<i>In Vitro</i> and <i>In Vivo</i> Studies of the Trypanocidal Effect of Novel Quinolines

Abstract

Therapies for human African trypanosomiasis and Chagas disease, caused by <i>Trypanosoma brucei</i> and <i>Trypanosoma cruzi</i>, respectively, are limited, providing minimal therapeutic options for the millions of individuals living in very poor communities. Here the effects of 10 novel quinolines are evaluated <i>in silico</i> and by phenotypic studies using <i>in vitro</i> and <i>in vivo</i> models. Absorption, distribution, metabolism, excretion, and toxicity (ADMET) properties revealed that most molecules did not infringe on Lipinski's rules, which is a prediction of good oral absorption. These quinolines showed high probabilities of Caco2 permeability and human intestinal absorption and low probabilities of mutagenicity and of hERG1 inhibition. <i>In vitro</i> screens against bloodstream forms of <i>T. cruzi</i> demonstrated that all quinolines were more active than the reference drug (benznidazole [Bz]), except for DB2171 and DB2192, with five (DB2187, DB2131, DB2186, DB2191, and DB2217) displaying 50% effective concentrations (EC₅₀s) of <3 μM (4-fold lower than that of Bz). Nine quinolines were more effective than Bz (2.7 μM) against amastigotes, showing EC₅₀s ranging from 0.6 to 0.1 μM. All quinolines were also highly active <i>in vitro</i> against African trypanosomes, showing EC₅₀s of ≤0.25 μM. The most potent and highly selective candidates for each parasite species were tested in <i>in vivo</i> models. Results for DB2186 were promising in mice with <i>T. cruzi</i> and <i>T. brucei</i> infections, reaching a 70% reduction of the parasitemia load for <i>T. cruzi</i>, and it cured 2 out of 4 mice infected with <i>T. brucei</i> DB2217 was also active <i>in vivo</i> and cured all 4 mice (100% cure rate) with <i>T. brucei</i> infection.