Mefloquine–oxazolidine derivatives, derived from mefloquine and arenecarbaldehydes: In vitro activity including against the multidrug-resistant tuberculosis strain T113

• Published in: Bioorganic & medicinal chemistry 2012-01, Vol.20 (1), p.243-248
• Main Authors: Gonçalves, Raoni S.B., Kaiser, Carlos R., Lourenço, Maria C.S., Bezerra, Flavio A.F.M., de Souza, Marcus V.N., Wardell, James L., Wardell, Solange M.S.V., Henriques, Maria das Graças M.de O., Costa, Thadeu
• Format: Article
• Language: English
• Subjects: Aldehydes - chemistry; Animals; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antiparasitic agents; Antitubercular Agents - chemical synthesis; Antitubercular Agents - chemistry; Antitubercular Agents - pharmacology; Biological and medical sciences; Cells, Cultured; chemistry; cytotoxicity; Drug Resistance, Multiple, Bacterial - drug effects; drugs; Ethambutol - chemistry; Ethambutol - pharmacology; isoniazid; macrophages; Medical sciences; Mefloquine; Mefloquine - chemistry; Mefloquine - pharmacology; Mice; Microbial Sensitivity Tests; minimum inhibitory concentration; Molecular Conformation; Multidrug-resistant tuberculosis; multiple drug resistance; Mycobacterium tuberculosis; Mycobacterium tuberculosis - drug effects; Mycobacterium tuberculosis - isolation & purification; ofloxacin; Oxazoles - chemistry; Oxazoles - pharmacology; Pharmacology. Drug treatments; Quinoline; rifampicin; tuberculosis
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2011.11.006

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-C6H2) 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-C6H3) 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.