Novel 2-Nitroimidazole and Imidazooxazole Derivatives and their Activity against Trypanosoma cruzi and Mycobacterium tuberculosis.

Autor:	Faria JV; Departamento de Síntese de Farmacos, Fundação Oswaldo Cruz, Instituto de Tecnologia em Fármacos, Farmanguinhos - Fiocruz, Manguinhos, Rio de Janeiro, RJ, CEP 21041-250, Brazil.; Pós-graduação em Química, Universidade Federal Fluminense - UFF, Campus do Valonguinho, Niterói, RJ, CEP 24020-150, Brazil., Passos FPZ; Departamento de Síntese de Farmacos, Fundação Oswaldo Cruz, Instituto de Tecnologia em Fármacos, Farmanguinhos - Fiocruz, Manguinhos, Rio de Janeiro, RJ, CEP 21041-250, Brazil., da Costa PHA; Departamento de Síntese de Farmacos, Fundação Oswaldo Cruz, Instituto de Tecnologia em Fármacos, Farmanguinhos - Fiocruz, Manguinhos, Rio de Janeiro, RJ, CEP 21041-250, Brazil., de Oliveira AP; Departamento de Síntese de Farmacos, Fundação Oswaldo Cruz, Instituto de Tecnologia em Fármacos, Farmanguinhos - Fiocruz, Manguinhos, Rio de Janeiro, RJ, CEP 21041-250, Brazil., Cruz YODD; Departamento de Síntese de Farmacos, Fundação Oswaldo Cruz, Instituto de Tecnologia em Fármacos, Farmanguinhos - Fiocruz, Manguinhos, Rio de Janeiro, RJ, CEP 21041-250, Brazil., Castelo-Branco FS; Departamento de Síntese de Farmacos, Fundação Oswaldo Cruz, Instituto de Tecnologia em Fármacos, Farmanguinhos - Fiocruz, Manguinhos, Rio de Janeiro, RJ, CEP 21041-250, Brazil., Lourenço MCS; Fundacao Oswaldo Cruz, Instituto Nacional de Infectologia Evandro Chagas, Laboratorio de Bacteriologia e Bioensaios em Micobacterias, Rio de Janeiro, RJ, CEP 21045-900, Brazil., Murta SMF; Instituto René Rachou, Fiocruz Minas Gerais, Belo Horizonte, MG, CEP 30190-002, Brazil., Junior PAS; Instituto René Rachou, Fiocruz Minas Gerais, Belo Horizonte, MG, CEP 30190-002, Brazil., Bernardino AMR; Pós-graduação em Química, Universidade Federal Fluminense - UFF, Campus do Valonguinho, Niterói, RJ, CEP 24020-150, Brazil., Bastos MM; Departamento de Síntese de Farmacos, Fundação Oswaldo Cruz, Instituto de Tecnologia em Fármacos, Farmanguinhos - Fiocruz, Manguinhos, Rio de Janeiro, RJ, CEP 21041-250, Brazil., Boechat N; Departamento de Síntese de Farmacos, Fundação Oswaldo Cruz, Instituto de Tecnologia em Fármacos, Farmanguinhos - Fiocruz, Manguinhos, Rio de Janeiro, RJ, CEP 21041-250, Brazil.
Jazyk:	angličtina
Zdroj:	Medicinal chemistry (Shariqah (United Arab Emirates)) [Med Chem] 2022; Vol. 18 (6), pp. 701-709.
DOI:	10.2174/1573406418666211116144952
Abstrakt:	Background: Tuberculosis (TB) is one of the top ten causes of death worldwide, while Chagas disease (CD) is the parasitic disease that kills the largest number of people in the Americas. TB is the leading cause of death for patients with AIDS; it kills 1.5 million people and causes 10 million new cases every year. The lack of newly developed chemotherapeutic agents and insufficient access to health care services for a diagnosis increase the incidence of multidrug-resistant TB (MDRTB) cases. Although CD was identified in 1909, the chronic stages of the disease still lack adequate treatment. Objective: The purpose of this work was to design and synthesize two new series of 2-nitroimidazole 5a-e and imidazooxazoles 6a-e with 1H-1,2,3-triazolil nucleus and evaluate their activities against Tc and Mycobacterium tuberculosis (Mtb). Methods: Two series of five compounds were synthesized in a 3 or 4-step route in moderated yields, and their structures were confirmed by NMR spectral data analyses. The in vitro antitrypanosomal evaluation of products was carried out in an intracellular model using L929 cell line infected with trypomastigotes and amastigote forms of Tc of β-galactosidase-transfected Tulahuen strain. Their antimycobacterial activity was evaluated against Mtb strain H37Rv. Results: In general, 2-nitroimidazolic derivatives proved to be more potent in regard to antitrypanocidal and antimycobacterial activity. The non-cytotoxic 2-nitroimidazole derivative 5b was the most promising with a half maximum inhibitory concentration of 3.2 μM against Tc and a minimum inhibitory concentration of 65.3 μM against Mtb. Conclusion: Our study reinforced the importance of 2-nitroimidazole and 1H-1,2,3-triazole nuclei in antimicrobial activity. In addition, derivative 5b proved to be the most promising, presenting important activity against Tc and Mtb and could be used as a starting point for the development of new agents against these diseases. (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)
Databáze:	MEDLINE
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