Abstract

In continuation our effort to research the chemical space of aryloxy-naphthoquinones as potential anti-Chagas agents, we synthesized nine derivatives and these compounds were evaluated in vitro against the epimastigote and trypomastigote forms of Mexican strains of Trypanosoma cruzi (T. cruzi). Most of these derivatives are highly active against epimastigote forms (IC50 < 1.0 µM) compared to the reference drug benznidazole (Bzn). Then these were evaluated on trypomastigotes, which is showing better potency results than Bzn for compounds 3b and 3g. In addition, the cytotoxicity of these compounds was determined on the murine macrophage cell line J774. 3b and 3i were the most selective compounds against NINOA trypomastigote and INC-5 epimastigote forms, respectively. Further these compounds also have good oral bioavailability according to theoretical predictions. Finally, we were able to determine optimal substitution patterns using pharmacophoric models. All these results are provided very useful structural information to continue our designing of naphthoquinone derivatives against T. cruzi. [Figure not available: see fulltext.]