title: Mefloquine-oxazolidine derivatives, derived from mefloquine and arenecarbaldehydes: In vitro activity including against the multidrug-resistant tuberculosis strain T113.
abstract: Ten new mefloquine-oxazolidine derivatives, 4-[(1S,8aR)-3-(aryl)hexahydro[1,3]oxazolo[3,4-a]pyridin-1-yl]-2,8-bis(trifluoromethyl)quinoline (1: aryl=substituted phenyl) and 4-[(1S,8aR)-3-(heteroaryl)hexahydro[1,3]oxazolo[3,4-a]pyridin-1-yl]-2,8-bis(trifluoromethyl)quinoline [2: heteroaryl=5-nitrothien-2-yl (2a); 5-nitrofuran-2-yl (2b) and 4H-imidazol-2-yl) (2c)], have been synthesized and evaluated against Mycobacterium tuberculosis. Compounds 1f (aryl=3-ethoxyphenyl), 1g (Ar=3,4,5-(MeO)(3)-C(6)H(2)) and 2c were slightly more active than mefloquine (MIC=33μM) with MICs=24.5, 22.5 and 27.4, respectively, whereas compounds 1e (aryl=3,4-(MeO)(2)-C(6)H(3)) and 2a (MICs=11.9 and 12.1μM, respectively) were ca. 2.7 times more active than mefloquine, with a better tuberculostatic activity than the first line tuberculostatic agent ethambutol (MIC=15.9). The compounds were also assayed against the MDR strain T113 and the same MICs were observed. Thus the new derivatives have advantages over such anti-TB drugs as isoniazid, rifampicin, ethambutol and ofloxacin, for which this strain is resistant. The most active compounds were not cytotoxic to Murine Macrophages Cells in a concentration near their MIC values.
authors.affiliation: FioCruz-Fundação Oswaldo Cruz, Instituto de Tecnologia em Fármacos-Far-Manguinhos, Rua Sizenando Nabuco, 100, Manguinhos, 21041-250 Rio de Janeiro, RJ, Brazil.
authors.forename: Raoni S B
authors.initials: RS
authors.lastname: Gonçalves
authors.forename: Carlos R
authors.initials: CR
authors.lastname: Kaiser
authors.forename: Maria C S
authors.initials: MC
authors.lastname: Lourenço
authors.forename: Flavio A F M
authors.initials: FA
authors.lastname: Bezerra
authors.forename: Marcus V N
authors.initials: MV
authors.lastname: de Souza
authors.forename: James L
authors.initials: JL
authors.lastname: Wardell
authors.forename: Solange M S V
authors.initials: SM
authors.lastname: Wardell
authors.forename: Maria das Graças M de O
authors.initials: Md
authors.lastname: Henriques
authors.forename: Thadeu
authors.initials: T
authors.lastname: Costa
mesh_terms: D000447:Aldehydes / Q000737:chemistry*; D000818:Animals; D000995:Antitubercular Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D002478:Cells, Cultured; D024901:Drug Resistance, Multiple, Bacterial / Q000187:drug effects; D004977:Ethambutol / Q000737:chemistry / Q000494:pharmacology*; D015767:Mefloquine / Q000737:chemistry* / Q000494:pharmacology; D051379:Mice; D008826:Microbial Sensitivity Tests; D008968:Molecular Conformation; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000302:isolation & purification; D010080:Oxazoles / Q000737:chemistry* / Q000494:pharmacology
chemical_list: D000447:Aldehydes; D000995:Antitubercular Agents; D010080:Oxazoles; C064210:oxazolidine; D004977:Ethambutol; D015767:Mefloquine