title: Discovery of novel pyridinopolyamines with potent antimicrobial activity: deconvolution of mixtures synthesized by solution-phase combinatorial chemistry.
abstract: A 1638-member pyridinopolyamine library, consisting of 13 sublibraries of 126 members prepared by a solution-phase approach, was completely deconvoluted from orthogonally protected intermediates by a combination of iterative and positional scanning procedures. Antibacterial assays against Streptococcus pyogenes and Escherichia coli imp- and a Candida albicans yeast specificity assay were employed to follow the activity of sublibraries. Screening of the 13 sublibraries, which were prepared by a synthetic method that places the differentiating functionality in a selected position A (secondary amine), at the end of the synthesis (fix last), provided several first-round activities. Subsequently, six single pyridinopolyamines (2-7) were prepared where the first-round winner, a hydrogen atom, is in the first deconvoluted position and the remaining three positions contained the same functionalities. The range of antibacterial and yeast activities of these single compounds suggested that a more active and selective compound may be discovered by completely deconvoluting the first-round active sublibraries. Pyridinopolyamine positions B (secondary benzylamine) and C (primary benzylamine) were then sequentially positionally scanned with a set of six meta-substituted benzyl functionalities to generate two sets of second/third-round sublibraries, containing 21 or 36 compounds in each sublibrary, respectively. High-throughput screening yielded sublibraries 15, 18, and 21 with MICs of 1-5 microM against S. pyogenes and E. coli imp-. Using rounds 1 and 2/3 screening data, two sets of single compounds (22-27) and (28-32) with the combination of m-(trifluoromethyl)-benzyl group at position C and m-(trifluoromethyl)benzyl or m-methylbenzyl group at position B with position D (primary benzylamine) fixed were synthesized in the fourth round deconvolution. Subsequently, broader screening of deconvoluted compounds against a tier II panel of wild-type bacteria identified eight compounds (5, 7, 27, and 29-32) with approximately 100-fold greater selectivity for Gram-positive than Gram-negative bacteria. Thus, S. pyogenes, S. pyogenes (wild-type), Streptomyces aureus, and Enterococcus faecalis were inhibited at MICs of 1-12 microM, whereas MICs for E. coli, Klebsiella pneumoniae, Proteus vulgaris, and Pseudomonas aeruginosa were > 100 microM. These eight compounds were not active (> 100 microM) against fungus C. albicans.
authors.affiliation: Department of Medicinal Chemistry, Isis Pharmaceuticals, Inc., Carlsbad, California 92008, USA.
authors.forename: H
authors.initials: H
authors.lastname: An
authors.forename: B D
authors.initials: BD
authors.lastname: Haly
authors.forename: P D
authors.initials: PD
authors.lastname: Cook
mesh_terms: D000900:Anti-Bacterial Agents; D000890:Anti-Infective Agents / Q000138:chemical synthesis / Q000494:pharmacology; D002176:Candida albicans / Q000187:drug effects; D015195:Drug Design; D013293:Enterococcus faecalis / Q000187:drug effects; D004926:Escherichia coli / Q000187:drug effects; D007711:Klebsiella pneumoniae / Q000187:drug effects; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D011073:Polyamines / Q000138:chemical synthesis* / Q000494:pharmacology*; D011514:Proteus vulgaris / Q000187:drug effects; D011550:Pseudomonas aeruginosa / Q000187:drug effects; D011725:Pyridines / Q000138:chemical synthesis* / Q000494:pharmacology*; D013291:Streptococcus / Q000187:drug effects; D013297:Streptococcus pyogenes / Q000187:drug effects; D013329:Structure-Activity Relationship
chemical_list: D000900:Anti-Bacterial Agents; D000890:Anti-Infective Agents; D011073:Polyamines; D011725:Pyridines