Anti-malarial potential of novel aminoalkylated eugenol derivatives: synthesis, in-vitro, in-silico evaluation and mechanistic profiling.

The increasing resistance of Plasmodium falciparum (P. falciparum) and Plasmodium vivax (P. vivax) to commonly used antimalarial drugs underscores the urgent need for new and more effective therapeutic agents. In this study, a series of aminoalkylated eugenol derivatives were synthesized via the Mannich reaction and structurally characterized using HPLC, UV-Vis, FT-IR, 1H NMR, and 13C NMR spectroscopy. Their antimalarial potential was evaluated through a combination of in-silico and in-vitro approaches. Density Functional Theory (DFT) analysis revealed stable electronic properties and favorable reactivity descriptors, supporting their drug-like characteristics. Molecular docking, molecular dynamics (MD) simulations, and MM/PBSA free energy calculations were performed to assess interactions with a key P. vivax target protein. Compounds 2a, 2b, and 2c displayed strong binding affinities (-40.25 to -46.35 kcal/mol) and formed stable complexes, as indicated by MD parameters (RMSD, RMSF, Rg, SASA). The Molecular Mechanics Poisson-Boltzmann Surface Area (MM/PBSA) results further confirmed favorable binding energies (-21.81 to -26.42 kcal/mol). In-vitro antiplasmodial assays against P. falciparum strains (Pf3D7 and PfDD2) showed potent activity, particularly for compound 2c, with IC50 values of 0.063 μM and 2.923 μM, respectively. Mechanistic insights from network pharmacology indicated involvement in PI3K-Akt, Ras, MAPK, and sphingolipid signaling pathways. Overall, these findings suggest that compound 2c is a promising lead for further development as a novel antimalarial agent capable of addressing drug resistance.