Trypanosoma cruzi Malic Enzyme Is the Target for Sulfonamide Hits from the GSK Chagas Box

Abstract

Chagas disease, an infectious condition caused byTrypanosoma cruzi, lacks treatment with drugs with desired efficacy and safety profiles. To address this unmet medical need, a set of trypanocidal compounds were identified through a large multicenter phenotypic-screening initiative and assembled in the GSK Chagas Box. In the present work, we report the screening of the Chagas Box against T. cruzi malic enzymes (MEs) and the identification of three potent inhibitors of its cytosolic isoform (TcMEc). One of these compounds, TCMDC-143108 (1), came out as a nanomolar inhibitor of TcMEc, and 14 new derivatives were synthesized and tested for target inhibition and efficacy against the parasite. Moreover, we determined the crystallographic structures of TcMEc in complex with TCMDC-143108 (1) and six derivatives, revealing the allosteric inhibition site and the determinants of specificity. Our findings connect phenotypic hits from the Chagas Box to a relevant metabolic target in the parasite, providing data to foster new structure−activity guided hit optimization initiatives.

In Vitro Evaluation of Arylsulfonamide Derivatives against Trypanosoma cruzi

“…Given the negative economic and social impact caused by Chagas disease, the search for new drugs has become increasingly necessary to treat this disease. Arylsulfonamide compounds have demonstrated promising activity against T. cruzi [7][8][9][10][11][12][13][14][15][16][17]. In order to meet this deficit in new drug candidates for Chagas disease, we have prepared and tested arylsulfonamide derivatives against T. cruzi, evaluated their cytotoxic effects against L929 cells, and determined the selectivity index.…”

“…Given the negative economic and social impact caused by Chagas disease, the search for new drugs has become increasingly necessary to treat this disease. Arylsulfonamide compounds have demonstrated promising activity against T. cruzi [7][8][9][10][11][12][13][14][15][16][17]. The arylsulfonamide motif was an important structural component of piperazines with anti T. cruzi activity and improved metabolic stability [7].…”

“…Interestingly, arylsulfonamide compounds demonstrated promising activity against T. cruzi by targeting the T. cruzi proteasome, binding at the interface key subunits important for catalyzing chymotrypsin-like peptidase activity [8]. Furthermore, the T. cruzi cytosolic malic enzyme (TcMEc) has been targeted by an arylsulfonamide TcMEc inhibitor, TCMDC-143108, and 14 analogues of this same compound [9]. Impressive results have been described with the sulfonamide series of 4-aminopyridyl-based inhibitors, which were reported to have achieved high picomolar and low nanomolar inhibition of TcCYP51, important for its role in the biosynthesis of ergosterol [10].…”