5v49

Publication Abstract from PubMed

Potent inhibitors of Trypanosoma brucei methionyl-tRNA synthetase were previously designed using a structure-guided approach. Compounds 1 and 2 were the most active compounds in the cyclic and linear linker series, respectively. To further improve cellular potency, SAR investigation of a binding fragment targeting the "enlarged methionine pocket" (EMP) was performed. The optimization led to the identification of a 6,8-dichloro-tetrahydroquinoline ring as a favorable fragment to bind the EMP. Replacement of 3,5-dichloro-benzyl group (the EMP binding fragment) of inhibitor 2 using this tetrahydroquinoline fragment resulted in compound 13, that exhibited an EC50 of 4nM.

Optimization of a binding fragment targeting the "enlarged methionine pocket" leads to potent Trypanosoma brucei methionyl-tRNA synthetase inhibitors.,Huang W, Zhang Z, Ranade RM, Gillespie JR, Barros-Alvarez X, Creason SA, Shibata S, Verlinde CLMJ, Hol WGJ, Buckner FS, Fan E Bioorg Med Chem Lett. 2017 Jun 15;27(12):2702-2707. doi:, 10.1016/j.bmcl.2017.04.048. Epub 2017 Apr 17. PMID:28465105^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.