Vitamin B1-catalyzed green synthesis and antiplasmodial evaluation of 2-amino-7-hydroxy-4-aryl-4H-chromene-3-carbonitrile derivatives: computational insights into putative PfNDH2 targeting.

A green and sustainable synthetic protocol was developed for the preparation of a previously unreported series of 2-amino-7-hydroxy-4-aryl-4H-chromene-3-carbonitrile derivatives (PPA1-PPA5) using vitamin B1 (thiamine hydrochloride) as an inexpensive and environmentally benign organocatalyst under mild aqueous ethanol conditions. The synthesized derivatives were comprehensively characterized by FTIR, 1H/13C NMR, HRMS, and elemental analyses, and subsequently evaluated for their in vitro antiplasmodial activity against the chloroquine-sensitive Plasmodium falciparum 3D7 strain together with their antioxidant potential using the DPPH radical scavenging assay. The compounds exhibited encouraging antiplasmodial activity with IC50 values ranging from 0.62 to 0.89 µg mL-1 and antioxidant activity with IC50 values between 17.6 and 27.8 µg mL-1. Among the synthesized derivatives, PPA3 displayed the highest antiplasmodial potency (IC50 = 0.62 ± 0.02 µg mL-1; 1.01 µM) and the strongest antioxidant activity (IC50 = 17.6 ± 0.5 µg mL-1) within this preliminary compound series. To gain molecular-level insights into its potential mode of action, an integrated computational workflow comprising molecular docking, 500 ns molecular dynamics simulations, MM-GBSA binding free energy calculations, and WaterMap hydration-site analysis was performed using P. falciparum NADH-ubiquinone oxidoreductase (PfNDH2; PDB ID: 5JWA) as the molecular target. The synthesized derivatives demonstrated favorable binding affinities (-7.7 to -8.3 kcal mol-1), with PPA3 exhibiting the strongest predicted binding (-8.3 kcal mol-1), the most favorable MM-GBSA binding free energy (-42.7 kcal mol-1), and a stable protein-ligand complex throughout the simulation, supported by persistent hydrogen-bonding interactions and compact conformational behavior. Overall, this study demonstrates that vitamin B1-mediated synthesis provides an efficient and sustainable route to biologically active 4H-chromene derivatives, while the combined experimental and computational findings identify PPA3 as a promising lead for further biological validation, expanded structure-activity relationship investigations, and rational optimization toward the development of new antimalarial agents.