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

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−activity rela...

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Published in:Journal of medicinal chemistry 2011-03, Vol.54 (5), p.1276-1287
Main Authors: Ding, Dazhong, Meng, Qingqing, Gao, Guangwei, Zhao, Yaxue, Wang, Qing, Nare, Bakela, Jacobs, Robert, Rock, Fernando, Alley, Michael R. K, Plattner, Jacob J, Chen, Guoqiang, Li, Dawei, Zhou, Huchen
Format: Article
Language:English
Subjects:
Animals
Boronic Acids - chemical synthesis
Boronic Acids - chemistry
Boronic Acids - pharmacology
Cell Line
Drug Design
Leucine-tRNA Ligase - antagonists & inhibitors
Mice
Models, Molecular
Stereoisomerism
Structure-Activity Relationship
Trypanocidal Agents - chemical synthesis
Trypanocidal Agents - chemistry
Trypanocidal Agents - pharmacology
Trypanosoma brucei brucei - drug effects
Trypanosoma brucei brucei - enzymology
Trypanosoma brucei brucei - growth & development
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Summary: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−activity 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 μM 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.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm101225g