Abstract

Malaria is a disease that necessitates the development of new treatments not only to combat Plasmodium but also to alleviate infection symptoms such as fever and inflammation. Chloroquine (CQ) and Primaquine (PQ) were coupled to the pharmacophoric group found in phenylacetic anti-inflammatory medicines to create a sequence of 21 hybrid molecules. These chemicals were created with a dual purpose in mind: to kill Plasmodium while also acting on the inflammatory process caused by malaria infection. Nine different biological approaches were used to test the substances. In vitro, the carbonylated CQ derivative was more effective than CQ, reduced parasitemia in P. berghei by up to 37% on day 7. PQ derivative 17 was slightly carbonylated. PQ is less powerful. In mosquitoes, the gem-difluoro PQ derivative showed a high level of transmission blocking of the malaria sporogonic cycle. Compounds 6 and 20 lowered No generation and suppressed TNF production in LPS-stimulated J774A.1 macrophages in a dose-dependent manner. Our findings suggest a plausible and intriguing strategy for developing new chemical entities that operate as transmission-blocking medications for treating malaria caused by Plasmodium falciparum and Plasmodium vivax, as well as the anti-inflammatory mechanism associated with the condition. We introduce a new family of hybrid compounds made up of the anti-plasmodial medicines primaquine and chloroquine. To yet, no treatment has been found to be effective against all phases of Plasmodium’s life cycle. We devised and synthesized a new-generation molecule including both primaquine and chloroquine components from accessible precursors, with the goal of developing medicines with bioactivity against different stages of the parasite’s life cycle. The hybrid molecule 3 has activity against asexual and sexual P. falciparum blood stages, as well as P. berghei sporozoites and liver stages, in vitro. The hybrid is active against P. berghei liver and blood stages in vivo. The concept of using one chemical to combine distinct mechanisms of action that attack different Plasmodium stages in the mammalian host was successfully validated by our findings. It is our hope that the pathogen will be outwitted by the new design of such chemicals in the spread of drug resistance. The chemical is accessible in a smooth and adaptable manner according to the streamlined synthesis process, and it is open to additional molecular modification.