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Novel 3-Phenylcoumarin–Lipoic Acid Conjugates As Multi-Functional Agents for Potential Treatment of Alzheimer's Disease Publisher Pubmed



Jalilibaleh L1 ; Nadri H2 ; Forootanfar H3 ; Samzadehkermani A4 ; Kucukkilinc TT5 ; Ayazgok B5 ; Rahimifard M1 ; Baeeri M1 ; Doostmohammadi M6 ; Firoozpour L7 ; Bukhari SNA8 ; Abdollahi M1 ; Ganjali MR9, 10 ; Emami S11 Show All Authors
Authors
  1. Jalilibaleh L1
  2. Nadri H2
  3. Forootanfar H3
  4. Samzadehkermani A4
  5. Kucukkilinc TT5
  6. Ayazgok B5
  7. Rahimifard M1
  8. Baeeri M1
  9. Doostmohammadi M6
  10. Firoozpour L7
  11. Bukhari SNA8
  12. Abdollahi M1
  13. Ganjali MR9, 10
  14. Emami S11
  15. Khoobi M1, 12
  16. Foroumadi A6, 13
Show Affiliations
Authors Affiliations
  1. 1. The Institute of Pharmaceutical Sciences (TIPS), Tehran University of Medical Sciences, Tehran, 1417614411, 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. Pharmaceutics Research Center, Institute of Neuropharmacology, Kerman University of Medical Sciences, Kerman, Iran
  7. 7. Drug Design and Development Research Center, The Institute of Pharmaceutical Sciences (TIPS), Tehran University of Medical Sciences, Tehran, 1417614411, Iran
  8. 8. Department of Pharmaceutical Chemistry, College of Pharmacy, Jouf University, Aljouf, 2014, Sakaka, Saudi Arabia
  9. 9. Biosensor Research Center, Endocrinology and Metabolism Molecular-Cellular Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
  10. 10. Center of Excellence in Electrochemistry, Faculty of Chemistry, University of Tehran, Tehran, Iran
  11. 11. Department of Medicinal Chemistry and Pharmaceutical Sciences Research Center, Faculty of Pharmacy, Mazandaran University of Medical Sciences, Sari, Iran
  12. 12. Department of Pharmaceutical Biomaterials, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
  13. 13. Department of Medicinal Chemistry, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran

Source: Bioorganic Chemistry Published:2018


Abstract

New series of triazole-containing 3-phenylcoumarin–lipoic acid conjugates were designed as multi-functional agents for treatment of Alzheimer's disease. The target compounds 4a-o were synthesized via the azide-alkyne cycloaddition reaction and their biological activities were primarily evaluated in terms of neuroprotection against H 2 O 2 -induced cell death in PC12 cells and AChE/BuChE inhibition. The promising compounds 4j and 4i containing four carbons spacer were selected for further biological evaluations. Based on the obtained results, the benzocoumarin derivative 4j with IC 50 value of 7.3 µM was the most potent AChE inhibitor and displayed good inhibition toward intracellular reactive oxygen species (ROS). This compound with antioxidant and metal chelating ability showed also protective effect on cell injury induced by Aβ 1-42 in SH-SY5Y cells. Although the 8-methoxycoumarin analog 4i was slightly less active than 4j against AChE, but displayed higher protection ability against H 2 O 2 -induced cell death in PC12 and could significantly block Aβ-aggregation. The results suggested that the prototype compounds 4i and 4j might be promising multi-functional agents for the further development of the disease-modifying treatments of Alzheimer's disease. © 2018 Elsevier Inc.
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