TB Discovery Research, Infectious Disease Research Institute , Seattle, WA , USA.
PeerJ. 2014 Oct 7;2:e612. doi: 10.7717/peerj.612. eCollection 2014.
We demonstrated that the 3-substituted benzothiophene-1,1-dioxide class of compounds are effective inhibitors of Mycobacterium tuberculosis growth under aerobic conditions. We examined substitution at the C-3 position of the benzothiophene-1,1-dioxide series systematically to delineate structure-activity relationships influencing potency and cytotoxicity. Compounds were tested for inhibitory activity against virulent M. tuberculosis and eukaryotic cells. The tetrazole substituent was most potent, with a minimum inhibitory concentration (MIC) of 2.6 µM. However, cytotoxicity was noted with even more potency (Vero cell TC50 = 0.1 µM). Oxadiazoles had good anti-tubercular activity (MICs of 3-8 µM), but imidazoles, thiadiazoles and thiazoles had little activity. Cytotoxicity did not track with anti-tubercular activity, suggesting different targets or mode of action between bacterial and eukaryotic cells. However, we were unable to derive analogs without cytotoxicity; all compounds synthesized were cytotoxic (TC50 of 0.1-5 µM). We conclude that cytotoxicity is a liability in this series precluding it from further development. However, the series has potent anti-tubercular activity and future efforts towards identifying the mode of action could result in the identification of novel drug targets.
我们证明了 3-取代苯并噻吩-1,1-二氧化物类化合物是有氧条件下抑制结核分枝杆菌生长的有效抑制剂。我们系统地研究了苯并噻吩-1,1-二氧化物系列化合物在 C-3 位置的取代，以描绘影响效力和细胞毒性的结构-活性关系。测试了化合物对有毒结核分枝杆菌和真核细胞的抑制活性。四唑取代基最有效，最小抑菌浓度（MIC）为 2.6 µM。然而，即使更有效（Vero 细胞 TC50 = 0.1 µM）也会出现细胞毒性。恶二唑具有良好的抗结核活性（MIC 为 3-8 µM），但咪唑、噻二唑和噻唑活性较低。细胞毒性与抗结核活性不相关，表明细菌和真核细胞之间的靶标或作用模式不同。然而，我们无法衍生无细胞毒性的类似物；所有合成的化合物都具有细胞毒性（TC50 为 0.1-5 µM）。我们得出结论，细胞毒性是该系列化合物的一个缺陷，使其无法进一步开发。然而，该系列具有很强的抗结核活性，未来努力确定作用模式可能会确定新的药物靶标。
