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.

Genetic Validation of Aminoacyl-tRNA Synthetases as Drug Targets in Trypanosoma brucei

“…Several T. brucei aaRS genes have been reported to be essential in parasites in either the insect stage (procyclic) or the mammalian stage (21,(25)(26)(27)(28)(29)(30). Several groups have also reported the identification of MetRS, IleRS, and LeuRS inhibitors with antitrypanosome activity (30)(31)(32)(33)(34)(35). Crystal structures have been solved for many of the aaRSs across several species (15), including the structures of HisRS (36) and TrpRS (37) from T. brucei, which will aid in understanding how to target these enzymes for HAT drug discovery.…”

Highlights on Trypanosomatid Aminoacyl-tRNA Synthesis

“…Benzoxaborole derived T. brucei LeuRS inhibitors with IC50 as low as 1.6 μM were discovered. The most potent enzyme inhibitors in this study also showed excellent T. brucei parasite growth inhibition activity (Ding et al 2011 ). In a separate investigation, a number of 2-pyrrolinones were discovered to be good LeuRS inhibitors and they have potential as lead compounds for the design of other drugs (Zhao et al 2012 ).…”

“…For trypanosomatids there have been screenings for inhibitors of only LysRS and LeuRS (Farrera-Sinfreu et al 2008 ;Ding et al 2011 ;Koh et al 2012 ;Zhao et al 2012 ). Benzoxaborole derived T. brucei LeuRS inhibitors with IC50 as low as 1.6 μM were discovered.…”

Identification of Mycobacterium tuberculosis leucyl-tRNA synthetase (LeuRS) inhibitors among the derivatives of 5-phenylamino-2H-[1,2,4]triazin-3-one

“…The compound ZCL039, a benzoxaborolebased derivative of AN2690, was reported as potent antipneumococcal agent that inhibits Streptococcus pneumonia LeuRS activity 8 . Ding et al discovered effective Trypanosoma brucei LeuRS inhibitors 9 . Recently, we have found inhibitors of Mycobacterium tuberculosis LeuRS among the derivatives of N-Benzylidene-N 0 -thiazol-2-yl-hydrazine 10 .…”