2 N N N NH 2 H 2 N NA N NH 2 - 0 0 0 0 NH 2 NH 2 H H I H H H 2 N N N I- N N NH 2 0 0 0 0 NH 2 NH 2 H H H H H H H 2 N N N N I- r N N N NH 2 NH 0 0 0 0 NH HN NH 2 HN NH 2 NH NH H H O H sH H H 2 N N N N N NH 2 NH O 0 0 0 NH NH 2 NH 2 H 2 NH I , NH 2 H 2 N- O0 0 0 0 0_- NH 2 WO 2004/082634 PCT/US2004/008155 -177 NH 2 NH 2 S N H S H 2 N N NH 2 NH 2 NH 2 NH 2 S N N S N N S H 2 N N N N N NH 2 - 0 0 - 0 0 NH 2 NH 2 H H S H H H H H 2 N N N N '- N N N NH 2 NH 0 O 0 0 NH

51. The method of claim 16 or claim 49, wherein the microbial infection is a bacterial infection, a fungal infection, or a viral infection.

52. A method of killing or inhibiting the growth of a microorganism, said method comprising contacting the microorganism with an effective amount of an oligomer of claim 16 or claim 49.

53. The method of claim 52, wherein the microorganism is a bacterial cell, a fungus, or a virus.

54. A method of providing an antidote to low molecular weight heparin overdose in an animal, said method comprising administering to the animal an WO 2004/082634 PCT/US2004/008155 - 178 effective amount of a pharmaceutical composition comprising an oligomer of claim 16 or claim 49.

