Abstract
Six structural analogues of hydroxychloroquine (HCQ) were designed by retaining key pharmacophoric features while modifying side chains to enhance antimalarial efficacy and mitigate safety concerns, contributing to Sustainable Development Goal 3 targets for communicable disease control. Density Functional Theory (DFT) optimization and electronic property analysis identified compound 6 as the most promising candidate, exhibiting low electrophilicity and strong electron-accepting potential. Molecular docking against Plasmodium falciparum lactate dehydrogenase (PfLDH, PDB ID: 1CET) revealed that Compound6-1CET demonstrated the highest binding affinity (−6.04 kcal/mol), forming stable interactions with key residues ASP53, TYR85, and GLU122. Absorption, Distribution, Metabolism, Excretion, and Toxicity (ADMET) profiling highlighted its favorable pharmacokinetics, minimal toxicity risks, and superior drug-likeness compared to HCQ and chloroquine (CQ). Molecular dynamics (MD) simulations confirmed the stability of the LDH-Compound6 complex, with low root-mean-square deviation and root-mean-square fluctuation, and a compact radius of gyration (~4.5 nm). Protein–Ligand Interaction Profiler (PLIP) analysis further validated sustained interactions, reinforcing the compound’s binding strength. These findings position compound 6 as a promising antimalarial candidate, warranting further preclinical investigations.