Atividade antileishmania in vitro de análogos isoxazólicos clorados derivados das neolignanas veraguensina, grandisina e machilina G

Abstract

Cutaneous leishmaniasis (CL) is the most common clinical manifestation of leishmaniasis, with social, economic, and psychological consequences, affecting approximately 1.5 million people annually. Current treatments, initially with pentavalent antimonials and, in case of first-line treatment inefficacy, pentamidine and liposomal amphotericin B, exhibit several adverse effects, such as high toxicity. Therefore, the need for new agents to treat CL is prominent. In this study, we describe the biological activity of five new chloro-isoxazole analogs inspired by the structure of tetrahydrofuran neolignans veraguensin, grandisin, and machilin G, namely 4a, 4c, 4i, 4g, and 4e. In vitro experiments assessed the anti-leishmania activity against intracellular amastigote forms of L. amazonensis and cytotoxicity with peritoneal macrophages infected with L. amazonensis. The results showed that 4e was active against amastigotes with an IC50 value similar to the control treated with amphotericin (IC50 = 2.2 ± 0.4 µM and IC50 = 2.0 ± 0.1, respectively) and with a selectivity index for amastigotes of 22.7, higher than the tested reference drugs.

Keywords: amastigotes; L. amazonensis; peritoneal macrophages; isoxazole nucleus