Human African trypanosomiasis (HAT), caused by the protozoan parasite Trypanosoma brucei, is a
neglected fatal disease. Leucyl-tRNA synthetase (LeuRS), which has been successfully applied in the
development of antifungal agent, represents a potential antiprotozoal drug target. In this study, a 3D
model of T. brucei LeuRS (TbLeuRS) synthetic active site was constructed and subjected to virtual screening
using a combination of pharmacophore- and docking-based methods. A new 2-pyrrolinone scaffold
was discovered and the structure–activity relationship (SAR) studies aided by the docking model and
organic synthesis were carried out. Compounds with various substituents on R1, R2 and R3 were synthesized
and their SAR was discussed.