Synthesis and biological activity of novel 4-aminoquinoline/1,2,3-triazole hybrids against Leishmania amazonensis

Biomedicine & Pharmacotherapy

Adilson David da Silva¹  Isabelle Karine da Costa Nunes²  Luciana Maria Ribeiro Antinarelli³  Nícolas Glanzmann⁴  Henrique Marcelo Gualberto Pereira⁵  Eduardo Antonio Ferraz Coelho⁵  Elaine Soares Coimbra⁶ 

[1] Departamento de Patologia Clínica, COLTEC, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais 31270-901, Brazil;Programa de Pós-Graduação em Ciências da Saúde: Infectologia e Medicina Tropical, Faculdade de Medicina, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais 30.130-100, Brazil;Departamento de Parasitologia, Microbiologia e Imunologia, Instituto de Ciências Biológicas, Universidade Federal de Juiz de Fora, Campus Universitário, Juiz de Fora, Minas Gerais 36.036-900, Brazil;Departamento de Química, Instituto de Ciências Exatas, Universidade Federal de Juiz de Fora, Campus Universitário, Juiz de Fora, Minas Gerais 36.036-900, Brazil;Laboratório de Apoio ao Desenvolvimento Tecnológico, Polo de Química, Universidade Federal do Rio de Janeiro, Cidade Universitária Ilha do Fundão, Rio de Janeiro 21.941-598, Brazil;Programa de Pós-Graduação em Ciências da Saúde: Infectologia e Medicina Tropical, Faculdade de Medicina, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais 30.130-100, Brazil;

关键词: Leishmania;    Antileishmanial activity;    Quinoline;    1,2,3-triazolic derivative;    Apoptosis;    Necrosis;   

DOI  :  

来源: DOAJ

【 摘 要 】

Quinoline and 1,2,3-triazoles are well-known nitrogen-based heterocycles presenting diverse pharmacological properties, although their antileishmanial activity is still poorly exploited. As an effort to contribute with studies involving these interesting chemical groups, in the present study, a series of compounds derived from 4-aminoquinoline and 1,2,3-triazole were synthetized and biological studies using L. amazonensis species were performed. The results pointed that the derivative 4, a hybrid of 4-aminoquinoline/1,2,3-triazole exhibited the best antileishmanial action, with inhibitory concentration (IC50) values of ~1 µM against intramacrophage amastigotes of L. amazonensis , and being 16-fold more active to parasites than to the host cell. The mechanism of action of derivative 4 suggest a multi-target action on Leishmania parasites, since the treatment of L. amazonensis promastigotes caused mitochondrial membrane depolarization, accumulation of ROS products, plasma membrane permeabilization, increase in neutral lipids, exposure of phosphatidylserine to the cell surface, changes in the cell cycle and DNA fragmentation. The results suggest that the antileishmanial effect of this compound is primarily altering critical biochemical processes for the correct functioning of organelles and macromolecules of parasites, with consequent cell death by processes related to apoptosis-like and necrosis. No up-regulation of reactive oxygen and nitrogen intermediates was promoted by derivative 4 on L. amazonensis -infected macrophages, suggesting a mechanism of action independent from the activation of the host cell. In conclusion, data suggest that derivative 4 presents selective antileishmanial effect, which is associated with multi-target action, and can be considered for future studies for the treatment against disease.

【 授权许可】

Unknown