New hybrid trifluoromethylquinolines as antiplasmodium agents.

Autor: da Silva RMRJ; Programa de Pós-Graduação Farmacologia e Química Medicinal, Instituto de Ciências Biomédicas, UFRJ, Av. Carlos Chagas, 373 - bl. K, 2° andar, sala 35 - Prédio do Centro de Ciências da Saúde, Cidade Universitária, Ilha do Fundão, Rio de Janeiro, RJ 21941-902, Brazil; Departamento de Síntese Orgânica, Instituto de Tecnologia em Fármacos - Farmanguinhos - Fiocruz, Rua Sizenando Nabuco, 100 Manguinhos, Rio de Janeiro, RJ 21041-250, Brazil., Gandi MO; Programa de Pós-Graduação Farmacologia e Química Medicinal, Instituto de Ciências Biomédicas, UFRJ, Av. Carlos Chagas, 373 - bl. K, 2° andar, sala 35 - Prédio do Centro de Ciências da Saúde, Cidade Universitária, Ilha do Fundão, Rio de Janeiro, RJ 21941-902, Brazil; Departamento de Síntese Orgânica, Instituto de Tecnologia em Fármacos - Farmanguinhos - Fiocruz, Rua Sizenando Nabuco, 100 Manguinhos, Rio de Janeiro, RJ 21041-250, Brazil; Faculdade de Farmácia Universidade Iguaçu-UNIG, Av. Abílio Augusto Távora, 2134, Nova Iguaçu, RJ 26275-580, Brazil., Mendonça JS; Departamento de Síntese Orgânica, Instituto de Tecnologia em Fármacos - Farmanguinhos - Fiocruz, Rua Sizenando Nabuco, 100 Manguinhos, Rio de Janeiro, RJ 21041-250, Brazil., Carvalho AS; Departamento de Síntese Orgânica, Instituto de Tecnologia em Fármacos - Farmanguinhos - Fiocruz, Rua Sizenando Nabuco, 100 Manguinhos, Rio de Janeiro, RJ 21041-250, Brazil., Coutinho JP; Laboratório de Malária, Instituto René Rachou, Fiocruz/MG, Avenida Augusto de Lima, 1715, Barro Preto, Belo Horizonte, MG 30190-002, Brazil., Aguiar ACC; Laboratório de Malária, Instituto René Rachou, Fiocruz/MG, Avenida Augusto de Lima, 1715, Barro Preto, Belo Horizonte, MG 30190-002, Brazil., Krettli AU; Laboratório de Malária, Instituto René Rachou, Fiocruz/MG, Avenida Augusto de Lima, 1715, Barro Preto, Belo Horizonte, MG 30190-002, Brazil., Boechat N; Departamento de Síntese Orgânica, Instituto de Tecnologia em Fármacos - Farmanguinhos - Fiocruz, Rua Sizenando Nabuco, 100 Manguinhos, Rio de Janeiro, RJ 21041-250, Brazil. Electronic address: nubia.boechat@far.fiocruz.br.
Jazyk: angličtina
Zdroj: Bioorganic & medicinal chemistry [Bioorg Med Chem] 2019 Mar 15; Vol. 27 (6), pp. 1002-1008. Date of Electronic Publication: 2019 Feb 02.
DOI: 10.1016/j.bmc.2019.01.044
Abstrakt: Malaria remains a major public health problem worldwide, and it is responsible for high rates of morbidity and mortality. Resistance to current antimalarial drugs has been identified, and new drugs are urgently needed. In this study, we designed and synthesized seventeen novel quinolines based on the structures of mefloquine ((2,8-bis(trifluoromethyl)quinolin-4-yl)(piperidin-2-yl)methanol) and amodiaquine (4-((7-chloroquinolin-4-yl)amino)-2-((diethylamino)methyl)phenol) using ring bioisosteric replacement and molecular hybridization of the functional groups. The compounds were evaluated in vitro against Plasmodium falciparum and in vivo in mice infected with P. berghei. All derivatives presented anti-P. falciparum activity with IC 50 values ranging from 0.083 to 33.0 µM. The compound with the best anti-P. falciparum activity was N-(5-methyl-4H-1,2,4-triazol-3-yl)-2,8-bis(trifluoromethyl)quinolin-4-amine (12) which showed an IC 50 of 0.083 µM. The three most active compounds were selected for antimalarial activity tests against P. berghei-infected mice. Compound 12 was the most active on the 5th day after infection, reducing parasitemia by 66%, which is consistent with its in vitro activity. This is an important result as 12, a simpler molecule than mefloquine, does not contain the stereogenic center, and consequently, its synthesis in the laboratory is easier and less expensive. This system proved promising for the design of potential antimalarial compounds.
(Copyright © 2019 Elsevier Ltd. All rights reserved.)
Databáze: MEDLINE
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