Design, Synthesis, and Structure鈭扐ctivity Relationship of Trypanosoma brucei Leucyl-tRNA Synthetase Inhibitors as Antitrypanosomal Agents

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• 作者：Dazhong Ding ; Qingqing Meng ; Guangwei Gao ; Yaxue Zhao ; Qing Wang ; Bakela Nare ; Robert Jacobs ; Fernando Rock ; Michael R. K. Alley ; Jacob J. Plattner ; Guoqiang Chen ; Dawei Li ; Huchen Zhou
• 刊名：Journal of Medicinal Chemistry
• 出版年：2011
• 出版时间：March 10, 2011
• 年：2011
• 卷：54
• 期：5
• 页码：1276-1287
• 全文大小：1068K
• 年卷期：v.54,no.5(March 10, 2011)
• ISSN：1520-4804

文摘

African trypanosomiasis, caused by the proto zoal pathogen Trypanosoma brucei (T. brucei), is one of the most neglected tropical diseases that are in great need of new drugs. We report the design and synthesis of T. brucei leucyl-tRNA synthetase (TbLeuRS) inhibitors and their structure鈭抋ctivity relationship. Benzoxaborole was used as the core structure and C(6) was modified to achieve improved affinity based on docking results that showed further binding space at this position. Indeed, compounds with C(7) substitutions showed diminished activity due to clash with the eukaryote specific I4ae helix while substitutions at C(6) gave enhanced affinity. TbLeuRS inhibitors with IC₅₀ as low as 1.6 渭M were discovered, and the structure鈭抋ctivity relationship was discussed. The most potent enzyme inhibitors also showed excellent T. brucei parasite growth inhibition activity. This is the first time that TbLeuRS inhibitors are reported, and this study suggests that leucyl-tRNA synthetase (LeuRS) could be a potential target for antiparasitic drug development.