From Serendipity to Rational Antituberculosis Drug Discovery of Mefloquine-Isoxazole Carboxylic Acid Esters

Abstract

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