Malaria, caused by Plasmodium falciparum , remains a major global health challenge, exacerbated by increasing resistance to frontline therapies. This computational study evaluated 43 quinoline-4-carboxamide derivatives ( 1-43 ) against validated P. falciparum and human off-target proteins. Molecular docking identified ligand 24 as the most potent inhibitor of P. falciparum aminopeptidase N (3EBH; −10.3 kcal mol⁻ 1 ), outperforming chloroquine and quinine (−8.3 kcal mol⁻ 1 ). Ligand 24 complied with Lipinski and Veber drug-likeness rules, exhibited favorable ADMET (absorption, distribution, metabolism, excretion, toxicity) properties (clogP = 2.3, TPSA = 92 Å 2 , hERG pIC₅₀ = 0.79), and showed no predicted toxicity alerts. Molecular-dynamics simulations (20 ns) across 300-320 K confirmed stable interactions within the 3EBH-ligand 24 complex, with optimal stability at 310 K (root mean square deviation-RMSD <0.3 nm). Principal-component analysis (PCA) further indicated reliable conformational sampling (PC1 variance 60.8%, cosine content 0.36). Comparative profiling established ligand 24 as the leading candidate, integrating strong binding affinity with favorable pharmacokinetic and safety profiles. Ligand 7 also displayed promising electronic features. These findings collectively designate ligand 24 as a priority scaffold for experimental validation toward developing novel antimalarial therapeutics.
Meem et al. (Wed,) studied this question.