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: Raoni S B Gonçalves, Carlos R Kaiser, Maria C S Lourenço, Flavio A F M Bezerra, Marcus V N de Souza, James L Wardell, Solange M S V Wardell, Maria das Graças M de O Henriques, Thadeu Costa
• Journal: Bioorganic & medicinal chemistry (Bioorg Med Chem) Vol. 20 Issue 1 Pg. 243-8 (Jan 01 2012) ISSN: 1464-3391 [Electronic] England
• PMID: 22142615 (Publication Type: Journal Article)
• Copyright: Copyright © 2011 Elsevier Ltd. All rights reserved.

Chemical References

• Aldehydes
• Antitubercular Agents
• Oxazoles
• oxazolidine
• Ethambutol
• Mefloquine

Topics

• Aldehydes (chemistry)
• Animals
• Antitubercular Agents (chemical synthesis, chemistry, pharmacology)
• Cells, Cultured
• Drug Resistance, Multiple, Bacterial (drug effects)
• Ethambutol (chemistry, pharmacology)
• Mefloquine (chemistry, pharmacology)
• Mice
• Microbial Sensitivity Tests
• Molecular Conformation
• Mycobacterium tuberculosis (drug effects, isolation & purification)
• Oxazoles (chemistry, pharmacology)