Structural design, synthesis and pharmacological evaluation of thiazoles against Trypanosoma cruzi.

Autor: de Oliveira Filho GB; Laboratório de Planejamento em Química Medicinal - LpQM, Departamento de Ciências Farmacêuticas, Centro de Ciências da Saúde, Universidade Federal de Pernambuco - UFPE, 50740-520, Recife, PE, Brazil; Faculdade de Integração do Sertão - FIS, Rua João Luiz de Melo, 2110, COHAB, Serra Talhada, PE, Brazil. Electronic address: gev_filho@hotmail.com., Cardoso MVO; Colegiado de Nutrição, Universidade de Pernambuco, CEP 56328-903, Petrolina, PE, Brazil., Espíndola JWP; Laboratório de Planejamento em Química Medicinal - LpQM, Departamento de Ciências Farmacêuticas, Centro de Ciências da Saúde, Universidade Federal de Pernambuco - UFPE, 50740-520, Recife, PE, Brazil., Oliveira E Silva DA; Laboratório de Planejamento em Química Medicinal - LpQM, Departamento de Ciências Farmacêuticas, Centro de Ciências da Saúde, Universidade Federal de Pernambuco - UFPE, 50740-520, Recife, PE, Brazil., Ferreira RS; Departamento de Bioquímica e Imunologia, Universidade Federal de Minas Gerais, CEP 31270-901, Belo Horizonte, MG, Brazil., Coelho PL; Departamento de Bioquímica e Imunologia, Universidade Federal de Minas Gerais, CEP 31270-901, Belo Horizonte, MG, Brazil., Anjos PSD; Instituto Gonçalo Moniz, Fundação Oswaldo Cruz, CEP 40296-710, Salvador, BA, Brazil., Santos ES; Instituto Gonçalo Moniz, Fundação Oswaldo Cruz, CEP 40296-710, Salvador, BA, Brazil., Meira CS; Instituto Gonçalo Moniz, Fundação Oswaldo Cruz, CEP 40296-710, Salvador, BA, Brazil., Moreira DRM; Instituto Gonçalo Moniz, Fundação Oswaldo Cruz, CEP 40296-710, Salvador, BA, Brazil., Soares MBP; Instituto Gonçalo Moniz, Fundação Oswaldo Cruz, CEP 40296-710, Salvador, BA, Brazil; Centro de Biotecnologia e Terapia Celular, Hospital São Rafael, Salvador, BA, Brazil., Leite ACL; Laboratório de Planejamento em Química Medicinal - LpQM, Departamento de Ciências Farmacêuticas, Centro de Ciências da Saúde, Universidade Federal de Pernambuco - UFPE, 50740-520, Recife, PE, Brazil. Electronic address: acllb2003@yahoo.com.br.
Jazyk: angličtina
Zdroj: European journal of medicinal chemistry [Eur J Med Chem] 2017 Dec 01; Vol. 141, pp. 346-361. Date of Electronic Publication: 2017 Sep 22.
DOI: 10.1016/j.ejmech.2017.09.047
Abstrakt: Chagas disease is one of the most significant health problems in the American continent. benznidazole (BDZ) and nifurtimox (NFX) are the only drugs approved for treatment and exhibit strong side effects and ineffectiveness in the chronic stage, besides different susceptibility among T. cruzi DTUs (Discrete Typing Units). Therefore, new drugs to treat this disease are necessary. Thiazole compounds have been described as potent trypanocidal agents. Here we report the structural planning, synthesis and anti-T. cruzi evaluation of a new series of 1,3-thiazoles (7-28), which were designed by placing this heterocycle instead of thiazolidin-4-one ring. The synthesis was conducted in an ultrasonic bath with 2-propanol as solvent at room temperature. By varying substituents attached to the phenyl and thiazole rings, substituents were observed to retain, enhance or greatly increase their anti-T. cruzi activity. In some cases, methyl at position 5 of the thiazole (compounds 9, 12 and 23) increased trypanocidal property. The exchange of phenyl for pyridinyl heterocycle resulted in increased activity, giving rise to the most potent compound against the trypomasigote form (14, IC 50trypo  = 0.37 μM). Importantly, these new thiazoles were toxic for trypomastigotes without affecting macrophages and cardiomyoblast viability. The compounds were also evaluated against cruzain, and five of the most active compounds against trypomastigotes (7, 9, 12, 16 and 23) inhibited more than 70% of enzymatic activity at 10 μM, among which compound 7 had an IC 50 in the submicromolar range, suggesting a possible mechanism of action. In addition, examination of T. cruzi cell death showed that compound 14 induces apoptosis. We also examined the activity against intracellular parasites, revealing that compound 14 inhibited T. cruzi infection with potency similar to benznidazole. The antiparasitic effect of 14 and benznidazole in combination was also investigated against trypomastigotes and revealed that they have synergistic effects, showing a promising profile for drug combination. Finally, in mice acutely-infected with T. cruzi,14 treatment significanty reduced the blood parasitaemia and had a protective effect on mortality. In conclusion, we report the identification of compounds (7), (12), (15), (23) and (26) with similar trypanocidal activity of benznidazole; compounds (9) and (21) as trypanocidal agents equipotent with BDZ, and compound 14 with potency 28 times better than the reference drug without affecting macrophages and cardiomyoblast viability. Mechanistically, the compounds inhibit cruzain, and 14 induces T. cruzi cell death by an apoptotic process, being considered a good starting point for the development of new anti-Chagas drug candidates.
(Copyright © 2017 Elsevier Masson SAS. All rights reserved.)
Databáze: MEDLINE
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