RESUMO
The first solid-phase synthesis of the natural product gougerotin has been accomplished. The synthetic route is versatile and allows for diversification at position C-4 of the heterocycle, C-6' of the sugar ring, and both residues of the peptidic moiety at N-4' in a parallel fashion. [structure: see text]
Assuntos
Antibacterianos/síntese química , Antifúngicos/síntese química , Produtos Biológicos/síntese química , Técnicas de Química Combinatória , Antibacterianos/farmacologia , Antifúngicos/farmacologia , Produtos Biológicos/farmacologia , Candida albicans/efeitos dos fármacos , Escherichia coli/efeitos dos fármacos , Nucleosídeos de Pirimidina/síntese química , Nucleosídeos de Pirimidina/farmacologiaRESUMO
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).
Assuntos
Antibacterianos/síntese química , Proteínas de Bactérias/antagonistas & inibidores , Compostos Heterocíclicos/síntese química , Antibacterianos/química , Antibacterianos/farmacologia , Proteínas de Bactérias/biossíntese , Técnicas de Química Combinatória , Escherichia coli/química , Escherichia coli/efeitos dos fármacos , Escherichia coli/genética , Compostos Heterocíclicos/química , Compostos Heterocíclicos/farmacologia , Lipopolissacarídeos/química , Mutação , Biossíntese de Proteínas/efeitos dos fármacos , Quinoxalinas/química , RNA Bacteriano/metabolismo , RNA Ribossômico/metabolismo , Relação Estrutura-Atividade , Transcrição Gênica/efeitos dos fármacosRESUMO
A technique for lead discovery vs RNA targets utilizing mass spectrometry (MS) screening methods is described. The structure-activity relationships (SAR) derived from assaying weak binding motifs allows the pharmacophores discovered to be elaborated via "SAR by MS" to higher affinity ligands. Application of this strategy to a subdomain of the 23S rRNA afforded a new class of compounds with functional activity.
Assuntos
Relação Quantitativa Estrutura-Atividade , RNA/química , Aminoácidos/química , Ligantes , Espectrometria de Massas , Quinoxalinas/química , EstereoisomerismoRESUMO
The preparation and evaluation of 2-aminobenzimidazole dimers as antibacterial agents is described. Biological screening of the dimers indicated that compounds with multiple chloro substituents possessed optimal antibacterial activity.
Assuntos
Antibacterianos/síntese química , Benzimidazóis/síntese química , Benzimidazóis/farmacologia , Antibacterianos/farmacologia , Bactérias/efeitos dos fármacos , Benzimidazóis/química , Dimerização , Enterococcus faecalis/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Relação Estrutura-AtividadeRESUMO
Novel quinolone-macrocycle conjugates displayed submicromolar antibacterial activity against Escherichia coli and Staphylococcus aureus bacterial strains. An analogous open-chain structure was not active at 100 microM against the same pathogenic strains.
Assuntos
Antibacterianos/química , Compostos Heterocíclicos/farmacologia , Quinolonas/farmacologia , Antibacterianos/farmacologia , Escherichia coli/efeitos dos fármacos , Compostos Heterocíclicos/química , Testes de Sensibilidade Microbiana , Quinolonas/química , Staphylococcus aureus/efeitos dos fármacos , Relação Estrutura-AtividadeRESUMO
We report on lead optimization of a compound that was originally discovered to bind bacterial 23S rRNA near the L11 binding site and inhibit translation in vitro, but lacked detectable antibacterial activity. In this study, we were able to generate compounds with antibacterial activity against Gram-negative and Gram-positive pathogens, including a methicillin-resistant S. aureus strain.
Assuntos
Antibacterianos/síntese química , Furanos/síntese química , Piperazinas/síntese química , Antibacterianos/química , Antibacterianos/farmacologia , Furanos/química , Furanos/farmacologia , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Positivas/efeitos dos fármacos , Espectrometria de Massas , Resistência a Meticilina , Testes de Sensibilidade Microbiana , Piperazinas/química , Piperazinas/farmacologia , RNA Ribossômico 23S/metabolismo , Relação Estrutura-AtividadeRESUMO
A structure-activity relationship analysis was carried out on a high-throughput small molecule screening lead for HCV-IRES translation inhibition. The study led to the identification of a guanidine-based structure with low microM inhibitory activity.
Assuntos
Antivirais/química , Guanidinas/química , Hepacivirus/genética , Biossíntese de Proteínas/efeitos dos fármacos , Proteínas Virais/antagonistas & inibidores , Antivirais/farmacologia , Bases de Dados Factuais , Hepacivirus/metabolismo , Ribossomos/efeitos dos fármacos , Ribossomos/genética , Relação Estrutura-Atividade , Transcrição Gênica/efeitos dos fármacos , Proteínas Virais/biossínteseRESUMO
The preparation and evaluation of novel aryl urea analogs as broad-spectrum antibacterial agents is described. Numerous compounds showed low micromolar minimum inhibitory concentrations (MIC) against both Gram-positive and Gram-negative bacteria. Selected analogs also exhibited in vivo efficacy in a lethal murine model of bacterial septicemia.