Glycosyl Thiourea: Synthesis, Cyclization, Reaction, Molecular Docking, and Evaluation as Potential Acetylcholinesterase Inhibitors

Abstract

In this research, we successfully synthesized a distinctive group of iminothiazolidinone derivatives, using glucose isothiocyanate as the starting material. The structural elucidation of these newly created compounds was achieved through a combination of analytical techniques, including IR, 1H NMR, and 13C NMR. We then evaluated the inhibitory activity of these compounds against acetylcholinesterase (AChE) using the Ellman's method spectrophotometer, comparing their performance to standard drugs like donepezil, rivastigmine, and tacrine. Impressively, the majority of the tested compounds demonstrated inhibitory activity against AChE, with iminothiazolidinone derivative (5a) standing out as the most potent (IC50 = 0.209 μg/mL). It even surpassed the effectiveness of rivastigmine and tacrine, coming close to the potency of donepezil. Further investigation into the potential of these compounds as AChE inhibitors for Alzheimer's disease drug development involved docking simulations using Molecular Operating Environment (MOE). Derivatives 3,5-disubstituted-(2,3,4,6-tetra-o-acetyl-β-D-glucopyranosyl) imino) thiazolidin-4-ones (5a), (5f), (6c) and 3,5-disubstituted-(β-D-glucopyranosyl)imino)thiazolidin-4-one (6d) displayed promising docking scores in MOE simulations. In Silico ADMET experiments assessed their pharmacokinetic and toxicity studies, demonstrating strong binding affinity and favorable interactions with the target protein. Pharmacophore models confirmed their potential as selective enzyme inhibitors through 3D virtual screening.