Optimization of anti-Trypanosoma cruzi oxadiazoles leads to identification of compounds with efficacy in infected mice.

dc.creatorSantos Filho, José Maurício dos
dc.creatorMoreira, Diogo Rodrigo Magalhães
dc.creatorSimone, Carlos Alberto de
dc.creatorFerreira, Rafaela Salgado
dc.creatorMcKerrow, James H
dc.creatorMeira, Cássio Santana
dc.creatorGuimarães, Elisalva Teixeira
dc.creatorSoares, Milena Botelho Pereira
dc.date2014-10-10T18:25:40Z
dc.date2014-10-10T18:25:40Z
dc.date2012
dc.date.accessioned2023-09-26T20:28:36Z
dc.date.available2023-09-26T20:28:36Z
dc.identifierSANTOS FILHO, J. M. et al. Optimization of anti-Trypanosoma cruzi oxadiazoles leads to identification of compounds with efficacy in infected mice. Bioorganic & Medicinal Chemistry, v. 20, n. 21, p. 6423-6433, 2012.
dc.identifier1464-3391
dc.identifierhttps://www.arca.fiocruz.br/handle/icict/8576
dc.identifier10.1016/j.bmc.2012.08.047
dc.identifier.urihttps://repositorioslatinoamericanos.uchile.cl/handle/2250/8857752
dc.descriptionWe recently showed that oxadiazoles have anti-Trypanosoma cruzi activity at micromolar concentrations. These compounds are easy to synthesize and show a number of clear and interpretable structure–activity relationships (SAR), features that make them attractive to pursue potency enhancement. We present here the structural design, synthesis, and anti-T. cruzi evaluation of new oxadiazoles denoted 5a–h and 6a–h. The design of these compounds was based on a previous model of computational docking of oxadiazoles on the T. cruzi protease cruzain. We tested the ability of these compounds to inhibit catalytic activity of cruzain, but we found no correlation between the enzyme inhibition and the antiparasitic activity of the compounds. However, we found reliable SAR data when we tested these compounds against the whole parasite. While none of these oxadiazoles showed toxicity for mammalian cells, oxadiazoles 6c (fluorine), 6d (chlorine), and 6e (bromine) reduced epimastigote proliferation and were cidal for trypomastigotes of T. cruzi Y strain. Oxadiazoles 6c and 6d have IC50 of 9.5 ± 2.8 and 3.5 ± 1.8 lM for trypomastigotes, while Benznidazole, which is the currently used drug for Chagas disease treatment, showed an IC50 of 11.3 ± 2.8 lM. Compounds 6c and 6d impair trypomastigote development and invasion in macrophages, and also induce ultrastructural alterations in trypomastigotes. Finally, compound 6d given orally at 50 mg/kg substantially reduces the parasitemia in T. cruzi-infected BALB/c mice. Our drug design resulted in potency enhancement of oxadiazoles as anti-Chagas disease agents, and culminated with the identification of oxadiazole 6d, a trypanosomicidal compound in an animal model of infection
dc.formatapplication/pdf
dc.languageeng
dc.publisherElsevier Ltd
dc.rightsopen access
dc.subjectChagas disease
dc.subjectTrypanosoma cruzi
dc.subjectCruzain
dc.subjectOxadiazoles
dc.subjectHydrazones
dc.subjectBioisosterism
dc.subjectAntiprotozoários/farmacologia
dc.subjectModelos Animais de Doenças
dc.subjectOxidiazóis/farmacologia
dc.subjectTrypanosoma cruzi/efeitos de drogas
dc.subjectTripanossomíase/quimioterapia
dc.subjectAnimais
dc.subjectAntiprotozoários/administração & dosagem
dc.subjectAntiprotozoários/química
dc.subjectRelação Dose-Resposta a Droga
dc.subjectCamundongos
dc.subjectCamundongos Endogâmicos BALB C
dc.subjectModelos Moleculares
dc.subjectEstrutura Molecular
dc.subjectOxidiazóis/administração & dosagem
dc.subjectOxidiazóis/química
dc.subjectTestes de Sensibilidade Parasitária
dc.subjectRelação Estrutura-Atividade
dc.titleOptimization of anti-Trypanosoma cruzi oxadiazoles leads to identification of compounds with efficacy in infected mice.
dc.typeArticle


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