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Abstract: Human African trypanosomiasis is a fatal parasitic infection caused by the protozoan Trypanosoma brucei. The development of novel antitrypanosomal agents is urgently needed. Here we report the synthesis and structure–activity relationship of a new class of benzoxaboroles as antitrypanosomal agents. These compounds showed antiparasitic IC50 values ranging from 4.02 to 0.03 μg/mL and satisfactory cytotoxicity profile. Three of the lead compounds were demonstrated to cure the parasitic infection in a murine acute infection model. The structure–activity relationship of the pyrrolobenzoxaboroles are also discussed. [Copyright &y& Elsevier]

Human African trypanosomiasis (HAT), caused by the parasitic protozoa Trypanosoma brucei , is one of the fatal diseases in tropical areas and current medicines are insufficient. Thus, development of new drugs for HAT is urgently needed. Leucyl-tRNA synthetase (LeuRS), a recently clinically validated antimicrobial target, is an attractive target for development of antitrypanosomal drugs. In this work, we report a series of α-phenoxy- N -sulfonylphenyl acetamides as T. brucei LeuRS inhibitors. The most potent compound 28g showed an IC 50 of 0.70 μM which was 250-fold more potent than the starting hit compound 1. The structure-activity relationship was also discussed. These acetamides provided a new scaffold and lead compounds for the further development of clinically useful antitrypanosomal agents. Image 1 • An α-phenoxy- N -sulfonylphenyl acetamide scaffold discovered to inhibit Tb LeuRS with good potency. • A series of new Tb LeuRS inhibitors synthesized and a structure-activity relationship discussed. • Compound 28g showed an IC 50 as low as 0.70 μM. [ABSTRACT FROM AUTHOR]