State Key Laboratory of Microbial Metabolism, School of Pharmacy, Shanghai Jiao Tong University, Shanghai, 200240, People's Republic of China.
State Key Laboratory of Microbial Metabolism, School of Pharmacy, Shanghai Jiao Tong University, Shanghai, 200240, People's Republic of China.
Eur J Med Chem. 2021 May 5;217:113319. doi: 10.1016/j.ejmech.2021.113319. Epub 2021 Mar 8.
The protozoan parasite Trypanosoma brucei (T. brucei) causes human African trypanosomiasis (HAT), which is a fatal and neglected disease in the tropic areas, and new treatments are urgently needed. Leucyl-tRNA synthetase (LeuRS) is an attractive target for the development of antimicrobial agents. In this work, starting from the hit compound thiourea ZCL539, we designed and synthesized a series of amides as effective T. brucei LeuRS (TbLeuRS) synthetic site inhibitors. The most potent compounds 74 and 91 showed IC of 0.24 and 0.25 μM, which were about 700-fold more potent than the starting hit compound. The structure-activity relationship was also discussed. These compounds provided a new scaffold and lead compounds for further development of antitrypanosomal agents.
原生动物寄生虫布氏锥虫（Trypanosoma brucei，T. brucei）引起人类非洲锥虫病（Human African trypanosomiasis，HAT），这是热带地区一种致命且被忽视的疾病，急需新的治疗方法。亮氨酰-tRNA 合成酶（Leucyl-tRNA synthetase，LeuRS）是开发抗菌药物的一个有吸引力的靶点。在这项工作中，我们从命中化合物硫脲 ZCL539 出发，设计并合成了一系列酰胺作为有效的 T. brucei LeuRS（TbLeuRS）合成部位抑制剂。最有效的化合物 74 和 91 的 IC 为 0.24 和 0.25 μM，比起始命中化合物的活性高约 700 倍。还讨论了构效关系。这些化合物为进一步开发抗锥虫药物提供了新的骨架和先导化合物。
