Synthesis and biological evaluation of new N-benzylpyridinium-based benzoheterocycles as potential anti-Alzheimer's agents


Salehi N., Mirjalili B. B. F. , Nadri H., Abdolahi Z., Forootanfar H., Samzadeh-Kermani A., ...More

Bioorganic Chemistry, vol.83, pp.559-568, 2019 (SCI-Expanded) identifier identifier identifier

  • Publication Type: Article / Article
  • Volume: 83
  • Publication Date: 2019
  • Doi Number: 10.1016/j.bioorg.2018.11.010
  • Journal Name: Bioorganic Chemistry
  • Journal Indexes: Science Citation Index Expanded (SCI-EXPANDED), Scopus
  • Page Numbers: pp.559-568
  • Keywords: Alzheimer's disease, Benzothiazole, Pyridinium, AChE, A beta aggregation, Neuroprotection, AMYLOID AGGREGATION, ACETYLCHOLINESTERASE, DERIVATIVES, BINDING, BUTYRYLCHOLINESTERASE, INHIBITION, COUMARINS, DOCKING, DESIGN
  • Hacettepe University Affiliated: Yes

Abstract

A novel series of benzylpyridinium-based benzoheterocycles (benzimidazole, benzoxazole or benzothiazole) were designed as potent acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) inhibitors. The title compounds 4a-q were conveniently synthesized via condensation reaction of 1,2-phenylenediamine, 2-amino-phenol or 2-aminothiophenol with pyridin-4-carbalehyde, followed by N-benzylation using various benzyl halides. The results of in vitro biological assays revealed that most of them, especially 4c and 4g, had potent anticholinesterase activity comparable or more potent than reference drug, donepezil. The kinetic study demonstrated that the representative compound 4c inhibits AChE in competitive manner. According to the ligand-enzyme docking simulation, compound 4c occupied the active site at the vicinity of catalytic triad. The compounds 4c and 4g were found to be inhibitors of A beta self-aggregation as well as AChE-induced A beta aggregation. Meanwhile, these compounds could significantly protect PC12 cells against H2O2-induced injury and showed no toxicity against HepG2 cells. As multi-targeted structures, compounds 4c and 4g could be considered as promising candidate for further lead developments to treat Alzheimer's disease.