From serendipity to rational antituberculosis drug discovery of mefloquine-isoxazole carboxylic acid esters.
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 microM and 2.6 microM 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.
Institute for Tuberculosis Research, College of Pharmacy, University of Illinois at Chicago, 833 South Wood Street, Chicago, Illinois 60612, USA.
Jialin
J
Mao
Hai
H
Yuan
Yuehong
Y
Wang
Baojie
B
Wan
Marco
M
Pieroni
Qingqing
Q
Huang
Richard B
RB
van Breemen
Alan P
AP
Kozikowski
Scott G
SG
Franzblau
D000818:Animals; D000995:Antitubercular Agents / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology* / Q000633:toxicity; D002522:Chlorocebus aethiops; D055808:Drug Discovery; D004952:Esters / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology* / Q000633:toxicity; D005260:Female; D006801:Humans; D007555:Isoxazoles / Q000737:chemistry*; D015767:Mefloquine / Q000031:analogs & derivatives* / Q000737:chemistry; D051379:Mice; D008826:Microbial Sensitivity Tests; D008862:Microsomes, Liver / Q000378:metabolism; D009169:Mycobacterium tuberculosis / Q000187:drug effects; D014709:Vero Cells
D000995:Antitubercular Agents; D004952:Esters; D007555:Isoxazoles; C057006:Ro 21-5104; D015767:Mefloquine