Newer Coumarin-linked Heterocyclic Hybrids: Design, Synthesis and Biological Assessment as Possible Anti-Alzheimer Drugs

As newer acetyl cholinesterase antagonists which could be effective in Alzheimer’s disease management, derivatives of 4-hydroxycoumarin were prepared. The 2-((2-oxo-2H-chromen-4-yl)oxy)-N-(pyridin-3-yl)acetamide derivative (4c) and 2-((2-oxo-2H-chromen-4-yl)oxy)-N-(pyridin-4-yl)acetamide (4d) showed the maximum AChE inhibition effect (IC50 = 0.957 ± 0.014 and 1.377 ± 0.018 mM, respectively) among the 16 coumarin-derived compounds evaluated against human acetylcholinesterase (hAChE). PHE 338 and HID 447 are responsible for ligand identification and trafficking by creating a polar π-π interaction with the pyridine ring of m-aminopyridine moiety according to the docking research of the most potent molecule 4c. Furthermore, the stabilization of the ligand in the active site may result in a stronger interdict of the enzyme by the development of a second hydrophobic π-π interaction between the phenyl ring of coumarin moiety and Trp 286 of the peripheral anionic site. In compound 4d, the coumarin moiety exhibited π-π stacking with amino acids (TYR 341 and TRP 286), hydrophobic interaction with TYR 72, pyridine ring of p-aminopyridine showed π-π stacking with TYR 124. The C=O group of coumarin ring formed a hydrogen bond with PHE 295 and the coumarin moiety also formed a hydrophobic interaction with PHE 297 at acyl binding pocket. The findings could be applied to the logical development of formidable and selective AChE inhibitors.