Antiproliferative activity and ultrastructural changes in promastigote and amastigote forms of Leishmania amazonensis caused by limonene-acylthiosemicarbazide hybrids.

Leishmaniasis is a tropical zoonotic disease. It is found in 98 countries, with an estimated 1.3 million people being affected annually. During the life-cycle, the Leishmania parasite alternates between promastigote and amastigote forms. The first line treatment for leishmaniasis are the pentavalent antimonials, such as N-methylglucamine antimoniate (Glucantime®) and sodium stibogluconate (Pentostam®). These drugs are commonly related to be associated with dangerous side effects such as cardiotoxicity, nephrotoxicity, hepatotoxicity, and pancreatitis. Considering these aspects, this work aimed to obtain a new series of limonene-acylthiosemicarbazides hybrids as an alternative for the treatment of leishmaniasis. For this, promastigotes, axenic amastigotes, and intracellular amastigotes of Leishmania amazonensis were used in the antiproliferative assay; J774-A1 macrophages for the cytotoxicity assay; and electron microscopy techniques were performed to analyze the morphology and ultrastructure of parasites. ATZ-S-04 compound showed the best result in both tests. Its IC50, in promastigotes, axenic amastigotes and intracellular amastigotes was 0.35 ± 0.08 μM, 0.49 ± 0.06 μM, and 15.90 ± 2.88 μM, respectively. Cytotoxicity assay determined a CC50 of 16.10 ± 1.76 μM for the same compound. By electron microscopy, it was observed that ATZ-S-04 affected the Golgi complex, in addition to morphological changes in promastigote forms of L. amazonensis.