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

Authored by: Lourdes Encinas ‡, Heather O’Keefe †, Margarete Neu §, Modesto J. Remuiñán ‡, Amish M. Patel †, Ana Guardia ‡, Christopher P. Davie †, Natalia Pérez-Macías , Hongfang Yang †, Maire A. Convery §, Jeff A. Messer †, Esther Pérez-Herrán ‡, Paolo A. Centrella , Daniel Álvarez-Gómez ‡, Matthew A. Clark , Sophie Huss ‡, Gary K. O’Donovan †, Fátima Ortega-Muro ‡, William McDowell #, Pablo Castañeda ‡, Christopher C. Arico-Muendel †, Stane Pajk ∞, Joaquín Rullás ‡, Iñigo Angulo-Barturen ‡, Emilio Álvarez-Ruíz ×, Alfonso Mendoza-Losana ‡, Lluís Ballell Pages ‡, Julia Castro-Pichel *‡, and Ghotas Evindar *†


Tuberculosis (TB) is one of the world’s 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–activity relationships of a hundred analogues synthesized, and the results of the in vivo efficacy studies performed with the lead compound 65.

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