Coumarin derivatives bearing benzoheterocycle moiety: synthesis, cholinesterase inhibitory, and docking simulation study

Objective(s): To investigate the efficiency of a novel series of coumarin derivatives bearing benzoheterocycle moiety as novel cholinesterase inhibitors. Materials and Methods: Different ۷-hydroxycoumarin derivatives were synthesized via Pechmann or Knoevenagel condensation and conjugated to different benzoheterocycle (۸-hydroxyquinoline, ۲-mercaptobenzoxazole or ۲-mercaptobenzimidazole) using dibromoalkanes ۳a-m. Final compounds were evaluated against acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) by Ellman's method. Kinetic study of AChE inhibition and ligand-protein docking simulation were also carried out for the most potent compound ۳b. Results: Some of the compounds revealed potent and selective activity against AChE. Compound ۳b containing the quinoline group showed the best activity with an IC۵۰ value of ۸.۸۰ µM against AChE. Kinetic study of AChE inhibition revealed the mixed-type inhibition of the enzyme by compound ۳b. Ligand-protein docking simulation also showed that the flexibility of the hydrophobic five carbons linker allows the quinoline ring to form π-π interaction with Trp۲۷۹ in the PAS. Conclusion: We suggest these synthesized compounds could become potential leads for AChE inhibition and prevention of AD symptoms.

کلیدواژه ها:

acetylcholinesterase ، Alzheimer’s disease ، Benzoheterocycles Butyrylcholinesterase ، Coumarin