Jelcic_2025_Eur.J.Med.Chem_302_118375

A series of fourteen novel phenol carbamates was synthesized and evaluated as potential selective butyrylcholinesterase (BChE) inhibitors targeting cholinergic dysfunction in Alzheimer's disease (AD). The compounds were prepared efficiently from resveratrol analogs via a Wittig reaction followed by carbamoylation, and their structures were confirmed by NMR, MS, and HRMS analyses. All derivatives were screened for inhibitory activity against acetylcholinesterase (AChE) and BChE using a modified Ellman method. None of the compounds inhibited AChE, whereas all selectively inhibited BChE, with IC(50) values ranging from 0.045 to 6.840 microM. The most potent inhibitor, compound 13, bearing a pyrrolidine moiety, exhibited an IC(50) value of 0.045 microM, outperforming the reference drug galantamine by more than two orders of magnitude. Molecular docking and dynamics simulations confirmed strong Pi-Pi and alkyl-Pi interactions between the ligands and the enzyme's active site, accounting for their high affinity and selectivity. In silico ADME(T) analysis predicted excellent intestinal absorption, blood-brain barrier penetration, and low cytotoxicity, while minor genotoxicity alerts were observed for a few derivatives. In vitro cytotoxicity assays in HepG2 cells confirmed the absence of toxicity at concentrations up to 30 microM. These results highlight methoxy-substituted phenol carbamates, particularly compound 13, as promising lead structures for the design of selective BChE inhibitors and potential therapeutic agents for the treatment of AD.