Molecular modeling study of a series of amodiaquine analogues with antimalarial activity

A molecular modeling study was applied to a data set of 21 analogues (2a–2u) of amodiaquine (2) exhibiting remarkable in vitro activity against the chloroquine- and pyrimethamine-resistant Plasmodium falciparum K1 strain (Guglielmo et al. in Eur J Med Chem 44:5071–5079, 2009). Attempting to correlate structural features with the antiparasitic activity, quantum chemical properties were calculated. In silico ADMET studies were conducted in order to recognize and find the most promising compounds with the potential of becoming new antimalarial agents. The binding mode to the heme group was studied by molecular docking, and the interactions observed in the ligand-heme complex of one of the highly active (2p) and one of the least active (2l) compounds were compared. In order to crosscheck the docking results, compound 2p was submitted to 50 ns of molecular dynamic simulation. According to that result, 2p and amodiaquine share similar binding interaction with the heme group. Additionally, a charged-assisted hydrogen bond between the protonated quinolone and the heme carboxylate group was observed. The introduction of the piperazine moiety increases the antimalarial activity profile of amodiaquine analogues by conformational features that allow these interactions. The results of this study can be used as a guide for the design of new compounds for treatment against malaria.