540779-02-0Relevant articles and documents
Optimization of a binding fragment targeting the “enlarged methionine pocket” leads to potent Trypanosoma brucei methionyl-tRNA synthetase inhibitors
Huang, Wenlin,Zhang, Zhongsheng,Ranade, Ranae M.,Gillespie, J. Robert,Barros-álvarez, Ximena,Creason, Sharon A.,Shibata, Sayaka,Verlinde, Christophe L.M.J.,Hol, Wim G.J.,Buckner, Frederick S.,Fan, Erkang
supporting information, p. 2702 - 2707 (2017/05/29)
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 4?nM.
