Antileishmanial activity 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

• Published in: Bioorganic chemistry 2020-12, Vol.105, p.104437, Article 104437
• Main Authors: Holanda, Vanderlan Nogueira, 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
• Format: Article
• Language: English
• Subjects: 1,2,3-triazole; Chemotherapy; Click chemistry; Leishmaniasis; Phthalimide
• ISSN: 0045-2068; 1090-2120
• DOI: 10.1016/j.bioorg.2020.104437

[Display omitted] •The leishmanicidal activity of a triazole-phthalimide derivative (PT4) was evaluated.•PT4 decrease the growth and survival of promastigote and amastigotes.•PT4 showed inhibitory potential over the CYP51 enzyme of Leishmania spp.•PT4 induced an increase in ROS and depolarization of the mitochondrial membrane.•Our results pointed PT4 as a promissory agent against Cutaneous Leishmaniasis. Organic compounds obtained by 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 effects 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 on L. amazonensis and L. braziliensis, the causative agents 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 assays showed that PT4 was more selective for both Leishmania species than to mammalian cells. This compound also presented 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 simulations 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 pointed PT4 as promissing therapeutic agent against CL.