Estudo pré-clínico de análogos isoxazólicos derivados das neolignanas tetrahidrofurânicas: a busca por novos candidatos a fármacos com atividade antileishmania

Abstract

Leishmaniasis is a complex of neglected diseases caused by Trypanosomatidae parasites belonging to the Leishmania genus and a health threat to vulnerable populations in endemic areas, such as Brazil. Adverse effects, toxicity, and parasite resistance limit the available antileishmanial treatment. In this context, searching for new drug candidates is relevant, providing improved treatment possibilities to individuals with this disease. Tetrahydrofuran neolignans present several biological activities, including its antileishmanial potential. This work aims to study synthetic isoxazole analogs inspired by the scaffold of neolignans veraguensin, grandisin, and machilin G and designed with molecular modification strategies such as hybridization and bioisosterism. Thus, to continue the in vitro study previously concluded with relevant results, we planned to investigate the in vivo antileishmanial activity with a murine model experimentally infected with Leishmania (Leishmania) amazonensis by intralesional treatment. Also, we were interested in analyzing the parasite load by the limiting dilution technique as the kinetics of lesions during the treatment. Hence, we proposed to perform the in silico toxicity parameters of the analogs and to evaluate the mutagenicity potential (Ames test) of the analogs with therapeutic effect in vivo. Another segment of this work was to perform a preclinical in vitro and in vivo study of chlorine-isoxazole analogs as further in silico assessment and mutagenicity evaluation. Hence this work provides a relevant milestone in searching for new drug candidates once two analogs, a hybrid between veraguensin and grandisin, and a chlorine derivative of grandisin and machilin G, showed significant therapeutic effect after the intralesional treatment of BALB/ c mice infected with L. amazonensis compared to the control group. Furthermore, there was a non-significative difference between the groups treated with isoxazole derivatives and Glucantime. These findings suggest that isoxazole-neolignan analogs might be promising alternatives to treat cutaneous leishmaniasis.