and Studies of the Trypanocidal Effect of Novel Quinolines.

Therapies for human African trypanosomiasis and Chagas disease, caused by and , 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 and by phenotypic studies using and 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. screens against bloodstream forms of 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 (ECs) of <3 μM (4-fold lower than that of Bz). Nine quinolines were more effective than Bz (2.7 μM) against amastigotes, showing ECs ranging from 0.6 to 0.1 μM. All quinolines were also highly active against African trypanosomes, showing ECs of ≤0.25 μM. The most potent and highly selective candidates for each parasite species were tested in models. Results for DB2186 were promising in mice with and infections, reaching a 70% reduction of the parasitemia load for , and it cured 2 out of 4 mice infected with DB2217 was also active and cured all 4 mice (100% cure rate) with infection.