Design and synthesis of 6-chloro-1,3,5-triazine-2,4-diamine linked chalcone derivatives and their antimalarial activity evaluation

A series of nine triazine-chalcone hybrid compounds (7a–i) were designed and synthesized through a molecular hybridization strategy integrating 1,3,5-triazine and chalcone moieties. The hybrids were synthesized via sequential nucleophilic substitution reactions and characterized by 1 H NMR, 13 C NMR, and HRMS spectroscopy. All compounds were evaluated for β-hematin inhibition, while selected compounds ( 3a–c and 7a–c ) were further assessed for in vitro antiplasmodial activity against the chloroquine-sensitive Plasmodium falciparum 3D7 strain. The hybrid derivatives demonstrated superior β-hematin inhibition (IC 50 = 79–207 µM) compared to the chalcones and the reference drug. Among the series, compounds 7b and 7c exhibited the most potent antiplasmodial activity, with IC 50 values of 0.28 and 0.21 µM, respectively. Molecular docking and molecular dynamics simulations suggested favorable binding of the hybrid compound to both Pf DHFR-TS and falcipain-2, with binding free energies of − 40.06 and − 34.07 kcal/mol, respectively, supporting these proteins may serve as potential targets for these compounds.