1 research outputs found
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 <i>Mycobacterium tuberculosis</i> InhA
Tuberculosis
(TB) is one of the world’s oldest and deadliest
diseases, killing a person every 20 s. InhA, the enoyl-ACP reductase
from <i>Mycobacterium tuberculosis</i>, 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 <b>7</b> 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 <b>65</b>