Natural isothiocyanate anti-malaria: Molecular docking, physicochemical, adme, toxicity and synthetic accessibility study of eugenol and cinnamaldehyde

Objective: This study aims to evaluate novel compounds of isothiocyanate (ITC) based on eugenol and cinnamaldehyde derivatives as the drug candidate of Plasmodium falciparum anti-malaria using in silico method, physicochemical, pharmacokinetics, toxicity, and synthetic accessibility prediction. This present study also describes molecular docking and pharmacoinformatics of natural ITC in Moringa oleifera leaves. Methods: A series of novel ITC compounds (3, 5, and 6) were designed and analyzed with a series of natural ITC compounds (7, 8, 9, 10) for P. falciparum anti-malaria. This research is descriptive qualitative and uses the reverse molecular docking method, proving the biological activity of compounds theoretically using software and database information. Results: Molecular docking study showed that compound 6 exhibits binding affinity (-5.3 Kcal/mol) on Van der Waals interaction with the residual active site (His159, Cys25) of cysteine protease. All designed ITC compounds are obeyed the Lipinski and Veber Rule, have a well-brain penetrant character and have a medium risk for mutagenic, tumorigenic, and reproductive prediction. They are also in the simple rate of synthetic accessibility (SA) estimation. In regards to natural ITCs, they all have better assay characteristics except the SA. Conclusion: Molecular docking, physicochemical, pharmacokinetic, and toxicity studies show that methyl eugenol isothiocyanate and cinnamaldehyde isothiocyanate are promising anti-malaria compounds. Substituents of hydroxy, acetate and tetrahydropyran groups in the building block ring are suggested for better in silico profiles enhancement.