PMID:12139453
| Citation |
Jefferson, EA, Arakawa, S, Blyn, LB, Miyaji, A, Osgood, SA, Ranken, R, Risen, LM and Swayze, EE (2002) New inhibitors of bacterial protein synthesis from a combinatorial library of macrocycles. J. Med. Chem. 45:3430-9 |
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| Abstract |
A mixture-based combinatorial library of 14-membered macrocycles was synthesized to target ribosomal RNA and uncover a new class of antibacterial agents. High-throughput screening identified a macrocyclic mixture that inhibited cell-free-coupled transcription/translation in Escherichia coli-derived extracts, with an IC(50) value in the 25-50 microM range. In a follow-up library of 64 single macrocycles, 8 gave IC(50) values ranging from 12 to 50 microM in the cell-free protein synthesis inhibition assay. Some of the macrocycles were screened in a translation inhibition assay, and IC(50) values generally paralleled those obtained in the uncoupled transcription/translation assay. Additional analogues were prepared in a preliminary structure-activity relationship study, and more potent macrocycles were identified with low micromolar activity (IC(50) values = 2-3 microM). Some of these macrocycles displayed antibacterial activity against lipopolysaccharide mutant E. coli bacterial cells (IC(50) values = 12-50 microM). |
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| Keywords |
Anti-Bacterial Agents/chemical synthesis; Anti-Bacterial Agents/chemistry; Anti-Bacterial Agents/pharmacology; Bacterial Proteins/antagonists & inhibitors; Bacterial Proteins/biosynthesis; Combinatorial Chemistry Techniques; Escherichia coli/chemistry; Escherichia coli/drug effects; Escherichia coli/genetics; Heterocyclic Compounds/chemical synthesis; Heterocyclic Compounds/chemistry; Heterocyclic Compounds/pharmacology; Lipopolysaccharides/chemistry; Mutation; Protein Biosynthesis/drug effects; Quinoxalines/chemistry; RNA, Bacterial/metabolism; RNA, Ribosomal/metabolism; Structure-Activity Relationship; Transcription, Genetic/drug effects |
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