Design, synthesis, and evaluation of new thiadiazole-based direct inhibitors of enoyl acyl carrier protein reductase (InhA) for the treatment of tuberculosis.
|
| Abstract |
Mycobacterial enoyl acyl carrier protein reductase (InhA) is a clinically validated target for the treatment of tuberculosis infections, a disease that still causes the death of at least a million people annually. A known class of potent, direct, and competitive InhA inhibitors based on a tetracyclic thiadiazole structure has been shown to have in vivo activity in murine models of tuberculosis infection. On the basis of this template, we have here explored the medicinal chemistry of truncated analogues that have only three aromatic rings. In particular, compounds 8b, 8d, 8f, 8l, and 8n show interesting features, including low nanomolar InhA IC50, submicromolar antimycobacterial potency, and improved physicochemical profiles in comparison with the tetracyclic analogues. From this series, 8d is identified as having the best balance of potency and properties, whereby the resolved 8d S-enatiomer shows encouraging in vivo efficacy.
|
|---|---|
| Authors | Roman Šink, Izidor Sosič, Matej Živec, Raquel Fernandez-Menendez, Samo Turk, Stane Pajk, Daniel Alvarez-Gomez, Eva Maria Lopez-Roman, Carolina Gonzales-Cortez, Joaquin Rullas-Triconado, Inigo Angulo-Barturen, David Barros, Lluís Ballell-Pages, Robert J Young, Lourdes Encinas, Stanislav Gobec |
| Journal | Journal of medicinal chemistry (J Med Chem) Vol. 58 Issue 2 Pg. 613-24 (Jan 22 2015) ISSN: 1520-4804 [Electronic] United States |
| PMID | 25517015 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't) |
| Chemical References |
|
| Topics |
|
Join CureHunter, for free Research Interface BASIC access!
Realize the full power of the drug-disease research graph!