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Synthesis and Evaluation of Novel Arylisoxazoles Linked to Tacrine Moiety: In Vitro and in Vivo Biological Activities Against Alzheimer’S Disease Publisher Pubmed



Rastegari A1 ; Safavi M2 ; Vafadarnejad F3 ; Najafi Z4 ; Hariri R3 ; Bukhari SNA5 ; Iraji A6, 7 ; Edraki N8 ; Firuzi O8 ; Saeedi M1, 9 ; Mahdavi M10 ; Akbarzadeh T1, 3
Authors
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Authors Affiliations
  1. 1. Persian Medicine and Pharmacy Research Center, Tehran University of Medical Sciences, Tehran, Iran
  2. 2. Department of Biotechnology, Iranian Research Organization for Science and Technology (IROST), Tehran, Iran
  3. 3. Department of Medicinal Chemistry, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
  4. 4. Department of Medicinal Chemistry, School of Pharmacy, Hamadan University of Medical Sciences, Hamadan, Iran
  5. 5. Department of Pharmaceutical Chemistry, College of Pharmacy, Jouf University, Sakaka, Aljouf, 2014, Saudi Arabia
  6. 6. Stem Cells Technology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
  7. 7. Central Research laboratory, Shiraz University of Medical Sciences, Shiraz, Iran
  8. 8. Medicinal and Natural Products Chemistry Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
  9. 9. Medicinal Plants Research Center, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
  10. 10. Endocrinology and Metabolism Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran

Source: Molecular Diversity Published:2022


Abstract

Abstract: Alzheimer’s disease (AD) is now ranked as the third leading cause of death after heart disease and cancer. There is no definite cure for AD due to the multi-factorial nature of the disease, hence, multi-target-directed ligands (MTDLs) have attracted lots of attention. In this work, focusing on the efficient cholinesterase inhibitory activity of tacrine, design and synthesis of novel arylisoxazole-tacrine analogues was developed. In vitro acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibition assay confirmed high potency of the title compounds. Among them, compounds 7l and 7b demonstrated high activity toward AChE and BChE with IC50 values of 0.050 and 0.039 μM, respectively. Both compounds showed very good self-induced Aβ aggregation and AChE-induced inhibitory activity (79.4 and 71.4% for compound 7l and 61.8 and 58.6% for compound 7b, respectively). Also, 7l showed good anti-BACE1 activity with IC50 value of 1.65 µM. The metal chelation test indicated the ability of compounds 7l and 7b to chelate biometals (Zn2+, Cu2+, and Fe2+). However, they showed no significant neuroprotectivity against Aβ-induced damage in PC12 cells. Evaluation of in vitro hepatotoxicity revealed comparable toxicity of compounds 7l and 7b with tacrine. In vivo studies by Morris water maze (MWM) task demonstrated that compound 7l significantly reversed scopolamine-induced memory deficit in rats. Finally, molecular docking studies of compounds 7l and 7b confirmed establishment of desired interactions with the AChE, BChE, and BACE1 active sites. Graphic Abstract: [Figure not available: see fulltext.] © 2021, The Author(s), under exclusive licence to Springer Nature Switzerland AG.
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