Plasmodium falciparum histoaspartic protease inhibitor: Toxicity investigation and docking study of 2-(2-benzoyl-4-methylphenoxy) quinoline-3-carbaldehyde derivatives

Aspartic proteases can hydrolyze peptide bonds, making them potential targets for drug development against malaria parasites. In particular, inhibiting the histoaspartic protease (HAP) can disrupt the growth phase of Plasmodium falciparum and its ability to degrade hemoglobin for protein synthesis. Compound 5, specifically designed as 2-(2-benzoyl-4-methylphenoxy)quinoline-3-carbaldehyde, served as the basis for designing 50 hypothetical compounds (A1-A50). These compounds were subjected to in silico screening to assess their toxicity profiles, pharmacokinetics, bioactivity scores, and theoretical binding affinities, as a part of the drug design protocol. Out of the 50 compounds, nine lead candidates showed no toxicity to human cells. In addition, ten standard reference antimalarial drugs were included in this study for comparison. The highest binding energies were observed for compound A5 (−11.2 kcal/mol) and A31 (−11.3 kcal/mol), surpassing the performance of mefloquine, the best reference drug, which ranked ninth with a binding energy of (−9.6 kcal/mol). Compound A31 did not exhibit the evidence of interaction with either Asp215 or His32, whereas compound A5 displayed π-π stacking interactions with His32. Mefloquine also did not show any interaction with Asp215 or His32. Moreover, compound A5 demonstrated greater hydrophobic interactions at the active site with most binding residues, except for Lys7 in the hydrophobic region. This characteristic suggests that compound A5 may have the ability to adopt a smaller surface area, exhibit increased biological activity, and have reduced interactions with water, which could facilitate slower clearance. Based on the assessment of various drug-likeness parameters, compound A5 (2-(2-benzoyl-4-methylphenoxy)-7-methylquinoline-3-carbaldehyde) is a potential lead candidate for the development of a new antimalarial drug.