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首页> 外文期刊>RSC Advances >SAR studies on 1,2,4-triazolo[3,4-b][1,3,4] thiadiazoles as inhibitors of Mtb shikimate dehydrogenase for the development of novel antitubercular agents
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SAR studies on 1,2,4-triazolo[3,4-b][1,3,4] thiadiazoles as inhibitors of Mtb shikimate dehydrogenase for the development of novel antitubercular agents

机译：1,2,4-三唑并[3,4-b] [1,3,4]噻二唑作为Mtb sh草酸脱氢酶抑制剂的SAR研究，用于开发新型抗结核药

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摘要

Shikimate dehydrogenase, an essential protein for the biosynthesis of the chorismate end product, is a highly promising therapeutic target, especially for the discovery and development of new-generation anti-TB agents. Following up the identification of one lead 3,6-disubstituted 1,2,4-triazolo[3,4-b][1,3,4] thiadiazole (1), targeting Mt SD in our previous study, an extensive SAR study for optimization of the lead compound was performed through systematic modification of the 3 and 6 positions. This study has successfully led to the discovery of two highly potent advanced leads 6d-4, 6c-4 and several other compounds with comparable potencies (6d-4, MIC-H37Rv = 0.5 mu g mL(-1); MIC-MDRTB = 4.0 mu g mL(-1); MIC-RDRTB = 0.5 mu g mL(-1); Mt SD-IC50 = 14.20 mu g mL(-1); and 6c-4, MIC-H37Rv = 0.5 mu g mL(-1); MIC-MDRTB = 4.0 mu g mL(-1); MIC-RDRTB = 1.0 mu g mL(-1); Mt SD-IC50 = 6.82 mu g mL(-1)). These advanced lead compounds possess a para-halogen phenyl at the 3 position. In vitro Mt SD inhibitory assay indicates that Mt SD is the target for their antitubercular activity. Moreover, the BacT/ALERT 3D liquid culture technology and in vitro Mt SD inhibitory assay were initially applied.
机译：Shikimate脱氢酶是分支酸终产物生物合成的必需蛋白，是高度有前途的治疗靶标，尤其是对于新一代抗结核病药物的发现和开发。在我们先前的一项广泛SAR研究中，针对一种3,6-二取代的1,2,4-三唑并[3,4-b] [1,3,4]噻二唑（1）进行鉴定通过系统地修饰3和6位来优化前导化合物。这项研究成功地导致发现了两种高效的高级铅6d-4、6c-4和其他几种具有可比效价的化合物（6d-4，MIC-H37Rv = 0.5μg mL（-1）; MIC-MDRTB = 4.0μg mL（-1）; MIC-RDRTB = 0.5μg mL（-1）; Mt SD-IC50 = 14.20μg mL（-1）; 6c-4，MIC-H37Rv = 0.5μg mL（ -1）; MIC-MDRTB = 4.0μg mL（-1）; MIC-RDRTB = 1.0μg mL（-1）; Mt SD-IC50 = 6.82μg mL（-1））。这些先进的铅化合物在3位上具有对卤素苯基。体外Mt SD抑制试验表明Mt SD是其抗结核活性的靶标。此外，最初应用了BacT / ALERT 3D液体培养技术和体外Mt SD抑制分析。

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