Design, Synthesis, and Structure-Activity Relationship of Trypanosoma brucei Leucyl-tRNA Synthetase Inhibitors as Antitrypanosomal Agents
Design, Synthesis, and Structure-Activity Relationship of Trypanosoma brucei Leucyl-tRNA Synthetase Inhibitors as Antitrypanosomal Agents
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DOI：
10.1021/jm101225g
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发表时间：
2011-03-10
影响因子：
7.3
通讯作者：
Zhou, Huchen
中科院分区：
文献类型：
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作者：
Ding, Dazhong;Meng, Qingqing;Zhou, Huchen
非洲锥虫病是由原生动物布氏锥虫(Tlypanosoma brucei，Tlypanosoma brucei)引起的热带病，是最被忽视的热带病之一，急需新药治疗。本文报道了布鲁氏菌甲酰-tRNA合成酶(TbLeuRS)抑制剂的设计、合成及其构效关系。以苯并口恶硼为核心结构，对C(6)进行了修饰以获得更好的亲和力，对接结果表明该位置有更多的结合空间。事实上，具有C(7)取代的化合物由于与真核生物特有的I4ae螺旋发生碰撞而活性降低，而C(6)上的取代则增强了亲和力。发现了IC50低至1.6µM的TbLeuRS抑制剂，并对其构效关系进行了讨论。最有效的酶抑制剂也表现出很好的抑制布氏毛滴虫生长的活性。这是TbLeuRS抑制剂的首次报道，本研究表明亮氨酰-tRNA合成酶(Leucyl-tRNA Synthetase，LEUR)可能成为抗寄生虫药物开发的潜在靶点。
African trypanosomiasis, caused by the protozoal pathogen Tlypanosoma 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. bruceileucyl-tRNA synthetase (TbLeuRS) inhibitors and their structure activity relationship. Benzoxaborole was used as the core structure and C(6) was modified to achieve improved affinity bared 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 mu M were discovered, and the structure activity 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.