Discovery of N-(4-sulfamoylphenyl)thioureas as Trypanosoma brucei leucyl-tRNA synthetase inhibitors

Abstract

Human African trypanosomiasis (HAT) is one of the most neglected diseases in the tropic regions, which is fatal if not treated in time. There is an urgent need for new therapeutics, especially those in new chemical classes. Leucyl-tRNA synthetase (LeuRS) has been paid much attention as a recently clinically validated antimicrobial target. Our group has previously reported T. brucei LeuRS (TbLeuRS) inhibitors, including benzoxaboroles targeting the editing site and pyrrolinones targeting the synthetic site. Here we report the discovery of N-(4-sulfamoylphenyl)thioureas as a new class of TbLeuRS inhibitors. The R(1) and R(2) groups, reminiscent of the leucyl and adenyl regions of aa-AMP and aa-AMS, were optimized to result in a significant 13-fold increase of inhibitory activity (compound 19, IC50 = 13.7 μM). Aided by ligand-protein docking, the 1,3-substitution at the central phenyl ring was predicted and proved to give significantly improved activity (59, IC50 = 1.1 μM). This work provided a new scaffold for the exploration of novel inhibitors against TbLeuRS, which may become potential therapeutics for the treatment of HAT.

Targeting Toxoplasma gondii CPSF 3 as a new approach to control toxoplasmosis

“…Human foreskin fibroblasts (HFFs) were infected with tachyzoites of the virulent RH strain and treated with benzoxaboroles, pyrimethamine, the standard of care to treat toxoplasmosis, or vehicle (DMSO). We screened a group of 20 representative benzoxaboroles that were previously shown to have activity against bacteria, fungi or other eukaryotic parasites (Rock et al , ; Xia et al , ; Hernandez et al , ; Zhang et al , ; Palencia et al , ). Some of these compounds were known to target leucyl‐tRNA synthetase (LeuRS).…”

Aminoacyl-tRNA synthetases as drug targets in eukaryotic parasites

“…More recently, a new class of T. brucei LeuRS inhibitors, N-(4-sulfamoylphenyl)thioureas, which targets the synthetic catalytic site, has been discovered through the screening and modification of a small, targeted library of putative aaRS inhibitors (Zhang et al, 2013). This class of inhibitors are designed to inhibit by mimicking the intermediate product, aminoacyl-AMP.…”

In Silico Discovery of Aminoacyl-tRNA Synthetase Inhibitors

“…(2011) and Zhang et al (2013) investigated T. brucei LeuRS using a structure-based drug design approach [12,54]. …”

“…By screening an in-house database of 500 compounds, Zhang et al [54] identified a T. brucei LeuRS inhibitor with an N -(4-sulfamoylphenyl)thiourea core structure (compound 22 , IC 50 = 174.5 μM; Figure 9). Computational studies suggested thiourea compounds bind to the synthetic active site rather than the editing active site.…”