55. A method of treating a microbial infection in an animal in need thereof, said method comprising administering to the animal an effective amount of a pharmaceutical composition comprising an oligomer of Formula IV: R 1 -[-x-A1-x-z-y-A 2 -y-z m-R 2 (IV) or an acceptable salt or solvate thereof, wherein: x is NR, -NR NRg-, C=O, or 0; y is NR8, -NReNR 8 -, C=0, S, or 0; and Rg is hydrogen or alkyl; z is C=O, C=S, O=S=O, -NRNR -, or -C(=0)C(=0) A 1 and A 2 are independently optionally substituted arylene or optionally substituted heteroarylene, wherein A 1 and A 2 are independently optionally substituted with one or more polar (PL) group(s), one or more non-polar (NPL) group(s), or a combination of one or more polar (PL) group(s) and one or more non-polar (NPL) group(s); R1 is (i) hydrogen, a polar group (PL), or a non-polar group (NPL), and R 2 is -x-A 1 -x-R 1 , wherein A 1 is as defined above and is optionally substituted with one or more polar (PL) group(s), one or more non-polar (NPL) group(s), or a combination of one or more polar (PL) group(s) and one or more non-polar (NPL) group(s); or (ii) hydrogen, a polar group (PL), or a non-polar group (NPL), and R 2 is -x-Ai-x-z-y-A 2 -y-R 1 , wherein A 1 and A 2 are as defined above, and each of which is optionally substituted with one or more polar (PL) group(s), one or more non-polar (NPL) WO 2004/082634 PCT/US2004/008155 - 179 group(s), or a combination of one or more polar (PL) group(s) and one or more non-polar (NPL) group(s); or (iii) hydrogen, a polar group (PL), or a non-polar group (NPL), and R 2 is -x-A'-x-Rl, wherein A' is aryl or heteroaryl and is optionally substituted with one or more polar (PL) group(s), one or more non-polar (NPL) group(s), or a combination of one or more polar (PL) group(s) and one or more non-polar (NPL) group(s); or (iv) hydrogen, a polar group (PL), or a non-polar group (NPL), and R 2 is -x-A1-x-z-y-A'-y-R 1 , wherein A 1 is as defined above, A' is aryl or heteroaryl, and each of A 1 and A' is optionally substituted with one or more polar (PL) group(s), one or more non-polar (NPL) group(s), or a combination of one or more polar (PL) group(s) and one or more non-polar (NPL) group(s); or (v) -z-y-A' and R 2 is hydrogen, a polar group (PL), or a non-polar group (NPL), wherein A' is aryl or heteroaryl and is optionally substituted with one or more polar (PL) group(s), one or more non-polar (NPL) group(s), or a combination of one or more polar (PL) group(s) and one or more non-polar (NPL) group(s); or (vi) -z-y-A', and R2 is -x- A", wherein A' and A" are independently aryl or heteroaryl, and each of A' and A" is optionally substituted with one or more polar (PL) group(s), one or more non-polar (NPL) group(s), or a combination of one or more polar (PL) group(s) and one or more non-polar (NPL) group(s); or (vii) R 1 and R 2 are independently a polar group (PL) or a non-polar group (NPL); or (viii) R1 and R 2 together form a single bond; NPL is a nonpolar group independently selected from the group consisting of WO 2004/082634 PCT/US2004/008155 -180 -B(OR 4 ) 2 and -NR)qINPL-UNPL-(CH 2 )pNPL-(N ")q 2 NPL -R 4 ', wherein: R 3 , R, and R 3 " are independently selected from the group consisting of hydrogen, alkyl, and alkoxy; R 4 and R 4 ' are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and heteroaryl, any of which is optionally substituted with one or more alkyl or halo groups; UNPL is absent or selected from the group consisting of 0, S, S(=0), S(=0) 2 , NR 3 , -C(=0)-, -C(=0)-N=N-NR 3 -, -C(=O)-NR 3 -N=N-, -N=N-NR 3 -,-C(=N-N(R 3 ) 2 )-, -C(=NR 3 )-, -C(=0)O-, -C(=0)S-, -C(=S)-, -O-P(=0) 2 0-, -R 3 0-, -R 3 S-, -S-C=N- and -C(=0)-NR 3 -0- , wherein groups with two chemically nonequivalent termini can adopt both possible orientations; the -(CH2)pNPL- alkylene chain is optionally substituted with one or more amino or hydroxy groups, or is unsaturated; pNPL is 0 to 8; qlNPL and q2NPL are independently 0, 1 or 2; PL is a polar group selected from the group consisting of halo, hydroxyethoxymethyl, methoxyethoxymethyl, polyoxyethylene, and -(NR")qlPL-UPL(CH2)pPL-NR5)q2PL-V, wherein: R 5 , R", and R5" are independently selected from the group consisting of hydrogen, alkyl, and alkoxy; UPL is absent or selected from the group consisting of 0, S, S(=0), S(=0) 2 , NR, -C(=0)-, -C(=0)-N=N-NR 5 -, -C(=O)-NR 5 -N=N-, -N=N-NR 5 -, -C(=N-N(R) 2 )-, -C(=NR 5 )-, -C(=0)O-, -C(=0)S-, -C(=S)-, -O-P(=0) 2 0-, -R 5 0-, -R 5 S-, -S-C=N- and -C(=0)-NR 5 -0-, wherein groups with two chemically nonequivalent termini can adopt both possible orientations; V is selected from the group consisting of nitro, cyano, amino, hydroxy, alkoxy, alkylthio, alkylamino, dialkylamino, WO 2004/082634 PCT/US2004/008155 - 181 -NH(CH 2 )pNH 2 wherein p is 1 to 4, -N(CH 2 CH 2 NH 2 ) 2 , diazamino, amidino, guanidino, guanyl, semicarbazone, aryl, heterocycle and heteroaryl, any of which is optionally substituted with one or more of amino, halo, cyano, nitro, hydroxy, -NH(CH 2 )pNH 2 wherein p is 1 to 4, -N(CH 2 CH 2 NH 2 ) 2 , amidino, guanidino, guanyl, aminosulfonyl, aminoalkoxy, aminoalkythio, lower acylamino, or benzyloxycarbonyl; the -(CH 2 )pL- alkylene chain is optionally substituted with one or more amino or hydroxy groups, or is unsaturated; pPL is 0 to 8; qlPL and q2PL are independently 0, 1 or 2; and m is 1 to about 20; and a pharmaceutically acceptable carrier or diluent.

