by de Oliveira Rezende Júnior C, Grigol Martinez PD, Alves Ferreira RA, Koovits PJ, Soares BM, Ferreira LLG, Michelan-Duarte S, Consolin Chelucci R, Andricopulo AD, Matheeussen A, Van Pelt N, Caljon G, Maes L, Campbell S, Kratz JM, Mowbray CE, Dias LC. European Journal of Medicinal Chemistry 2022; 114925. doi: 10.1016/j.ejmech.2022.114925
Summary: There is an urgent need for new treatments for Chagas disease, caused by Trypanosoma cruzi. The authors of this manuscript describe the hit-to-lead optimization of a 2-aminobenzimidazole hit identified through in vitro phenotypic screening of a chemical library against intracellular Trypanosoma cruzi amastigotes. Multiparametric structure−activity relationships were investigated using a set of 277 derivatives. Although the physicochemical and biological properties of the initial hits were improved, a combination of low kinetic solubility and in vitro cytotoxicity against mammalian cells meant that they weren’t considered for an efficacy study using a mouse model of Chagas disease. Research is ongoing to identify the mechanism of action of this series and evaluate whether the antitrypanosomal activity can be decoupled from the cytotoxic effects observed.