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

• Published in: Bioorganic & medicinal chemistry 2020-12, Vol.28 (24), p.115832-115832, Article 115832
• Main Authors: Boechat, Nubia, Carvalho, Rita C.C., Ferreira, Maria de Lourdes G., Coutinho, Julia Penna, Sa, Paula M., Seito, Leonardo N., Rosas, Elaine C., Krettli, Antoniana U., Bastos, Monica M., Pinheiro, Luiz C.S.
• Format: Article
• Language: English
• Subjects: Anti-inflammatory; Antiplasmodial; Chloroquine; Malaria; Primaquine
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2020.115832

[Display omitted] •A series of 21 hybrids were designed from chloroquine and primaquine drugs.•The compounds have dual activity: antimalarial and anti-inflammatory.•The chloroquine derivative reduced P. berghei parasitemia up to 37% on day 7.•The primaquine derivative exhibited transmission blockage of the malaria.•Compounds dose-dependently reduced NO production and inhibited TNFα production. 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; R1 = Cl) was more potent than CQ in vitro, and 8 (n = 4; R1 = 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.