Searching for New Cures for Tuberculosis: Design, Synthesis, and Biological Evaluation of 2-Methylbenzothiazoles
Searching for New Cures for Tuberculosis: Design, Synthesis, and Biological Evaluation of 2-Methylbenzothiazoles
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DOI：
10.1021/jm901112f
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发表时间：
2009-11-12
影响因子：
7.3
通讯作者：
Kozikowski, Alan P.
中科院分区：
文献类型：
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作者：
Huang, Qingqing;Mao, Jialin;Kozikowski, Alan P.
由于疾病过程的复杂性，结核病新疗法的实际开发和临床应用多年来一直停滞不前，目前治疗结核病需要6个月以上的药物组合。因此，迫切需要发现和开发新的、更活跃、毒性更低的抗结核病药物。在这项研究中，我们报道了一系列有效的5-(2-methylbenzothiazol-5-yloxy-methyl)isoxazole-3-carboxamide衍生物的化学和生物学性质，它们被证明对复制的结核分枝杆菌H(37)轮状病毒具有活性。最强的化合物7J和7S在微摩尔浓度下对结核分枝杆菌的生长有抑制作用，其MIC值分别为1.4和1.9µM。令人印象深刻的是，所有活性化合物对Vero细胞都是无毒的(IC50和GT；128mM)。此外，这些化合物中最好的也被测试对原虫寄生虫，其中一些化合物被发现显示出活性，特别是对恶性疟原虫。因此，这些研究表明，某些基于2-甲基苯并噻唑的化合物可以作为有希望的铅支架，作为抗结核病药物和可能的抗疟疾药物进一步精制。
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 6 month period. There is thus all 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-yloxy-methyl)isoxazole-3-carboxamide derivatives, which proved to be active against replicating Mycobacterium tuberculosis (Mtb) H(37)Rv. The most potent compounds 7j and 7s were found to inhibit Mtb growth at micromolar concentrations, with MIC values of 1.4 and 1.9 mu M, respectively. Impressively, all active compounds were nontoxic toward Vero cells (IC50 > 128 mu M). 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.