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Synthesis and Biological Evaluation of New N-Benzylpyridinium-Based Benzoheterocycles As Potential Anti-Alzheimer's Agents Publisher Pubmed



Salehi N1 ; Mirjalili BBF1 ; Nadri H2 ; Abdolahi Z2 ; Forootanfar H3 ; Samzadehkermani A4 ; Kucukkilinc TT5 ; Ayazgok B5 ; Emami S6 ; Haririan I7 ; Sharifzadeh M8 ; Foroumadi A9, 10 ; Khoobi M11, 12
Authors
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Authors Affiliations
  1. 1. Department of Chemistry, College of Science, Yazd University, Yazd, P.O. Box 89195-741, Iran
  2. 2. Faculty of Pharmacy, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
  3. 3. Department of Pharmaceutical Biotechnology, Faculty of Pharmacy, Kerman University of Medical Sciences, Kerman, Iran
  4. 4. Department of Chemistry, Faculty of Sciences, University of Zabol, Zabol, Iran
  5. 5. Hacettepe University, Faculty of Pharmacy, Department of Biochemistry, Ankara, Turkey
  6. 6. Department of Medicinal Chemistry and Pharmaceutical Sciences Research Center, Faculty of Pharmacy, Mazandaran University of Medical Sciences, Sari, Iran
  7. 7. Department of Pharmaceutical Biomaterials, Medical Biomaterials Research Center, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
  8. 8. Department of Pharmacology and Toxicology, Faculty of Pharmacy, Toxicology and Poisoning Research Centre, Tehran University of Medical Sciences, Tehran, Iran
  9. 9. Neuroscience Research Center, Institute of Neuropharmacology, Kerman University of Medical Sciences, Kerman, Iran
  10. 10. Department of Medicinal Chemistry, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
  11. 11. The Institute of Pharmaceutical Sciences (TIPS), Tehran University of Medical Sciences, Tehran, 1417614411, Iran
  12. 12. Departmnt of Pharmaceutical Biomaterials, Medical Biomaterials Research Center, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran

Source: Bioorganic Chemistry Published:2019


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-aminophenol 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 Aβ self-aggregation as well as AChE-induced Aβ aggregation. Meanwhile, these compounds could significantly protect PC12 cells against H 2 O 2 -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. © 2018 Elsevier Inc.
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