Multitarget-directed carbamate and carbamothioate derivatives: Cholinesterase and monoamine oxidase inhibition, anti-β-amyloid (Aβ) aggregation, antioxidant and blood-brain barrier permeation properties against Alzheimer's disease

Eur J Med Chem. 2025 Nov 15:298:117986. doi: 10.1016/j.ejmech.2025.117986. Epub 2025 Jul 23.

Abstract

Neurodegenerative diseases are multifactorial disorders characterized by protein misfolding, oxidative stress, and neuroinflammation, finally resulting in neuronal loss and cognitive dysfunctions. Nowadays, an attractive strategy to improve the classical treatments is the development of multitarget-directed molecules able to synergistically interact with different enzymes and/or receptors. A novel series of chiral carbamate and carbamothioate derivatives were designed, synthesized, and investigated as inhibition of cholinesterases and monoamine oxidases, anti-β-amyloid aggregation and antioxidant activities against Alzheimer's disease. The enzymatic activity of butyrylcholinesterase (BChE) in the brain increases with the progression of Alzheimer's disease, thus classifying BChE as a promising drug target in advanced Alzheimer's disease. Two compounds, 4a-S and 4a-R, showed excellent and selective inhibitory activities against BChE (IC50: 0.051 μM; IC50: 0.059 μM). Compound 4a-S also exhibited selective hMAO-B (IC50 = 0.45 ± 0.02 μM) inhibitory activities. The molecular docking and dynamic simulations of compounds 4a-R and 4a-S in human BChE revealed that the piperidine and propargyl groups play crucial roles for the inhibition. Compound 1d-R had the greatest ability to hMAO-B inhibition (IC50 = 0.09 μM). Compound 2b exhibited significant ability to inhibit self-induced β-amyloid (Aβ1-42; IC50: 0.97 μM). Achiral carbamate derivatives 2c, 2j and 2a act as potential antioxidants. Among the compounds, 2c, 2i, 2j, 4a-S were selected for the PAMPA-BBB test. These compounds demonstrated excellent penetration into the central nervous system. Compounds 1d-R, 2b, 2c, 4a-S and 4a-R were assessed in vivo with Aluminium chloride induced Alzheimer mice model. Compounds 1d-R, 2b, and 4a-S increased learning according to Morris Water Maze test. Our preliminary findings may open-up the way for developing innovative carbamate and carbamothioate derivatives against neurodegenerative diseases.

Keywords: Alzheimer's disease; Anti-β-Amyloid; Carbamate; Carbamothioate; MTDL; Morris water maze test; PAMPA; hBChE; hMAO-B.

MeSH terms

  • Acetylcholinesterase / metabolism
  • Alzheimer Disease* / drug therapy
  • Alzheimer Disease* / metabolism
  • Amyloid beta-Peptides* / antagonists & inhibitors
  • Amyloid beta-Peptides* / metabolism
  • Animals
  • Antioxidants* / chemical synthesis
  • Antioxidants* / chemistry
  • Antioxidants* / pharmacology
  • Blood-Brain Barrier* / drug effects
  • Blood-Brain Barrier* / metabolism
  • Butyrylcholinesterase / metabolism
  • Carbamates* / chemical synthesis
  • Carbamates* / chemistry
  • Carbamates* / pharmacology
  • Cholinesterase Inhibitors* / chemical synthesis
  • Cholinesterase Inhibitors* / chemistry
  • Cholinesterase Inhibitors* / pharmacology
  • Dose-Response Relationship, Drug
  • Heterocyclic Compounds / chemical synthesis
  • Heterocyclic Compounds / chemistry
  • Heterocyclic Compounds / pharmacology
  • Humans
  • Molecular Docking Simulation
  • Molecular Structure
  • Monoamine Oxidase / metabolism
  • Monoamine Oxidase Inhibitors* / chemical synthesis
  • Monoamine Oxidase Inhibitors* / chemistry
  • Monoamine Oxidase Inhibitors* / pharmacology
  • Neuroprotective Agents / chemical synthesis
  • Neuroprotective Agents / chemistry
  • Neuroprotective Agents / pharmacology
  • Protein Aggregates / drug effects
  • Structure-Activity Relationship

Substances

  • Acetylcholinesterase
  • Amyloid beta-Peptides
  • Antioxidants
  • Butyrylcholinesterase
  • Carbamates
  • Cholinesterase Inhibitors
  • Monoamine Oxidase
  • Monoamine Oxidase Inhibitors
  • Neuroprotective Agents
  • Protein Aggregates
  • Heterocyclic Compounds