Seleno-indoles trigger reactive oxygen species and mitochondrial dysfunction in Leishmania amazonensis

Abstract

Leishmaniasis is an endemic disease caused by obligate intracellular protozoa of the genus Leishmania prevalent in the Americas, Africa, and Asia. Therapeutic options are limited for this disease and serious drawbacks are related to the administration of these drugs. Moreover, currently there is no vaccine against leishmaniasis, reinforcing the need to develop new therapeutic options. In the last decade several organoselenium and indolic compounds were reported for their ability to exert activity against different species of Leishmania, posing as promising scaffolds for the development of new drug candidates. In this study, we designed and synthesized a series of thirteen seleno-indoles and investigated their activity against Leishmania amazonensis promastigotes and amastigotes. The most promising seleno-indoles 2a, 2c, 2f, 2g and 3a show good activity against L. amazonensis promastigote and amastigote forms, presenting low toxicity to mammalian cells and good in silico ADMETox and druglikeness parameters, supporting the hypothesis as they being a promising scaffold for further investigation. Mechanistic studies revealed that seleno-indoles 2a, 2c, 2f, 2g and 3a can act interfering with membrane integrity, 2f, 2g and 3a also lead to mitochondrial dysfunction and ROS production, while compound 2a caused mitochondrial depolarization without alteration in ROS generation.