Rational synthesis, activity and mechanism insights of a new aminoquinoline salt against malaria parasites: in vitro and in vivo approaches

The lack of an effective vaccine against all Plasmodium species, combined with the emergence and spread of resistance to traditional antimalarials, has, together with other factors, contributed to the failure of malaria eradication campaigns around the world. Therefore, the search for drugs with antiplasmodial activity is one of the priorities of the global scientific community and is strongly supported by the WHO. In this study, 6 synthetic compounds derived from 4-aminoquinolines were synthesized. In silico analyzes of their physicochemical and pharmacokinetic properties suggest that all compounds have good oral bioavailability, while they were not cytotoxic in vitro assays. Although compounds 7 and 9 showed the best IC₅₀ values when evaluated in vitro against P. falciparum (chloroquine-resistant W2 strain), compound 9 showed the best effectiveness in vivo, with rates of inhibition of parasite multiplication varying from 72 to 50 % between days 5 and 9 post-infection. Docking-based inverse virtual screening indicated that compound 9 exhibited potential interaction against 1O5X (Triose-phosphate Isomerase), 2OK8 (Ferredoxin-NADP(+) Reductase), 4C81 (2C-methyl-D-erythritol-2,4-cyclodiphosphate synthase (IspF)), and 4N0Z (glutaredoxin 1) targets, while UV–Vis analysis suggested action of compound in the digestive vacuole of the parasite. Together these results suggest that compound 9 is promising as an antimalarial molecule.