Both in vitro and in vivo metabolism studies suggested that 5-(2,8-bis(trifluoromethyl)quinolin-4-yloxymethyl)isoxazole-3-carboxylic acid ethyl ester (compound 3) with previously reported antituberculosis activity is rapidly converted to two metabolites 3a and 3b. In order to improve the metabolic stability of this series, chemistry efforts were focused on the modification of the oxymethylene linker of compound 3 in the present study. Compound 9d with an alkene linker was found to be both more metabolically stable and more potent than compound 3, with a minimum inhibitory concentration (MIC) of 0.2 μM and 2.6 μM against replicating and nonreplicating Mycobaterium tuberculosis, respectively. These attributes make 9d an interesting lead compound. A number of modifications were made to the structure of 9d, and a series of active compounds were discovered. Although some neurotoxicity was observed at a high dosage, this new series was endowed with both improved in vitro anti-TB activity and metabolic stability in comparison to compound 3. ©2009 American Chemical Society.

From serendipity to rational antituberculosis drug discovery of mefloquine-isoxazole carboxylic acid esters / Mao, Jialin; Yuan, Hai; Wang, Yuehong; Wan, Baojie; Pieroni, Marco; Huang, Qingqing; Van Breemen, Richard B.; Kozikowski, Alan P; Franzblau, Scott G.. - In: JOURNAL OF MEDICINAL CHEMISTRY. - ISSN 0022-2623. - 52:22(2009), pp. 6966-6978. [10.1021/jm900340a]

From serendipity to rational antituberculosis drug discovery of mefloquine-isoxazole carboxylic acid esters

PIERONI, Marco;
2009-01-01

Abstract

Both in vitro and in vivo metabolism studies suggested that 5-(2,8-bis(trifluoromethyl)quinolin-4-yloxymethyl)isoxazole-3-carboxylic acid ethyl ester (compound 3) with previously reported antituberculosis activity is rapidly converted to two metabolites 3a and 3b. In order to improve the metabolic stability of this series, chemistry efforts were focused on the modification of the oxymethylene linker of compound 3 in the present study. Compound 9d with an alkene linker was found to be both more metabolically stable and more potent than compound 3, with a minimum inhibitory concentration (MIC) of 0.2 μM and 2.6 μM against replicating and nonreplicating Mycobaterium tuberculosis, respectively. These attributes make 9d an interesting lead compound. A number of modifications were made to the structure of 9d, and a series of active compounds were discovered. Although some neurotoxicity was observed at a high dosage, this new series was endowed with both improved in vitro anti-TB activity and metabolic stability in comparison to compound 3. ©2009 American Chemical Society.
2009
From serendipity to rational antituberculosis drug discovery of mefloquine-isoxazole carboxylic acid esters / Mao, Jialin; Yuan, Hai; Wang, Yuehong; Wan, Baojie; Pieroni, Marco; Huang, Qingqing; Van Breemen, Richard B.; Kozikowski, Alan P; Franzblau, Scott G.. - In: JOURNAL OF MEDICINAL CHEMISTRY. - ISSN 0022-2623. - 52:22(2009), pp. 6966-6978. [10.1021/jm900340a]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11381/2822819
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