Leishmanicidal and trypanocidal potential of ß,γ-unsaturated carboxylic acid synthetic derivatives

Leishmaniasis and Chagas disease are parasitic infections with limited treatment options due to drug toxicity and rising resistance. Leishmaniasis, caused by Leishmania spp., often manifests in a cutaneous form and is treated with drugs like amphotericin B and miltefosine, which can cause severe side effects. Chagas disease, caused by Trypanosoma cruzi, is endemic in the Americas and classified by the WHO as a neglected tropical disease. Existing treatments are effective mainly in the acute phase but have significant limitations. In search of new therapies, this study explored diversity-oriented synthesis to generate a library of β,γ-unsaturated carboxylic acid derivatives. From 23 synthesized compounds -12 reported for the first time- several showed promising antiparasitic activity. Four compounds were effective against Leishmania amazonensis, with three also targeting the amastigote form. Two compounds showed activity against Trypanosoma cruzi, outperforming reference drugs in selectivity. Signs of parasite apoptosis, including mitochondrial damage and ROS accumulation, suggest strong therapeutic potential for these derivatives.