Evaluation of Antiplasmodial Activity of Quinoline Derivatives Incorporating Arylnitro and Aminochalcone Moieties

Background/Objectives: The widespread emergence of chloroquine-resistant Plasmodium falciparum continues to drive the search for new quinoline-based antimalarial agents capable of retaining efficacy against resistant parasites. This study aimed to evaluate a series of synthetic quinoline derivatives incorporating arylnitro and aminochalcone moieties for their antiplasmodial activity and selectivity. Methods: A series of eighteen synthetic quinoline derivatives were evaluated for in vitro antiplasmodial activity against P. falciparum strains (3D7, K1, and Dd2), along with cytotoxicity in mammalian cells and hemolytic activity in human red blood cells. Structure–activity relationship analysis was performed, and molecular docking studies were conducted against β-hematin and the chloroquine resistance transporter (PfCRT). Results: Several compounds exhibited sub-micromolar activity against the chloroquine-sensitive 3D7 strain. The most potent compound (Compound 14), a nitro-substituted N-alkylated quinoline bearing a CF3-enriched aromatic chalcone framework, demonstrated high potency and selectivity (IC50 = 0.13 μM; SI = 1132.92). Importantly, this compound retained substantial activity against multidrug-resistant K1 and Dd2 strains, displaying lower resistance indices than chloroquine. Structure–activity relationship analysis revealed that nitro substitution, N-alkylation, and halogen/CF3-rich aromatic features critically influence potency and selectivity. Docking studies suggested that Compound 14 engages both β-hematin and PfCRT more extensively than chloroquine. Conclusions: These findings identify Compound 14 as a promising lead scaffold for further optimization toward next-generation antimalarial agents.