Avaliação in silico, in vitro e in vivo da ação esquizonticida sanguínea de compostos aminoquinolínicos

Abstract

With 247 million new cases and 619,000 deaths in 2021, malaria still remains a public health challenge worldwide. 96% of malaria cases are concentrated in Africa and Plasmodium falciparum, considered the most prevalent species on the African continent, is resistant to several antimalarials. The Americas, the Western Pacific, Southeast Asia and the Eastern Mediterranean, mainly affected by Plasmodium vivax, also present resistance to the antimalarial drugs used in therapy. The search for new drugs to treat malaria is considered an emergency and fundamental issue to avoid the current high rates of morbidity and mortality from the disease, since there is an increasing development and dissemination of parasites resistant to conventional antimalarials. Among antimalarial medications, those belonging to the aminoquinoline class act by inhibiting the polymerization of hemoglobin into hemozoin during the parasite's sexual life cycle. This study aims to evaluate the antimalarial potential of 16 new synthetic aminoquinoline compounds. The 16 new synthesized drugs were evaluated for their pharmacokinetic, physical-chemical properties, in vitro cytotoxicity activity and antiplasmodial activity. The most promising in vitro studies were then evaluated in an animal model of malaria infection.The pharmacokinetic results suggested good absorption and oral bioavailability for the tested molecules. For the most promising molecule, compound 9, docking molecular studies were carried out, demonstrating affinity for the receptors of the parasitophorous vacuole of the parasite, suggesting a mechanism of action similar to that of chloroquine. Satisfactory results were found for compound 9 for in vitro antiplasmodial activity of IC50 (0.44 µM/ml), CC50 (>100 µM/ml) and in vitro selectivity index data for antiplasmodial activity of 226 (standard drug chloroquine obtained 152). In vivo tests for compound 9 indicated good inhibition of parasite multiplication up to the tenth day of infection (31.02%). The interaction with ferriprotoporphyrin complex was investigated by UV-Vis spectrophotometric titration and its result was comparatively similar to that of chloroquine (Log K of the compound = 4.66, Log K of chloroquine = 4.97), suggesting this probable mechanism of action. Biochemical data did not demonstrate toxicity for the murine model in relation to the doses tested (15 mg/kg and 50 mg/kg). In conclusion, molecules derived from the aminoquinoline ring, especially compound 9, show promise for future studies aimed at therapeutic renewal, which is so essential for the control of malaria.