Hemoglobin degradation in parasitic acidic vacuole represents a major metabolic pathway, which is essential for the intraerythrocytic development of malaria parasites. Four members of a family of P. falciparum aspartic proteinases, termed as digestive plasmepsins (PMI, PMII, PMIV and HAP) have shown to be able to degrade hemoglobin in vitro¹. These enzymes have been identified as potential anti-malarial drug targets and their inhibition has been demonstrated to result in parasites death^2,3. The aim of this study was design and molecular docking analysis of 15 novel 9-aminoacridine derivatives with potential antimalarial activity, based on inhibition of plasmepsins I and II. Interactions of 9-aminoacridine derivatives with plasmepsins were analyzed in AutoDock Vina program. Crystal structures of selected targets (PMI and PMII) were obtained from the Protein Data Bank (PDB ID 3QS1 and 2IGY).

Derivatives with binding energies similar to the corresponding co-crystallized ligand KNI-10006 and which form some of the key binding interactions with PMI were 1 (N'-(acridin-9-yl)benzohydrazide), 6 (2-hydroxy-N'-(3-(trifluoromethyl)acridin-9-yl)benzohydrazide), 7 (N'-(3-(trifluoromethyl)acridin-9-yl)benzohydrazide), 8 (N-benzyl-3-(trifluoromethyl)acridin-9-amine), 10 (N-phenethyl-3-(trifluoromethyl)acridin-9-amine) and 15 (N-(3,4-dichlorophenyl)acridin-9-amine). Derivative 15 forms seven key binding interactions (Leu291, Val76, Thr218, Ile300, Asp215, Asp32 and Tyr75) with PMI, although its binding energies were slightly higher in comparison to KNI-10006. On the other hand, derivatives 1, 2 (N'-(acridin-9-yl)-2-hydroxybenzohydrazide), 6, 7 and 8 form some of the key binding interactions towards PMII with higher binding energies compared to the co-crystallized ligand. Derivative 2 forms five key binding interactions (Phe111, Ile32, Trp41, Ile123 and Met75) with PMII.