Synthesis, In vitro, and In silico Studies of Methyl Eugenol Derivatives for Plasmodium falciparum Inhibitor

Multidrug treatment has been piloted for Plasmodium falciparum malaria infection; however, multidrug resistance requires serious attention. Therefore, new antimalarial studies have been intensively carried out, including research on new compounds containing nitrogen and sulfur atoms that are predicted as active groups against antiplasmodial. This study aimed to synthesize two compounds derived from methyl eugenol, namely (1) isothiocyanates-based methyl eugenol and (2) thiosemicarbazide-based methyl eugenol. The synthesized compounds were characterized using FTIR, LCMS-MS, dissolution test, XRD, and SEM. The synthesized compounds were also tested in vitro for Plasmodium falciparum 3D7, molecular docking, and drug-likeness. Compound (1) was synthesized using methyl eugenol and thiocyanic acid at room temperature for 24 hours. The orange-coloured powder obtained contains dimer methyl eugenol isothiocyanate with a specific isothiocyanate wavenumber at 2055 cm^-1 and molecular mass m/z 416. Compound (2) was synthesized using compound (1) and hydrazine for 10 hours. The specific wavenumber of (2) was identified at 1648 cm^-1 (amine-free) and molecular mass of m/z 804. Compounds (1) and (2) have crystallite sizes of 5.38141 nm and 3.85276 nm, respectively. In vitro Plasmodium falciparum analysis resulted in IC₅₀ of 0.34 µg/mL for (1) and 1.47 µg/mL for (2). Molecular docking analysis showed that (1) and (2) had binding energies of-6.0 kcal/mol and-1.2 kcal/mol. Compounds (1) and (2) had character deviations of drug-likeness. The drug formulation development is suggested to overcome the drug-likeness aspect, considering the in vitro antimalarial potentials in the two synthetic products.