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Abstract: 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. [Copyright &y& Elsevier]

• Starting from initial hit compound 1 , a series of benzhydrol-oxaborole hybrid compounds were designed and synthesized as inhibitors of S. pneumoniae LeuRS. • Structure-based optimization led to the discovery of compound 46 and 54 , which showed improved potency (IC 50 = 0.368 and 0.950 μM) when compared with parent compound 1. • The co-crystal of compound 54 in the editing domain pocket of Sp LeuRS was obtained and revealed the binding mode of compound 54. Pneumonia caused by bacterium S. pneumoniae is a severe acute respiratory infectious disease with high morbidity and mortality, especially for children and immunity-compromised patients. The emergence of multidrug-resistant S. pneumoniae also presents a challenge to human health. Leucyl-tRNA synthetase (LeuRS) catalyzes the attachment of l -leucine to tRNALeu, which plays an essential role in protein translation and is considered an attractive antimicrobial drug target. In the present work, benzhydrol-oxaborole hybrid compounds were designed and synthesized as inhibitors of S. pneumoniae LeuRS. Exploration of the phenyl ring near Lysine 389 eventually yielded compounds 46 and 54 with submicromolar inhibitory potency. The co-crystal of compound 54 in the editing domain pocket of Sp LeuRS was obtained and confirmed the formation of an additional hydrogen bond between the carbonyl of 54 and Lysine 389. It also showed anti-pneumococcal activity in vitro. The structure–activity relationship was discussed. This work will provide an essential foundation for the further development of anti-pneumococcal agents by targeting LeuRS. [ABSTRACT FROM AUTHOR]