Synthesis, structure-activity relationship and trypanocidal activity of pyrazole-imidazoline and new pyrazole-tetrahydropyrimidine hybrids as promising chemotherapeutic agents for Chagas disease.

Autor: Monteiro ME; Laboratório de Ultraestrutura Celular, Instituto Oswaldo Cruz, Fiocruz, Av. Brasil 4365 Manguinhos, 21040-900, Rio de Janeiro, RJ, Brazil., Lechuga G; Laboratório de Ultraestrutura Celular, Instituto Oswaldo Cruz, Fiocruz, Av. Brasil 4365 Manguinhos, 21040-900, Rio de Janeiro, RJ, Brazil., Lara LS; Laboratório de Ultraestrutura Celular, Instituto Oswaldo Cruz, Fiocruz, Av. Brasil 4365 Manguinhos, 21040-900, Rio de Janeiro, RJ, Brazil., Souto BA; Laboratório de Síntese Orgânica (LABSINTO), Instituto de Física e Química, Universidade Federal de Itajubá, Avenida BPS, 1303, Pinheirinho, Itajubá, 37500-903, Minas Gerais, Brazil., Viganó MG; Laboratório de Síntese Orgânica (LABSINTO), Instituto de Física e Química, Universidade Federal de Itajubá, Avenida BPS, 1303, Pinheirinho, Itajubá, 37500-903, Minas Gerais, Brazil., Bourguignon SC; Laboratório de Interação Celular e Molecular, Departamento de Biologia Celular e Molecular, Universidade Federal Fluminense, Rua Outeiro São João Batista, 24020-141, Niterói, Rio de Janeiro, Brazil., Calvet CM; Laboratório de Ultraestrutura Celular, Instituto Oswaldo Cruz, Fiocruz, Av. Brasil 4365 Manguinhos, 21040-900, Rio de Janeiro, RJ, Brazil., Oliveira FOR Jr; Laboratório de Ultraestrutura Celular, Instituto Oswaldo Cruz, Fiocruz, Av. Brasil 4365 Manguinhos, 21040-900, Rio de Janeiro, RJ, Brazil., Alves CR; Laboratório de Biologia Molecular e Doenças Endêmicas, Instituto Oswaldo Cruz, Fiocruz, Av. Brasil 4365 Manguinhos, 21040-900, Rio de Janeiro, RJ, Brazil., Souza-Silva F; Laboratório de Biologia Molecular e Doenças Endêmicas, Instituto Oswaldo Cruz, Fiocruz, Av. Brasil 4365 Manguinhos, 21040-900, Rio de Janeiro, RJ, Brazil; Centro de Desenvolvimento Tecnológico em Saúde, Fiocruz, Avenida Brasil 4365, Manguinhos, 21040-900, Rio de Janeiro, RJ, Brazil., Santos MS; Laboratório de Síntese Orgânica (LABSINTO), Instituto de Física e Química, Universidade Federal de Itajubá, Avenida BPS, 1303, Pinheirinho, Itajubá, 37500-903, Minas Gerais, Brazil. Electronic address: mauriciosantos@unifei.edu.br., Pereira MCS; Laboratório de Ultraestrutura Celular, Instituto Oswaldo Cruz, Fiocruz, Av. Brasil 4365 Manguinhos, 21040-900, Rio de Janeiro, RJ, Brazil. Electronic address: mirian@ioc.fiocruz.br.
Jazyk: angličtina
Zdroj: European journal of medicinal chemistry [Eur J Med Chem] 2019 Nov 15; Vol. 182, pp. 111610. Date of Electronic Publication: 2019 Aug 10.
DOI: 10.1016/j.ejmech.2019.111610
Abstrakt: Drug therapy for Chagas disease remains a major challenge as potential candidate drugs have failed clinical trials. Currently available drugs have limited efficacy and induce serious side effects. Thus, the discovery of new drugs is urgently needed in the fight against Chagas' disease. Here, we synthesized and evaluated the biological effect of pyrazole-imidazoline (1a-i) and pyrazole-tetrahydropyrimidine (2a-i) derivatives against relevant clinical forms of Trypanosoma cruzi. The structure-activity relationship (SAR), drug-target search, physicochemical and ADMET properties of the major active compounds in vitro were also assessed in silico. Pyrazole derivatives showed no toxicity in Vero cells and also no cardiotoxicity. Phenotypic screening revealed two dichlorinated pyrazole-imidazoline derivatives (1c and 1d) with trypanocidal activity higher than that of benznidazole (Bz) against trypomastigotes; these were also the most potent compounds against intracellular amastigotes. Replacement of imidazoline with tetrahydropyrimidine in the pyrazole compounds completely abolished the trypanocidal activity of series 2(a-i) derivatives. The physicochemical and ADMET properties of the compounds predicted good permeability, good oral bioavailability, no toxicity and mutagenicity of 1c and 1d. Pyrazole nucleus had high frequency hits for cruzipain in drug-target search and structure activity relationship (SAR) analysis of pyrazole-imidazoline derivatives revealed enhanced activity when chlorine atom was inserted in meta-positions of the benzene ring. Additionally, we found evidence that both compounds (1c and 1d) have the potential to interact non-covalently with the active site of cruzipain and also inhibit the cysteine proteinase activity of T. cruzi. Collectively, the data presented here reveal pyrazole derivatives with promise for further optimization in the therapy of Chagas disease.
(Copyright © 2019 Elsevier Masson SAS. All rights reserved.)
Databáze: MEDLINE
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