Looking for approved-medicines to be repositioned as anti-Trypanosoma cruzi agents. Identification of new chemotypes with good individual- or in combination-biological behaviours

Abstract

BACKGROUND The neglected illness Chagas disease is treated with limited efficacy and adverse effects by old drugs. Due to the low interest of pharmaceutical industry in targeting economically depressed-patients, repurposing is a tool that should be applied because it can introduce new anti-Chagas entities into the clinic at reduced costs. OBJECTIVES To investigate the repurposing/combination of medicines strategies as anti-Chagas treatment. METHODS Epimastigotes, trypomastigotes and amastigotes of Trypanosoma cruzi were in vitro exposed to 28 Uruguayanapproved medicines not previously tested, 28 FDA-approved medicines previously evaluated, and three reference agents. Parasite inhibition was assessed and for the best drugs, in pairs-isobolographic studies, looking for synergism/additivity/antagonism, were done. Macrophages were used to study selectivity. For some relevant agents, we analysed whether medicines mammals´ action mechanisms are operative in epimastigotes-T. cruzi. FINDINGS From the anti-epimastigotes monotherapy-screening, we found that 18% of them showed better/comparable activities than references. Additionally, for the binary-combinations 8% were additive, 4% were synergic and the rest showed antagonism. Favourably, in macrophages-cytotoxicity four of the binary-combinations were antagonists. Naftazone and pinaverium bromide, not previously tested against T. cruzi, maintained their activity against trypomastigotes and amastigotes. The identified action mechanisms open the door to new strategies designing anti-T. cruzi drugs.