title: Design, synthesis, and structure-activity relationship of Trypanosoma brucei leucyl-tRNA synthetase inhibitors as antitrypanosomal agents.
abstract: 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 IC(50) 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.
authors.affiliation: School of Pharmacy, Shanghai Jiao Tong University, Shanghai, China.
authors.forename: Dazhong
authors.initials: D
authors.lastname: Ding
authors.forename: Qingqing
authors.initials: Q
authors.lastname: Meng
authors.forename: Guangwei
authors.initials: G
authors.lastname: Gao
authors.forename: Yaxue
authors.initials: Y
authors.lastname: Zhao
authors.forename: Qing
authors.initials: Q
authors.lastname: Wang
authors.forename: Bakela
authors.initials: B
authors.lastname: Nare
authors.forename: Robert
authors.initials: R
authors.lastname: Jacobs
authors.forename: Fernando
authors.initials: F
authors.lastname: Rock
authors.forename: Michael R K
authors.initials: MR
authors.lastname: Alley
authors.forename: Jacob J
authors.initials: JJ
authors.lastname: Plattner
authors.forename: Guoqiang
authors.initials: G
authors.lastname: Chen
authors.forename: Dawei
authors.initials: D
authors.lastname: Li
authors.forename: Huchen
authors.initials: H
authors.lastname: Zhou
mesh_terms: D000818:Animals; D001897:Boronic Acids / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002460:Cell Line; D015195:Drug Design; D007935:Leucine-tRNA Ligase / Q000037:antagonists & inhibitors*; D051379:Mice; D008958:Models, Molecular; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014344:Trypanocidal Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D014346:Trypanosoma brucei brucei / Q000187:drug effects* / Q000201:enzymology / Q000254:growth & development
chemical_list: D001897:Boronic Acids; D014344:Trypanocidal Agents; D007935:Leucine-tRNA Ligase