Synthesis and antituberculosis activity of novel mefloquine-isoxazole carboxylic esters as prodrugs.
5-(2,8-Bis(trifluoromethyl)quinolin-4-yloxymethyl)isoxazole-3-carboxylic acid ethyl ester (compound 3) was reported to have excellent antituberculosis activity against both replicating and non-replicating Mycobacterium tuberculosis, with a minimum inhibitory concentration (MIC) of 0.9 microM and 12.2 microM, respectively. In this study, the antituberculosis activity of compound 3 was further investigated. Its activity appeared to be very specific for organisms of the M. tuberculosis complex and it effected significant reductions of bacterial numbers in infected macrophages with an EC(90) of 4.1 microM. More importantly, the increased in vitro antituberculosis activity of the corresponding acid (compound 4) at pH 6.0 suggested that it may be active in vivo in an acidic environment produced as a consequence of inflammation in the lungs of TB patients. The fact that various ester bioisosteres of compound 3 lost anti-TB activity further suggested that the ester compound 3 may function as a prodrug. The detailed structure-activity relationships (SARs) from this study should facilitate our ultimate goal of improving the anti-TB potency of this isoxazole ester series.
Mao
Jialin
J
Institute for Tuberculosis Research, College of Pharmacy, University of Illinois at Chicago, IL 60612, United States.
Yuan
Hai
H
Wang
Yuehong
Y
Wan
Baojie
B
Pak
Dennis
D
He
Rong
R
Franzblau
Scott G
SG
D000995:Antitubercular Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D002264:Carboxylic Acids / Q000138:chemical synthesis* / Q000494:pharmacology; D004952:Esters; D006801:Humans; D007555:Isoxazoles / Q000138:chemical synthesis* / Q000494:pharmacology; D015767:Mefloquine / Q000138:chemical synthesis* / Q000494:pharmacology; D008826:Microbial Sensitivity Tests; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000254:growth & development*; D011355:Prodrugs / Q000138:chemical synthesis* / Q000494:pharmacology
D000995:Antitubercular Agents; D002264:Carboxylic Acids; D004952:Esters; D007555:Isoxazoles; D011355:Prodrugs; D015767:Mefloquine