TY - JOUR
T1 - Searching for new cures for tuberculosis
T2 - Design, synthesis, and biological evaluation of 2-methylbenzothiazoles
AU - Huang, Qingqing
AU - Mao, Jialin
AU - Wan, Baojie
AU - Wang, Yuehong
AU - Brun, Reto
AU - Franzblau, Scott G.
AU - Kozikowski, Alan P.
PY - 2009/11/12
Y1 - 2009/11/12
N2 - The actual development and clinical use of new therapeutics for tuberculosis (TB) have remained stagnant for years because of the complexity of the disease process, the treatment of which at present requires the administration of drug combinations over a 6month period. There is thus an urgent need for the discovery and development of novel, more active, and less toxic anti-TB agents. In this study, we report on the chemistry and biology of a series of potent 5-(2-methylbenzothiazol-5-yloxymethyl) isoxazole-3-carboxamide derivatives, which proved to be active against replicating Mycobacterium tuberculosis (Mtb) H37Rv. The most potent compounds 7j and 7s were found to inhibit Mtb growth at micromolar concentrations, with MICvalues of 1.4 and 1.9 μM, respectively. Impressively, all active compounds were nontoxic toward Vero cells (IC50 > 128 μM). Moreover, the best of these compounds were also tested against protozoan parasites, and some of these compounds were found to show activity, especially against Plasmodium falciparum. These studies thus suggest that certain 2-methylbenzothiazole based compounds may serve as promising lead scaffolds for further elaboration as anti-TB drugs and as possible antimalaria drugs.
AB - The actual development and clinical use of new therapeutics for tuberculosis (TB) have remained stagnant for years because of the complexity of the disease process, the treatment of which at present requires the administration of drug combinations over a 6month period. There is thus an urgent need for the discovery and development of novel, more active, and less toxic anti-TB agents. In this study, we report on the chemistry and biology of a series of potent 5-(2-methylbenzothiazol-5-yloxymethyl) isoxazole-3-carboxamide derivatives, which proved to be active against replicating Mycobacterium tuberculosis (Mtb) H37Rv. The most potent compounds 7j and 7s were found to inhibit Mtb growth at micromolar concentrations, with MICvalues of 1.4 and 1.9 μM, respectively. Impressively, all active compounds were nontoxic toward Vero cells (IC50 > 128 μM). Moreover, the best of these compounds were also tested against protozoan parasites, and some of these compounds were found to show activity, especially against Plasmodium falciparum. These studies thus suggest that certain 2-methylbenzothiazole based compounds may serve as promising lead scaffolds for further elaboration as anti-TB drugs and as possible antimalaria drugs.
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U2 - 10.1021/jm901112f
DO - 10.1021/jm901112f
M3 - Article
C2 - 19817445
AN - SCOPUS:71049161722
SN - 0022-2623
VL - 52
SP - 6757
EP - 6767
JO - Journal of medicinal chemistry
JF - Journal of medicinal chemistry
IS - 21
ER -