The Trypanocidal Effect of Novel Quinolines: In vitro And In vivo Studies [PublishAheadOfPrint]

The therapy for Human African Trypanosomiasis and Chagas Disease, caused by Trypanosoma brucei and Trypanosoma cruzi respectively, are limited providing minimal therapeutic options for the millions of individuals living in very poor communities. The effect of ten novel quinolines are evaluated herein through in silico and by phenotypic studies using in vitro and in vivo models. ADMET properties revealed that most molecules did not infringe Lipinski's rules, which is a prediction of good oral absorption. They showed good probability of CaCo₂ permeability and for human intestinal absorption, low probability of mutagenicity and of hERG1 inhibition. In vitro screens against bloodstream forms of T.cruzi demonstrated that all quinolines were more active than the reference drug (benznidazole —Bz), except DB2171 and DB2192, with five (DB2187, DB2131, DB2186, DB2191 and DB2217), displaying EC₅₀ <3 μM (<4-fold than Bz). Nine quinolines were more effective than Bz (2.7 μM) against amastigotes showing EC₅₀ values ranging from 0.6 to 0.1 μM. All quinolines were also in vitro highly active on African trypanosomes showing EC₅₀ values ≤ 0.25 μM. The most potent and highly selective candidates for each parasite species were tested in vivo models. Results for DB2186 were promising in mice with T.cruzi and T.brucei infection, reaching 70 % reduction of the parasitemia load and it cured 2 of 4 mice, respectively. DB2217 was in vivo also active and cured all 4 mice (100% cure rate) with T.brucei infection.

http://ift.tt/2klb0vV