56. A method of treating a microbial infection in an animal in need thereof, said method comprising administering to the animal an effective amount of a pharmaceutical composition comprising an oligomer of Formula IVa, Formula IVb, or Formula IVc: Rl-x-A1-x-z-y-A2-y-R2 (IVa) R(-x-A)-x-z-y-A2-y-z-x-A1-x-R2 (Ib) Rl-x-A1-x-z-y-A2-y-z-x-A1-x-z-y-A2-y-R 2 (IVe) or an acceptable salt or solvate thereof, wherein: x is NR', -MRmR-, C=0, or 0; y is NR 8 , -NR8NR-, C=O, S, or 0; and R 8 is hydrogen or alkyl; z is C=0, C=S, O=S=O, -NR'NR 5 -, or -C(=0)C(=0) A 1 and A 2 are independently optionally substituted arylene or optionally substituted heteroarylene, wherein A 1 and A 2 are independently WO 2004/082634 PCT/US2004/008155 -182 optionally substituted with one or more polar (PL) group(s), one or more non-polar (NPL) group(s), or a combination of one or more polar (PL) group(s) and one or more non-polar (NPL) group(s); R1 is hydrogen, a polar group (PL), or a non-polar group (NPL), and R 2 is R1; NPL is a nonpolar group independently selected from the group consisting of -B(OR 4 ) 2 and -(NR')qlNPL-UNPL-(CH2)pNPL-3"')q2NPL -R 4 ', wherein: R 3 , R 3 ', and R 3 " are independently selected from the group consisting of hydrogen, alkyl, and alkoxy; R 4 and R 4 ' are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and heteroaryl, any of which is optionally substituted with one or more alkyl or halo groups; UNPL is absent or selected from the group consisting of 0, S, S(=0), S(=0) 2 , NR 3 , -C(=0)-, -C(=0)-N=N-NR 3 -, -C(=0)-NR 3 -N=N-, -N=N-NR3-, -C(=N-N(RW)2)-, -C(=N ,R3)-, -C(=O)O-, -C(=0)S-, -C(=S)-, -0-P(=0) 2 0-, -R 3 0-, -R 3 S-, -S-C=N- and -C(=0)-NR 3 -0- , wherein groups with two chemically nonequivalent termini can adopt both possible orientations; the -(CH2)pNPL- alkylene chain is optionally substituted with one or more amino or hydroxy groups, or is unsaturated; pNPL is 0 to 8; qlNPL and q2NPL are independently 0, 1 or 2; PL is a polar group selected from the group consisting of halo, hydroxyethoxymethyl, methoxyethoxymethyl, polyoxyethylene, and -(NR)qlPL-UPL-(CH 2 )pPL-(NR')q 2 PL-V, wherein: R', R"', and R5" are independently selected from the group consisting of hydrogen, alkyl, and alkoxy; UPL is absent or selected from the group consisting of 0, S, S(=0), S(=0) 2 , NR, -C(=0)-, -C(=0)-N=N-NR 5 -, -C(=O)-NR 5 -N=N-, -N=N-NRs-, -C(=N-N(Rs) 2 )-, -C(=NR 5 )-, -C(=O)O-, -C(=0)S-, -C(=S)-, -0-P(=0) 2 0-, -R 5 0-, -R 5 S-, -S-C=N- and WO 2004/082634 PCT/US2004/008155 - 183 -C(=O)-NR 5 -O- , wherein groups with two chemically nonequivalent termini can adopt both possible orientations; V is selected from the group consisting of nitro, cyano, amino, hydroxy, alkoxy, alkylthio, alkylamino, dialkylamino, -NH(CH 2 )pNH 2 wherein p is 1 to 4, -N(CH 2 CH 2 NH 2 ) 2 , diazamino, amidino, guanidino, guanyl, semicarbazone, aryl, heterocycle and heteroaryl, any of which is optionally substituted with one or more of amino, halo, cyano, nitro, hydroxy, -NH(CH 2 )pNH 2 wherein p is 1 to 4, -N(CH 2 CH 2 NH 2 ) 2 , amidino, guanidino, guanyl, aminosulfonyl, aminoalkoxy, aminoalkythio, lower acylamino, or benzyloxycarbonyl; the -(CH2)pPL- alkylene chain is optionally substituted with one or more amino or hydroxy groups, or is unsaturated; pPL is 0 to 8; qlPL and q2PL are independently 0, 1 or 2; and a pharmaceutically acceptable carrier or diluent.

