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  3. Exploring the selective butyrylcholinesterase inhibition potential of phenol carbamates: Experimental and computational study

Exploring the selective butyrylcholinesterase inhibition potential of phenol carbamates: Experimental and computational study

  • Eur J Med Chem. 2026 Jan 15;302(Pt 3):118375. doi: 10.1016/j.ejmech.2025.118375.
Antonija Jelčić 1,  Stanislava Talić 2,  Ilijana Odak 3,  Milena Mlakić 4,  Zlata Lasić 5,  Sunčica Roca 6,  Ivana Šagud 7,  Tea Bruketa 8,  Martina Bosnar 9,  Danijela Barić 10,  Irena Škorić 11
Affiliations

Affiliations

  • 1 Department of Organic Chemistry, University of Zagreb Faculty of Chemical Engineering and Technology, Marulićev Trg 19, HR-10 000, Zagreb, Croatia. Electronic address: antonijajelcic11@gmail.com.
  • 2 Department of Chemistry, Faculty of Science and Education, University of Mostar, Matice Hrvatske bb, 88 000, Mostar, Bosnia and Herzegovina. Electronic address: stanislava.talic@fpmoz.sum.ba.
  • 3 Department of Chemistry, Faculty of Science and Education, University of Mostar, Matice Hrvatske bb, 88 000, Mostar, Bosnia and Herzegovina. Electronic address: ilijana.odak@fpmoz.sum.ba.
  • 4 Department of Organic Chemistry, University of Zagreb Faculty of Chemical Engineering and Technology, Marulićev Trg 19, HR-10 000, Zagreb, Croatia. Electronic address: mdragojev@fkit.unizg.hr.
  • 5 TEVA Global R&D, RA Pillar Zagreb, Pliva Hrvatska D.o.o., Prilaz Baruna Filipovića 25, HR-10 000, Zagreb, Croatia. Electronic address: Zlata.Lasic01@pliva.com.
  • 6 NMR Center, Ruđer Bošković Institute, Bijenička cesta 54, HR-10 000, Zagreb, Croatia. Electronic address: sroca@irb.hr.
  • 7 Croatian Agency for Medicinal Products and Medical Devices, Ksaverska cesta 4, HR-10 000, Zagreb, Croatia. Electronic address: Ivana.Sagud@halmed.hr.
  • 8 Pharmacology In Vitro, Selvita Ltd., Prilaz Baruna Filipovića 29, HR-10 000, Zagreb, Croatia. Electronic address: tea.bruketa@selvita.com.
  • 9 Pharmacology In Vitro, Selvita Ltd., Prilaz Baruna Filipovića 29, HR-10 000, Zagreb, Croatia. Electronic address: martina.bosnar@selvita.com.
  • 10 Group for Computational Life Sciences, Division of Physical Chemistry, Ruđer Bošković Institute, Bijenička cesta 54, HR-10 000, Zagreb, Croatia. Electronic address: dbaric@irb.hr.
  • 11 Department of Organic Chemistry, University of Zagreb Faculty of Chemical Engineering and Technology, Marulićev Trg 19, HR-10 000, Zagreb, Croatia. Electronic address: iskoric@fkit.unizg.hr.
PMID: 41313889 DOI: 10.1016/j.ejmech.2025.118375
Abstract

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 IC50 values ranging from 0.045 to 6.840 μM. The most potent inhibitor, compound 13, bearing a pyrrolidine moiety, exhibited an IC50 value of 0.045 μM, outperforming the reference drug galantamine by more than two orders of magnitude. Molecular docking and dynamics simulations confirmed strong π-π and alkyl-π 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 μM. 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.

Keywords

ADMET analysis; Alzheimer's disease; Butyrylcholinesterase inhibition; Molecular docking; Molecular dynamics simulation; Phenol carbamates; Structure–activity relationship.

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