In silico and in vitro antimalarial activity evaluation of eugenol’s transformation products against Plasmodium falciparum strain 3D7 using the Trager and Jensen method

Context: Endemic malaria occurs in tropical areas with high morbidity and mortality. First-line therapy using chloroquine and artemisinin-based combination therapy has reported resistance; therefore, new drugs need to be developed. Eugenol, a clove-derived phenolic compound, was selected due to its modifiable hydroxyl group and prior evidence of antimalarial potential. Aims: To develop an antimalarial drug candidate derived from eugenol transformation. Methods: Eugenol was transformed via the Mannich reaction using formaldehyde and aniline to form iminium salts, followed by reaction with eugenol. Product screening via GC-MS was conducted after refluxing for 4, 6, and 10 hours. Purification used column chromatography (silica gel 60; n-hexane:ethyl acetate = 10:1). Compound structures were confirmed by FTIR, 1H-NMR, and UV/Vis. ADMET screening was performed using pkCSM. Molecular docking and dynamics were conducted against plasmepsin II (PDB: 1LEE). In vitro antimalarial activity was tested using the Trager and Jensen method. Results: The study showed that compounds derived from eugenol transformation had potential as an antimalarial agent, surpassing the efficacy of the native ligand and chloroquine. Additionally, achieving good results in terms of ADMET screening. IC50 of the products was <10 µM, which is categorized as good activity, especially compounds 5 (6,6'-((phenylazanediyl)bis(methylene))bis(4-allyl-2-methoxyphenol) and compound 2 (1,3,5-triphenyl-1,3,5-triazinane). Both compounds showed IC50 <1 µM, which is categorized as excellent activity. Conclusions: The transformation products of eugenol can be further developed as potential antimalarial agents. Compound 5 exhibited unprecedented IC50 values (<0.02 µM), though its pharmacokinetic limitations warrant further optimization. Further research is focused on cytotoxic assays.