57. The method of claim 56, wherein the pharmaceutical composition comprises an oligomer of Formula IV'b, wherein: x is NR , y is NR , z is C=O, and R is hydrogen; A1 and A 2 are independently optionally substituted o-, in-, or p phenylene; NPL is -(NR3')q1NPL-UNPL-(CH2)pNPL- 3")q2NPL -R', wherein: R 4 ' is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and heteroaryl, any of which is optionally substituted with one or more alkyl or halo groups; UNPL is selected from the group consisting of 0, S, NR 3 , WO 2004/082634 PCT/US2004/008155 -184 -C(=O)-, -R 3 0-, and -R'S-, wherein groups with two chemically nonequivalent termini can adopt both possible orientations; the -(CH2)pNpL- alkylene chain is optionally substituted with one or more amino groups; pNPL is 0 to 8; qlNPL and q2NPL are 0; PL is-(NR")qlPL-UPL-(CH2)pPL-(NR5')q2PL-V, wherein: UPL is selected from the group consisting of 0, S, NR 5 , -C(=0), -R50- and -R 5 S-, wherein groups with two chemically nonequivalent termini can adopt both possible orientations; V is selected from the group consisting of amino, alkylamino, dialkylamino, -NH(CH 2 )pNH 2 wherein p is 1 to 4, -N(CH 2 CH 2 NH 2 ) 2 , diazamino, amidino, guanidino, guanyl, aryl, heterocycle and heteroaryl; the -(CH2)ppL- alkylene chain is optionally substituted with one or more amino groups; pPL is 0 to 8; and qlPL and q2PL are 0. WO 2004/082634 PCT/US2004/008155 - 185

58. The method of claim 56, wherein the oligomer is one of NH 2 NH 2 NH 2 NH 2 NH 2 SH H H 2 N N N NH 2 H N H H y I H 2 N N Nj ~ N N NH 2 S NH 2 NH 2 NH 2 NH 2 H2N NNH2 -~ 0 0 ~ 0

59. The method of claim 55 or 56, wherein the microbial infection is a bacterial infection, a fungal infection, or a viral infection.

60. A method of killing or inhibiting the growth of a microorganism, said method comprising contacting the microorganism with an effective amount of an oligomer of claim 55 or claim 56.

61. The method of claim 60, wherein the microorganism is a bacterial cell, a fungus, or a virus.

62. A method of providing an antidote to low molecular weight heparin overdose in an animal, said method comprising administering to the animal an effective amount of a pharmaceutical composition comprising an oligomer of claim 55 or claim 56. WO 2004/082634 PCT/US2004/008155 - 186

63. An oligomer of of Formula Ila: R-x-A 1 -x-y-A 2 -y-x- A 1 -x-R 2 (IIa) or an acceptable salt or solvate thereof, wherein: x is NR, 0, S, or -N(Rg)N(R8)-; and y is C=0, C=S, or O=S=0; wherein R 8 is hydrogen or alkyl; A 1 and A 2 are independently optionally substituted arylene or optionally substituted heteroarylene, wherein A 1 and A 2 are independently optionally substituted with one or more polar (PL) group(s), one or more non-polar (NPL) group(s), or a combination of one or more polar (PL) group(s) and one or more non-polar (NPL) group(s); R1 is a polar group (PL) or a non-polar group (NPL); and R 2 is R1; NPL is a nonpolar group independently selected from the group consisting of -B(OR 4 ) 2 and -- N )qlNPL-UNPL~ 2)pNPL- 3")q2NPL -R4', wherein: R 3, R 3, and R 3 " are independently selected from the group consisting of hydrogen, alkyl, and alkoxy; R 4 and R 4 ' are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and heteroaryl, any of which is optionally substituted with one or more alkyl or halo groups; UNPL is absent or selected from the group consisting of 0, S, S(=0), S(=0) 2 , NR3, -C(=0)-, -C(=0)-N=N-NR 3 -, -C(=0)-NR 3 -N=N-, -N=N-NR 3 -, -C(=N-N(R 3 ) 2 )-, -C(=NR 3 )-, -C(=O)O-, -C(=0)S-, -C(=S)-, -O-P(=0) 2 0-, -R 3 0-, -R 3 S-, -S-C=N- and -C(=O)-NR 3 -0- , wherein groups with two chemically nonequivalent termini can adopt both possible orientations; the -(CH2)pNPL- alkylene chain is optionally substituted with one or more amino or hydroxy groups, or is unsaturated; pNPL is 0 to 8; qlNPL and q2NPL are independently 0, 1 or 2; WO 2004/082634 PCT/US2004/008155 -187 PL is a polar group selected from the group consisting of halo, hydroxyethoxymethyl, methoxyethoxymethyl, polyoxyethylene, and (NR5)qlPL-UPL-(CH2)pPL-(NR')q2PL-V, wherein: R 5 , R", and R 5 " are independently selected from the group consisting of hydrogen, alkyl, and alkoxy; UPL is absent or selected from the group consisting of 0, S, S(=0), S(=0) 2 , NR, -C(=0)-, -C(=0)-N=N-NR 5 -, -C(=0)-NR 5 -N=N-, -N=N-NRs-, -C(=N-N(R 5 ) 2 )-, -C(=NR 5 )-, -C(=0)O-, -C(=0)S-, -C(=S)-, -0-P(=0) 2 0-, -R 5 0-, -R 5 S-, -S-C=N- and -C(=0)-NR 5 -0- , wherein groups with two chemically nonequivalent termini can adopt both possible orientations; V is selected from the group consisting of nitro, cyano, amino, hydroxy, alkoxy, alkylthio, alkylamino, dialkylamino, -NH(CH 2 )pNH 2 wherein p is 1 to 4, -N(CH 2 CH 2 NH 2 ) 2 , diazamino, amidino, guanidino, guanyl, semicarbazone, aryl, heterocycle and heteroaryl, any of which is optionally substituted with one or more of amino, halo, cyano, nitro, hydroxy, -NH(CH 2 )pNH 2 wherein p is 1 to 4, -N(CH 2 CH 2 NH 2 ) 2 , amidino, guanidino, guanyl, aminosulfonyl, aminoalkoxy, aminoalkythio, lower acylamino, or benzyloxycarbonyl; the -(CH2)pPL- alkylene chain is optionally substituted with one or more amino or hydroxy groups, or is unsaturated; pPL is 0 to 8; and qlPL and q2PL are independently 0, 1 or 2.

