Mefloquine-oxazolidine derivatives, derived from mefloquine and arenecarbaldehydes: In vitro activity including against the multidrug-resistant tuberculosis strain T113 |
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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 |
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Institution: | 1. FioCruz-Fundação Oswaldo Cruz, Instituto de Tecnologia em Fármacos-Far-Manguinhos, Rua Sizenando Nabuco, 100, Manguinhos, 21041-250 Rio de Janeiro, RJ, Brazil;2. Programa de Pós-Graduação em Química, Instituto de Química, Universidade Federal do Rio de Janeiro, CP 68563, 21945-970 Rio de Janeiro, Brazil;3. Instituto de Pesquisas Clínica Evandro Chagas—IPEC, Av. Brasil, 4365, Manguinhos, Rio de Janeiro, Brazil;4. Centro de Desenvolvimento Tecnológico em Saúde (CDTS), Fundação Oswaldo Cruz (FIOCRUZ), Casa Amarela, Campus de Manguinhos, Av. Brasil, 4365, 21040-900 Rio de Janeiro, RJ, Brazil;5. CHEMSOL, 1 Harcourt Road, Aberdeen AB15 5NY, Scotland, UK;6. Fundação Oswaldo Cruz, Instituto de Tecnologia em Fármacos-Far-Manguinhos/FIOCRUZ, Departamento de Farmacologia Aplicada, Av. Brasil, 4365, Manguinhos, Rio de Janeiro, Brazil |
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Abstract: | Ten new mefloquine-oxazolidine derivatives, 4-(1S,8aR)-3-(aryl)hexahydro1,3]oxazolo3,4-a]pyridin-1-yl]-2,8-bis(trifluoromethyl)quinoline (1: aryl=substituted phenyl) and 4-(1S,8aR)-3-(heteroaryl)hexahydro1,3]oxazolo3,4-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. |
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