Encoded Library Technology as a Source of Hits for the Discovery and Lead Optimization of a Potent and Selective Class of Bactericidal Direct Inhibitors of Mycobacterium tuberculosis InhA

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• 作者：Lourdes Encinas ; Heather O鈥橩eefe ; Margarete Neu ; Modesto J. Remui帽谩n ; Amish M. Patel ; Ana Guardia ; Christopher P. Davie ; Natalia P茅rez-Mac铆as ; Hongfang Yang ; Maire A. Convery ; Jeff A. Messer ; Esther P茅rez-Herr谩n ; Paolo A. Centrella ; Daniel 脕lvarez-G贸mez ; Matthew A. Clark ; Sophie Huss ; Gary K. O鈥橠onovan ; F谩tima Ortega-Muro ; William McDowell ; Pablo Casta帽eda ; Christopher C. Arico-Muendel ; Stane Pajk ; Joaqu铆n Rull谩s ; I帽igo Angulo-Barturen ; Emilio 脕lvarez-Ru铆z ; Alfonso Mendoza-Losana ; Llu铆s Ballell Pages ; Julia Castro-Pichel ; Ghotas Evindar
• 刊名：Journal of Medicinal Chemistry
• 出版年：2014
• 出版时间：February 27, 2014
• 年：2014
• 卷：57
• 期：4
• 页码：1276-1288
• 全文大小：658K
• 年卷期：v.57,no.4(February 27, 2014)
• ISSN：1520-4804

文摘

Tuberculosis (TB) is one of the world鈥檚 oldest and deadliest diseases, killing a person every 20 s. InhA, the enoyl-ACP reductase from Mycobacterium tuberculosis, is the target of the frontline antitubercular drug isoniazid (INH). Compounds that directly target InhA and do not require activation by mycobacterial catalase peroxidase KatG are promising candidates for treating infections caused by INH resistant strains. The application of the encoded library technology (ELT) to the discovery of direct InhA inhibitors yielded compound 7 endowed with good enzymatic potency but with low antitubercular potency. This work reports the hit identification, the selected strategy for potency optimization, the structure鈥揳ctivity relationships of a hundred analogues synthesized, and the results of the in vivo efficacy studies performed with the lead compound 65.