New Inhibitors of Bacterial Protein Synthesis from a Combinatorial Library of Macrocycles

• Published in: Journal of medicinal chemistry Vol. 45; no. 16; pp. 3430 - 3439
• Main Authors: Jefferson, Elizabeth A, Arakawa, Satoshi, Blyn, Lawrence B, Miyaji, Alycia, Osgood, Stephen A, Ranken, Raymond, Risen, Lisa M, Swayze, Eric E
• Format: Journal Article
• Language: English
• Published: Washington, DC American Chemical Society 01-08-2002
• Subjects: Anti-Bacterial Agents - chemical synthesis; Anti-Bacterial Agents - chemistry; Anti-Bacterial Agents - pharmacology; Antibacterial agents; Antibiotics. Antiinfectious agents. Antiparasitic agents; Bacterial Proteins - antagonists & inhibitors; Bacterial Proteins - biosynthesis; Biological and medical sciences; 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; Medical sciences; Mutation; Pharmacology. Drug treatments; Protein Biosynthesis - drug effects; Quinoxalines - chemistry; RNA, Bacterial - metabolism; RNA, Ribosomal - metabolism; Structure-Activity Relationship; Transcription, Genetic - drug effects; Quinoxaline derivatives; Nitrogen heterocycle; Escherichia coli; Lactam; Combinatorial chemistry; Guanidines; In vitro; Macrocycle; Screening; Structure activity relation; Chemical compound library; Bicyclic compound; Bacteria; Aromatic compound; Protein synthesis inhibitor; Solid phase; Antibacterial agent; Chemical synthesis; Enterobacteriaceae
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm010437x

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 IC50 value in the 25−50 μM range. In a follow-up library of 64 single macrocycles, 8 gave IC50 values ranging from 12 to 50 μM in the cell-free protein synthesis inhibition assay. Some of the macrocycles were screened in a translation inhibition assay, and IC50 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 (IC50 values = 2−3 μM). Some of these macrocycles displayed antibacterial activity against lipopolysaccharide mutant E. coli bacterial cells (IC50 values = 12−50 μM).