In <i>silico</i> evaluation of quinoline-4-carboxamides as potential antimalarial agents

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 &lt;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.