title: 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.affiliation: Faculty of Pharmacy, University of Ljubljana , Aškerčeva 7, 1000 Ljubljana, Slovenija.
authors.forename: Roman
authors.initials: R
authors.lastname: Šink
authors.forename: Izidor
authors.initials: I
authors.lastname: Sosič
authors.forename: Matej
authors.initials: M
authors.lastname: Živec
authors.forename: Raquel
authors.initials: R
authors.lastname: Fernandez-Menendez
authors.forename: Samo
authors.initials: S
authors.lastname: Turk
authors.forename: Stane
authors.initials: S
authors.lastname: Pajk
authors.forename: Daniel
authors.initials: D
authors.lastname: Alvarez-Gomez
authors.forename: Eva Maria
authors.initials: EM
authors.lastname: Lopez-Roman
authors.forename: Carolina
authors.initials: C
authors.lastname: Gonzales-Cortez
authors.forename: Joaquin
authors.initials: J
authors.lastname: Rullas-Triconado
authors.forename: Inigo
authors.initials: I
authors.lastname: Angulo-Barturen
authors.forename: David
authors.initials: D
authors.lastname: Barros
authors.forename: Lluís
authors.initials: L
authors.lastname: Ballell-Pages
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Young
authors.forename: Lourdes
authors.initials: L
authors.lastname: Encinas
authors.forename: Stanislav
authors.initials: S
authors.lastname: Gobec
mesh_terms: D000818:Animals; D000995:Antitubercular Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D015195:Drug Design; D005260:Female; D056945:Hep G2 Cells; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D010088:Oxidoreductases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013830:Thiadiazoles / Q000138:chemical synthesis* / Q000494:pharmacology
chemical_list: D000995:Antitubercular Agents; D001426:Bacterial Proteins; D013830:Thiadiazoles; D010088:Oxidoreductases; C085257:InhA protein, Mycobacterium