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1.
J Med Chem ; 41(5): 706-16, 1998 Feb 26.
Article in English | MEDLINE | ID: mdl-9513599

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.


Subject(s)
Anti-Infective Agents , Polyamines/chemical synthesis , Polyamines/pharmacology , Pyridines/chemical synthesis , Pyridines/pharmacology , Anti-Bacterial Agents , Anti-Infective Agents/chemical synthesis , Anti-Infective Agents/pharmacology , Candida albicans/drug effects , Drug Design , Enterococcus faecalis/drug effects , Escherichia coli/drug effects , Klebsiella pneumoniae/drug effects , Microbial Sensitivity Tests , Molecular Structure , Proteus vulgaris/drug effects , Pseudomonas aeruginosa/drug effects , Streptococcus/drug effects , Streptococcus pyogenes/drug effects , Structure-Activity Relationship
2.
Bioorg Med Chem Lett ; 8(17): 2345-50, 1998 Sep 08.
Article in English | MEDLINE | ID: mdl-9873539
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