Design and synthesis of N-(3-sulfamoylphenyl)amides as Trypanosoma brucei leucyl-tRNA synthetase inhibitors.

The protozoan parasite Trypanosoma brucei (T. brucei) causes human African trypanosomiasis (HAT), which is a fatal and neglected disease in the tropic areas, and new treatments are urgently needed. Leucyl-tRNA synthetase (LeuRS) is an attractive target for the development of antimicrobial agents. In this work, starting from the hit compound thiourea ZCL539, we designed and synthesized a series of amides as effective T. brucei LeuRS (TbLeuRS) synthetic site inhibitors. The most potent compounds 74 and 91 showed IC50 of 0.24 and 0.25 µM, which were about 700-fold more potent than the starting hit compound. The structure-activity relationship was also discussed. These compounds provided a new scaffold and lead compounds for further development of antitrypanosomal agents.

Progress in the Discovery of Small Molecule Modulators of DeSUMOylation.

SUMOylation and DeSUMOylation are reversible protein post-translational modification (PTM) processes involving small ubiquitin-like modifier (SUMO) proteins. These processes have indispensable roles in various cellular processes, such as subcellular localization, gene transcription, and DNA replication and repair. Over the past decade, increasing attention has been given to SUMO-related pathways as potential therapeutic targets. The Sentrin/SUMO-specific protease (SENP), which is responsible for deSUMOylation, has been proposed as a potential therapeutic target in the treatment of cancers and cardiac disorders. Unfortunately, no SENP inhibitor has yet reached clinical trials. In this review, we focus on advances in the development of SENP inhibitors in the past decade.

Design and synthesis of α-phenoxy-N-sulfonylphenyl acetamides as Trypanosoma brucei Leucyl-tRNA synthetase inhibitors.

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 IC50 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.

Design, Synthesis, and Structure-Activity Relationship of 7-Propanamide Benzoxaboroles as Potent Anticancer Agents.

Benzoxaboroles, as a novel class of bioactive molecules with unique physicochemical properties, have been shown to possess excellent antimicrobial activities with tavaborole approved in 2014 as an antifungal drug. Although urgently needed, the investigation of benzoxaboroles as anticancer agents has been lacking so far. In this study, we report the design, synthesis, and anticancer structure-activity relationship of a series of 7-propanamide benzoxaboroles. Compounds 103 and 115 showed potent activity against ovarian cancer cells with IC50 values of 33 and 21 nM, respectively. Apoptosis was induced by these compounds and colony formation was effectively inhibited. Furthermore, they also showed excellent efficacy in ovarian tumor xenograft mouse model.