title: 4-Substituted thioquinolines and thiazoloquinolines: potent, selective, and Tween-80 in vitro dependent families of antitubercular agents with moderate in vivo activity.
abstract: Two new families of closely related selective, non-cytotoxic, and potent antitubercular agents were discovered: thioquinolines and thiazoloquinolines. The compounds were found to possess potent antitubercular properties in vitro, an activity that is dependent on experimental conditions of MIC determination (resazurin test and the presence or absence of Tween-80). To clarify the therapeutic potential of these compound families, a medicinal chemistry effort was undertaken to generate a lead-like structure that would enable murine efficacy studies and help elucidate the in vivo implications of the in vitro observations. Although the final compounds showed only limited levels of systemic exposure in mice, modest levels of efficacy in vivo at nontoxic doses were observed.
authors.affiliation: Diseases of the Developing World (DDW), Tres Cantos Medicines Development Campus (TCMDC), GlaxoSmithKline, Severo Ochoa 2, 28760 Tres Cantos Madrid, Spain.
authors.forename: Jaime
authors.initials: J
authors.lastname: Escribano
authors.forename: Cristina
authors.initials: C
authors.lastname: Rivero-Hernández
authors.forename: Hilda
authors.initials: H
authors.lastname: Rivera
authors.forename: David
authors.initials: D
authors.lastname: Barros
authors.forename: Julia
authors.initials: J
authors.lastname: Castro-Pichel
authors.forename: Esther
authors.initials: E
authors.lastname: Pérez-Herrán
authors.forename: Alfonso
authors.initials: A
authors.lastname: Mendoza-Losana
authors.forename: Iñigo
authors.initials: I
authors.lastname: Angulo-Barturen
authors.forename: Santiago
authors.initials: S
authors.lastname: Ferrer-Bazaga
authors.forename: Elena
authors.initials: E
authors.lastname: Jiménez-Navarro
authors.forename: Lluís
authors.initials: L
authors.lastname: Ballell
mesh_terms: D000818:Animals; D000995:Antitubercular Agents / Q000737:chemistry* / Q000493:pharmacokinetics / Q000627:therapeutic use; D004195:Disease Models, Animal; D005260:Female; D051379:Mice; D008810:Mice, Inbred C57BL; D008826:Microbial Sensitivity Tests; D011136:Polysorbates / Q000737:chemistry*; D011804:Quinolines / Q000737:chemistry* / Q000493:pharmacokinetics / Q000627:therapeutic use; D013329:Structure-Activity Relationship; D014376:Tuberculosis / Q000188:drug therapy
chemical_list: D000995:Antitubercular Agents; D011136:Polysorbates; D011804:Quinolines