Plasmodium falciparum Histo-Aspartic Protease (HAP) inhibitor: Toxicity Investigation and Docking Study of 2-(2-benzoyl-4-methylphenoxy)quinoline-3-carbaldehyde derivatives

Abstract Aspartic proteases possess catalytic sites for hydrolysis of peptide bonds which makes them potentials drug target in the malaria parasites. Inhibiting Histo-Aspartic Protease (HAP), aspartate (Asp215) and histidine (His32) residues of the P. falciparum disrupts the growth phase and ability to catalyse erythrocyte hemoglobin degradation. We synthesized compound 5; 2-(2-benzoyl-4-methylphenoxy)quinoline-3-carbaldehyde via Vilsmier-Hack and sp2 C-H activation protocols. We then designed fifty hypothetical compounds A1-A50 which were screened in-silico for their toxicity, pharmacokinetics, bioactivity score and binding affinities. Nine lead compounds showed no toxicity to human cells. Ten standard antimalarial drugs were used as reference. The lead compounds were generally within (-0.28 to 0.32) as highly or moderately bioactive for six bioactivity score parameters. Compounds A31 had (-11.3 kcal/mol) and A5 (-11.2 kcal/mol) binding energies. Mefloquine with (-9.6 kcal/mole) was best reference drug coming in position 9. Whilst compound A31 and mefloquine both showed no interactions with either Asp215 or His32 in the binding pockets, compound A5 showed π-π stacking interactions. . We opine therefore, that based on other drug-likeness parameters investigated, compound A5; 2-(2-benzoyl-4-methylphenoxy)-7-methylquinoline-3-carbaldehyde can be recommended as a possible candidate for new antimalarial drug development in line with SDG goal 3 on health and well-being.