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Chromone–Lipoic Acid Conjugate: Neuroprotective Agent Having Acceptable Butyrylcholinesterase Inhibition, Antioxidant and Copper-Chelation Activities Publisher Pubmed



Jalilibaleh L1 ; Nadri H2 ; Forootanfar H3 ; Kucukkilinc TT4 ; Ayazgok B4 ; Sharifzadeh M5 ; Rahimifard M6 ; Baeeri M6 ; Abdollahi M6 ; Foroumadi A1 ; Khoobi M1
Authors
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Authors Affiliations
  1. 1. Biomaterials Group, Pharmaceutical Research Center, The Institute of Pharmaceutical Sciences (TIPS), Tehran University of Medical Sciences, Tehran, 1417614411, Iran
  2. 2. Faculty of Pharmacy and Pharmaceutical Sciences Research Center, 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. Faculty of Pharmacy, Department of Biochemistry, Hacettepe University, Ankara, Turkey
  5. 5. Department of Pharmacology and Toxicology, Faculty of Pharmacy, Toxicology and poisoning Research Centre, Tehran University of Medical Sciences, Tehran, Iran
  6. 6. Toxicology and Diseases Group, Pharmaceutical Sciences Research Center (PSRC), The Institute of Pharmaceutical Sciences (TIPS), Tehran University of Medical Sciences (TUMS), Tehran, Iran

Source: DARU# Journal of Pharmaceutical Sciences Published:2021


Abstract

Purpose: Alzheimer’s disease (AD) is a multifaceted neurodegenerative disease. To target simultaneously multiple pathological processes involved in AD, natural-origin compounds with unique characteristics are promising scaffolds to develop novel multi-target compounds in the treatment of different neurodegenerative disease, especially AD. In this study, novel chromone-lipoic acid hybrids were prepared to find a new multifunctional lead structure for the treatment of AD. Methods: Chromone-lipoic acid hybrids were prepared through click reaction and their neuroprotection and anticholinesterase activity were fully evaluated. The anti-amyloid aggregation, antioxidant and metal-chelation activities of the best compound were also investigated by standard methods to find a new multi-functional agent against AD. Results: The primary biological screening demonstrated that all compounds had significant neuroprotection activity against H2O2-induced cell damage in PC12 cells. Compound 19 as the most potent butyrylcholinesterase (BuChE) inhibitor (IC50 = 7.55 μM) having significant neuroprotection activity as level as reference drug was selected for further biological evaluations. Docking and kinetic studies revealed non-competitive mixed-type inhibition of BuChE by compound 19. It could significantly reduce formation of the intracellular reactive oxygen species (ROS) and showed excellent reducing power (85.57 mM Fe+2), comparable with quercetin and lipoic acid. It could also moderately inhibit Aβ aggregation and selectively chelate with copper ions in 2:1 M ratio. Conclusion: Compound 19 could be considered as a hopeful multifunctional agent for the further development gainst AD owing to the acceptable neuroprotective and anti-BuChE activity, moderate anti-Aβ aggregation activity, outstanding antioxidant activity as well as selective copper chelation ability. Graphical abstract: [Figure not available: see fulltext.] © 2021, Springer Nature Switzerland AG.
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