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

• Published in: Tetrahedron Vol. 135; p. 133329
• Main Authors: Santana Filho, Paulo Cesar, Brasil da Silva, Matheus, Malaquias da Silva, Bruna Nathália, Fazolo, Tiago, Dorneles, Gilson Pires, Braun de Azeredo, Juliano, Alf da Rosa, Mário, Rodrigues Júnior, Luiz Carlos, Peres, Alessandra, Santos Canto, Rômulo Faria, Torres Romão, Pedro Roosevelt
• Format: Journal Article
• Language: English
• Published: Elsevier Ltd 06.04.2023
• Subjects: Indoles; Leishmanicidal activity; Mitochondrial membrane depolarization; Organoselenium; Mitochondrial membrane depolarization; Indoles; Leishmanicidal activity; Organoselenium
• ISSN: 0040-4020; 1464-5416
• DOI: 10.1016/j.tet.2023.133329

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. [Display omitted] •The anti-Leishmania activity of thirteen seleno-indoles was evaluated.•Promastigote and intracellular amastigote stages of Leishmania amazonensis are susceptible to seven seleno-indoles.•A low toxicity of seleno-indoles was found in mammalian cells.•The seleno-indoles 2f, 2g and 3a altered the mitochondrial membrane potential of promastigotes and induce ROS production.