Antileishmanial effects of 4-phenyl-1-[2-(phthalimido-2-yl)ethyl]-1H-1,2,3-triazole (PT4) derivative on Leishmania amazonensis and Leishmania braziliensis: In silico ADMET, in vitro activity, docking and molecular dynamic simulations

• Autor(a) principal: Holanda, Vanderlan Nogueira
• Data de Publicação: 2020
• Outros Autores: Silva, Welson Vicente da, Nascimento, Pedro Henrique do, Silva, Sérgio Ruschi Bergamachi, Cabral Filho, Paulo Euzébio, Assis, Shalom Porto de Oliveira, Silva, César Augusto da, Oliveira, Ronaldo Nascimento de, Figueiredo, Regina Celia Bressan Queiroz de, Lima, Vera Lucia de Menezes
• Tipo de documento: Artigo
• Idioma: eng
• Título da fonte: Repositório Institucional da UFRN
• Texto Completo: https://repositorio.ufrn.br/handle/123456789/30497
• topic: Leishmaniasis; Click chemistry; Chemotherapy; Phthalimides; Phthalimide-1,2,3-triazole

Organic compounds obtained by the click chemistry reactions have demonstrated a broad spectrum of biological activities being widely applied for the development of molecules against pathogens of medical and veterinary importance. Cutaneous leishmaniasis (CL), caused by intracellular protozoa parasite of genus Leishmania, comprises a complex of clinical manifestations that affect the skin and mucous membranes. The available drugs for the treatment are toxic and costly, with long periods of treatment, and the emergence of resistant strains has been reported. In this study we investigated the in vitro effect of a phthalimide-1,2,3-triazole derivative, the 4-Phenyl-1- [2-(phthalimido-2-yl)ethyl]-1H-1,2,3-triazole (PT4) obtained by click chemistry, on mammalian cells and L. amazonensis and L. braziliensis, the causative agent of CL in Brazil. In silico ADMET evaluation of PT4 showed that this molecule has good pharmacokinetic properties with no violation of Lipinski’s rules. The in vitro assay showed that PT4 was selective for both Leishmania species than to mammalian cells. This compound also has a low cytotoxicity to mammalian cells with CC50 > 500 μM. Treatment of promastigote forms with different concentrations of PT4 resulted in ultrastructural alterations, such as plasma membrane wrinkling, shortening of cell body, increased cell volume and cell rupture. The molecular dynamic simulation results showed that PT4 interacts with Lanosterol 14 α-demethylase from Leishmania, an essential enzyme of lipid synthesis pathway in this parasite. Our results demonstrated PT4 was effective against both species of Leishmania. PT4 caused a decrease of mitochondrial membrane potential and increased production of reactive oxygen species, which may lead to parasite death. Taken together, our results show pointed PT4 as promissory therapeutic agent against CL