Resistance to chloroquine has driven the search for antimalarial agents targeting non–heme-based metabolic pathways. In this study, a series of pyridine-containing N -phenylpyrazoline derivatives ( NP1–NP7 ) were rationally designed as potential inhibitors of Plasmodium falciparum enoyl-acyl carrier protein reductase ( Pf ENR). The syntheses of NP1 – NP7 were performed via the cyclocondensation of phenylhydrazine with chalcones in the presence of a base catalyst under reflux. All compounds were elucidated using GC–MS or TLC scanner, IR, 1 H-, and 13 C NMR spectrometers. Their antimalarial activity was evaluated against P. falciparum 3D7 and FCR-3. Compound NP6 displayed the highest activity, demonstrating IC 50 values of 6.70 μM against the 3D7 strain and 9.94 μM against the FCR-3 strain. A docking study was conducted to investigate interactions between all compounds and the Pf ENR receptor as an antimalarial target. NP6 and NP7 exhibited conventional hydrogen-bond interactions with Ala319, demonstrating stable interactions with the active site of Pf ENR. The introduction of methoxy groups into N -phenylpyrazoline compounds can potentially enhance their antimalarial activity. Molecular dynamics and MM-PBSA analyses validated the stable binding of NP6 to Pf ENR, with consistent key interactions and favorable free energy (−25.52 kcal mol −1 ). ADMET predictions indicated that all compounds comply with Lipinski's Rule of Five, have acceptable drug-likeness profiles, and exhibit higher bioavailability than triclosan. Overall, these results highlight NP6 as a promising lead compound for further development of Pf ENR-targeted antimalarial agents. N -phenylpyrazoline derivatives ( NP1 – NP7 ) were synthesized via cyclocondensation of chalcones and phenylhydrazine and evaluated for their antimalarial potential. NP6 , bearing methoxy substituents at meta and para positions, showed the strongest activity with IC₅₀ values of 6.70 μM (3D7) and 9.94 μM (FCR-3). Docking, molecular dynamics, and MM-PBSA analyses confirmed the stable and favorable binding of the compound to the Pf ENR receptor, supported by a consistent stability profile, persistent hydrogen bonding, and a binding free energy comparable to that of the chloroquine– Pf ENR complex (−25.52 kcal mol −1 ). Furthermore, ADMET prediction revealed that all compounds met drug-likeness criteria, highlighting NP6 as a promising candidate for further antimalarial drug development. • N -phenylpyrazoline derivatives ( NP1–NP7 ) were synthesized via chalcone cyclocondensation. • NP6 showed the highest antimalarial activity against 3D7 and FCR-3 strains. • Docking and molecular dynamics confirmed stable NP6 – Pf ENR interactions. • MM-PBSA revealed binding energy comparable to chloroquine (−25.52 kcal·mol −1 ). • ADMET profiling identified NP6 as a promising antimalarial lead compound.
Syaadiyah et al. (Sun,) studied this question.