Novel Mannich based derivatives of isoliquiritigenin and liquiritigenin, bioactive constituents of <i>Glycyrrhiza glabra</i> , as potent antimalarial agents

Isoliquiritigenin and liquiritigenin were isolated from the plant Glycyrrhiza glabra. Fourteen new mannich-based derivatives of ISL and LTG were synthesised. Derivatives 3, 5 and 7 showed good antimalarial activity with IC50= 0.16, 0.37 and 0.53 μM respectively which was far better than the parent molecule ISL (IC50= 11.71 μM). Compound 12 (IC50= 1.67 μM) showed ten times better activity than the parent molecule, LTG (IC50= 15.62 μM). Integrated computational analyses including molecular docking, ADMET prediction, density functional theory (DFT), and molecular dynamics (MD) simulations were performed to elucidate their mechanism of action. Active derivatives showed strong binding to PfDHFR-TS with docking energies of −9.2 to −10.7 kcal/mol and consistent interactions with key catalytic residues (Asp54, Phe58, Ser108). DFT results indicated that potent compounds possess favourable frontier orbital energies, balanced hardness, and suitable electrophilicity, supporting stable protein ligand interactions, while 100 ns MD simulations confirmed stable complex formation through consistent RMSD, compactness, and persistent interactions.