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

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 = 33 mu M) 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 12.1 mu M, 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. (C) 2011 Elsevier Ltd. All rights reserved.