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; Ghotas Evindar
J. Med. Chem., 2014, 57, 4, 1276-1288
https://doi.org/10.1021/jm401326j

Abstract

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.