Please use this identifier to cite or link to this item: https://www.arca.fiocruz.br/handle/icict/45479
Title: 1,4-Disubstituted-1,2,3-Triazole Compounds Induce Ultrastructural Alterations in Leishmania amazonensis Promastigote: An in Vitro Antileishmanial and in Silico Pharmacokinetic Study
Authors: Souza, Fernando Almeida
Silva, Verônica Diniz da
Silva, Gabriel Xavier
Taniwaki, Noemi Nosomi
Hardoim, Daiana de Jesus
Buarque, Camila Djenne
Silva, Ana Lucia Abreu
Calabrese, Kátia da Silva
Affilliation: Universidade Estadual do Maranhão. Pós-graduação em Ciência Animal. São Luis, MA. Brasil / Fundação Oswaldo Cruz. Instituto Oswaldo Cruz, Laboratório de Imunomodulação e Protozoologia. Rio de Janeiro, RJ, Brasil.
Pontifícia Universidade Católica. Laboratório de Síntese Orgânica. Rio de Janeiro, RJ, Brasil / Universidade Nova de Lisboa. Faculdade de Ciência e Tecnologia. Caparica, Portugal.
Universidade Federal do Maranhão. Rede Nordeste de Biotecnologia. São Luis, MA, Brasil.
Instituto Adolfo Lutz. Núcleo de Microscopia Eletrônica. São Paulo, SP, Brasil.
Fundação Oswaldo Cruz. Instituto Oswaldo Cruz, Laboratório de Imunomodulação e Protozoologia. Rio de Janeiro, RJ, Brasil.
Pontifícia Universidade Católica. Laboratório de Síntese Orgânica. Rio de Janeiro, RJ, Brasil.
Universidade Estadual do Maranhão. Pós-graduação em Ciência Animal. São Luis, MA. Brasil.
Fundação Oswaldo Cruz. Instituto Oswaldo Cruz, Laboratório de Imunomodulação e Protozoologia. Rio de Janeiro, RJ, Brasil.
Abstract: The current standard treatment for leishmaniasis has remained the same for over 100 years, despite inducing several adverse effects and increasing cases of resistance. In this study we evaluated the in vitro antileishmanial activity of 1,4-disubstituted-1,2,3 triazole compounds and carried out in silico predictive study of their pharmacokinetic and toxicity properties. Ten compounds were analyzed, with compound 6 notably presenting IC50: 14.64 ± 4.392 µM against promastigotes, IC50: 17.78 ± 3.257 µM against intracellular amastigotes, CC50: 547.88 ± 3.256 µM against BALB/c peritoneal macrophages, and 30.81-fold selectivity for the parasite over the cells. It also resulted in a remarkable decrease in all the parameters of in vitro infection. Ultrastructural analysis revealed lipid corpuscles, a nucleus with discontinuity of the nuclear membrane, a change in nuclear chromatin, and kinetoplast swelling with breakdown of the mitochondrial cristae and electron-density loss induced by 1,4-disubstituted-1,2,3-triazole treatment. In addition, compound 6 enhanced 2.3-fold the nitrite levels in the Leishmania-stimulated macrophages. In silico pharmacokinetic prediction of compound 6 revealed that it is not recommended for topical formulation cutaneous leishmaniasis treatment, however the other properties exhibited results that were similar or even better than miltefosine, making it a good candidate for further in vivo studies against Leishmania parasites.
Keywords: Cytotoxicity
Transmission electron microscopy
Leishmaniasis
Treatment
ADME
Toxicity
keywords: Citotoxicidade
Microscopia eletrônica de transmissão
Leishmaniose
Tratamento
Toxicidade
Issue Date: 2020
Publisher: MDPI
Citation: SOUZA, Fernando Almeida et al. 1,4-Disubstituted-1,2,3-Triazole Compounds Induce Ultrastructural Alterations in Leishmania amazonensis Promastigote: An in Vitro Antileishmanial and in Silico Pharmacokinetic Study. International Journal of Molecular Sciences, v. 21, n. 16, p. 1-20, Sept. 2020.
DOI: 10.3390/ijms21186839
ISSN: 1661-6596
Copyright: open access
Appears in Collections:IOC - Artigos de Periódicos
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