Synthesis of chalcone derivatives with methoxybenzene and pyridine moieties as potential antimalarial agents

Malaria remains an endemic disease in tropical regions, urgently needed the search for effective antimalarial agents due to resistance
against existing drugs. This study investigated the potential antimalarial activity of pyridine-based chalcone derivatives against
P. falciparum 3D7 and FCR3 strains. The chalcones were synthesized through a one-pot method using various pyridine carbaldehyde,
resulting in yields ranging from 53.74 to 86.37%, and all products were characterized using FTIR, GC-MS, and NMR spectroscopies.
Among the six chalcones tested, chalcone A [1-(2-methoxyphenyl)-3-(pyridin-2-yl)prop-2-en-1-one] displayed the highest antimalarial
activity with IC50 values of 0.48 and 0.31 μg/mL against P. falciparum 3D7 and FCR3 strains, respectively, and a resistance index
of 0.65. Molecular docking studies highlighted the interaction of the carbonyl group of all chalcones with Asn108 amino acid residue
in the PfDHFR-TS active site via hydrogen bonding, demonstrating their potential as the antimalarial agent. Notably, the positioning
of methoxy and pyridine substituents significantly influenced the antimalarial activity of the chalcones.