Targeting Cholinesterases: Synthesis of Novel Thiosemicarbazone-Carbamate Derivatives

The design of dual inhibitors of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) enzymes is a highly significant strategy in the treatment of Alzheimer’s disease. In this study, six new thiosemicarbazone-carbamate derivatives (8a-c, 9a-c) were designed and synthesized, based on vanillin and isovanillin, as potential dual inhibitors of cholinesterases for the treatment of Alzheimer’s disease. In vitro biological activity assessments revealed that the synthesized compounds had greater potential to inhibit BChE than AChE. Compound 8a, which emerged as the most potent BChE inhibitor in the series, exhibited 81.49% inhibition at 100 µM and an IC50 of 58.41 µM, inhibiting the enzyme via a non-competitive mechanism, whilst compound 9c exhibited the highest AChE inhibition at the same concentration, with a rate of 40.27%. Molecular docking simulations supported the biological findings by confirming that the active compounds form hydrogen bonds and π-π interactions with critical amino acids in the catalytic sites of both enzymes. Furthermore, the in silico pharmacokinetic analyses conducted revealed that all derivatives possess a drug-like profile and exhibit high blood-brain barrier permeability scores (4.00–4.01), indicating their potential to reach the central nervous system.