64. An oligomer of Formula I: R -[-x-A1-y-x-A2-y-]m-R2teo or an acceptable salt or solvate thereof, WO 2004/082634 PCT/US2004/008155 - 188 wherein: x is NR, y is C=O, and R8 is hydrogen; A 1 is optionally substituted o-, m-, or p-phenylene and A 2 is -(CH2)q-, wherein q is 1, wherein one of A 1 and A 2 is substituted with one or two polar (PL) group(s), and the other of A 1 and A 2 is substituted with one or two non-polar (NPL) group(s); or A 2 is optionally substituted o-, m-, or p-phenylene and A 1 is -(CH2)q-, wherein q is 1, wherein one of A 1 and A 2 is substituted with one or two polar (PL) group(s), and the other of A 1 and A 2 is substituted with one or two non-polar (NPL) group(s); R 1 and R 2 are independently hydrogen, a polar (PL) group, or a non-polar (NPL) group; NPL is -(NR 3 ')qlNPL-UNPL-(CH 2 )pNPL-1 3 ")q2NPL -R 4 ', wherein: R' is selected from the group consisting of C 1 -C 10 alkyl, C 3 -C 18 branched alkyl, C 2 -Cio alkenyl, C 2 -CIO alkynyl, and C 6 -C 10 aryl, any of which is optionally substituted with one or more alkyl or halo groups; UNPL is absent or selected from the group consisting of NH, -C(=O)-, 0 and S; the -(CH2)pNPL- alkylene chain is optionally substituted with one or more amino groups; pNPL is 0 to 8; qlNPL and q2NPL are 0; PL is-(NR')qiPL-UPL-(CH2)pPL-(NR)q2PL-V, wherein: UPL is absent or selected from the group consisting of 0, S, NH, and -C(=0); V is selected from the group consisting of amino, C 1 -C 6 alkylamino, -NH(CH 2 )pNH 2 wherein p is 1 to 4, -N(CH 2 CH 2 NH 2 ) 2 , diazamino, amidino, and guanidino, any of which is optionally substituted with one or more of amino, halo, cyano, nitro, hydroxy, -NH(CH 2 )pNH 2 wherein p is 1 to 4, WO 2004/082634 PCT/US2004/008155 -189 -N(CH 2 CH 2 NH 2 ) 2 , amidino, guanyl, guanidino, or aminoalkoxy; the -(CH2)pPL- alkylene chain is optionally substituted with one or more amino groups; pPL is 0 to 8; qlPL and q2PL are 0; and m is 4 or 5.

65. A pharmceutical composition comprising an oligomer of claim 63 or claim 64 and a pharmaceutically acceptable carrier or diluent.