Antimalarial and anti-inflammatory activities of new chloroquine and primaquine hybrids: Targeting the blockade of malaria parasite transmission.

Autor: Boechat N; Laboratorio de Sintese de Farmacos, Instituto de Tecnologia em Farmacos, Farmanguinhos - FIOCRUZ, Fundacao Oswaldo Cruz. Rua Sizenando Nabuco 100, Manguinhos, Rio de Janeiro, RJ 21041-250, Brazil. Electronic address: nubia.boechat@far.fiocruz.br., Carvalho RCC; Laboratorio de Sintese de Farmacos, Instituto de Tecnologia em Farmacos, Farmanguinhos - FIOCRUZ, Fundacao Oswaldo Cruz. Rua Sizenando Nabuco 100, Manguinhos, Rio de Janeiro, RJ 21041-250, Brazil., Ferreira MLG; Laboratorio de Sintese de Farmacos, Instituto de Tecnologia em Farmacos, Farmanguinhos - FIOCRUZ, Fundacao Oswaldo Cruz. Rua Sizenando Nabuco 100, Manguinhos, Rio de Janeiro, RJ 21041-250, Brazil., Coutinho JP; Centro de Pesquisas Rene Rachou, CPqRR - FIOCRUZ, Fundacao Oswaldo Cruz, Belo Horizonte, MG 30190-002, Brazil., Sa PM; Laboratorio de Sintese de Farmacos, Instituto de Tecnologia em Farmacos, Farmanguinhos - FIOCRUZ, Fundacao Oswaldo Cruz. Rua Sizenando Nabuco 100, Manguinhos, Rio de Janeiro, RJ 21041-250, Brazil., Seito LN; Departamento de Farmacologia, Instituto de Tecnologia em Farmacos, Farmanguinhos - FIOCRUZ, Fundacao Oswaldo Cruz, Brazil., Rosas EC; Departamento de Farmacologia, Instituto de Tecnologia em Farmacos, Farmanguinhos - FIOCRUZ, Fundacao Oswaldo Cruz, Brazil., Krettli AU; Centro de Pesquisas Rene Rachou, CPqRR - FIOCRUZ, Fundacao Oswaldo Cruz, Belo Horizonte, MG 30190-002, Brazil., Bastos MM; Laboratorio de Sintese de Farmacos, Instituto de Tecnologia em Farmacos, Farmanguinhos - FIOCRUZ, Fundacao Oswaldo Cruz. Rua Sizenando Nabuco 100, Manguinhos, Rio de Janeiro, RJ 21041-250, Brazil., Pinheiro LCS; Laboratorio de Sintese de Farmacos, Instituto de Tecnologia em Farmacos, Farmanguinhos - FIOCRUZ, Fundacao Oswaldo Cruz. Rua Sizenando Nabuco 100, Manguinhos, Rio de Janeiro, RJ 21041-250, Brazil.
Jazyk: angličtina
Zdroj: Bioorganic & medicinal chemistry [Bioorg Med Chem] 2020 Dec 15; Vol. 28 (24), pp. 115832. Date of Electronic Publication: 2020 Nov 02.
DOI: 10.1016/j.bmc.2020.115832
Abstrakt: Malaria is a disease that requires new drugs not only to fight Plasmodium but also to reduce symptoms of infection such as fever and inflammation. A series of 21 hybrid compounds were designed from chloroquine (CQ) and primaquine (PQ) linked to the pharmacophoric group present in phenylacetic anti-inflammatory drugs. These compounds were designed to have dual activity: namely, to be capable of killing Plasmodium and still act on the inflammatory process caused by malaria infection. The compounds were assayed with nine different biological methods. The carbonylated CQ derivative 6 (n = 3; R 1  = Cl) was more potent than CQ in vitro, and 8 (n = 4; R 1  = H) reduced P. berghei parasitemia up to 37% on day 7. The carbonylated PQ derivative 17 (R = Br) was slightly less potent than PQ. The gem-difluoro PQ derivative 20 (R = Cl) exhibited high transmission blockade of the malaria sporogonic cycle in mosquitoes. Compounds 6 and 20 dose-dependently reduced nitric oxide (NO) production and inhibited TNFα production by LPS-stimulated J774A.1 macrophages. Our results indicate a viable and interesting approach in planning new chemical entities that act as transmission-blocking drugs for treating malaria caused by P. falciparum and P. vivax and the anti-inflammatory process related to this disease.
(Copyright © 2020 Elsevier Ltd. All rights reserved.)
Databáze: MEDLINE
Externí odkaz: