Please use this identifier to cite or link to this item: https://www.arca.fiocruz.br/handle/icict/8576
Title: Optimization of anti-Trypanosoma cruzi oxadiazoles leads to identification of compounds with efficacy in infected mice.
Authors: Santos Filho, José Maurício dos
Moreira, Diogo Rodrigo Magalhães
Simone, Carlos Alberto de
Ferreira, Rafaela Salgado
McKerrow, James H
Meira, Cássio Santana
Guimarães, Elisalva Teixeira
Soares, Milena Botelho Pereira
Affilliation: Universidade Federal de Pernambuco. Departamento de Engenharia Química, Centro de Tecnologia e Geociências. Recife, PE, Brasil
Universidade Federal de Pernambuco. Departamento de Departamento de Ciências Farmacêuticas. Centro de Tecnologia e Geociências. Recife, PE, Brasil / Fundação Oswaldo Cruz. Centro de Pesquisa Gonçalo Moniz. Salvador, BA, Brasil
Universidade de São Paulo. Instituto de Física. Departamento de Física e Informática. São Carlos, SP, Brasil
University of California. Sandler Center for Drug Discovery in Parasitic Diseases. San Francisco, CA, USA
University of California. Sandler Center for Drug Discovery in Parasitic Diseases. San Francisco, CA, USA
Fundação Oswaldo Cruz. Centro de Pesquisa Gonçalo Moniz. Salvador, BA, Brasil
Fundação Oswaldo Cruz. Centro de Pesquisa Gonçalo Moniz. Salvador, BA, Brasil / Universidade Estadual da Bahia. Departamento de Ciências da Vida. Salvador, BA, Brasil
Fundação Oswaldo Cruz. Centro de Pesquisa Gonçalo Moniz. Salvador, BA, Brasil / Hospital São Rafael. Centro de Biotecnologia e Terapia Celular. Salvador, BA, Brasil
Abstract: We 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
Keywords: Chagas disease
Trypanosoma cruzi
Cruzain
Oxadiazoles
Hydrazones
Bioisosterism
DeCS: Antiprotozoários/farmacologia
Modelos Animais de Doenças
Oxidiazóis/farmacologia
Trypanosoma cruzi/efeitos de drogas
Tripanossomíase/quimioterapia
Animais
Antiprotozoários/administração & dosagem
Antiprotozoários/química
Relação Dose-Resposta a Droga
Camundongos
Camundongos Endogâmicos BALB C
Modelos Moleculares
Estrutura Molecular
Oxidiazóis/administração & dosagem
Oxidiazóis/química
Testes de Sensibilidade Parasitária
Relação Estrutura-Atividade
Issue Date: 2012
Publisher: Elsevier Ltd
Citation: SANTOS 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.
DOI: 10.1016/j.bmc.2012.08.047
ISSN: 1464-3391
Copyright: open access
Appears in Collections:BA - IGM - Artigos de Periódicos

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