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Design and Synthesis of Multi-Target Directed 1,2,3-Triazole-Dimethylaminoacryloyl-Chromenone Derivatives With Potential Use in Alzheimer's Disease Publisher



Karimi Askarani H1 ; Iraji A2 ; Rastegari A3 ; Abbas Bukhari SN4 ; Firuzi O2 ; Akbarzadeh T1, 3 ; Saeedi M3, 5
Authors
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Authors Affiliations
  1. 1. Department of Medicinal Chemistry, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
  2. 2. Medicinal and Natural Products Chemistry Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
  3. 3. Persian Medicine and Pharmacy Research Center, Tehran University of Medical Sciences, Tehran, Iran
  4. 4. Department of Pharmaceutical Chemistry, College of Pharmacy, Aljouf University, Sakaka, 2014, Aljouf, Saudi Arabia
  5. 5. Medicinal Plants Research Center, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran

Source: BMC Chemistry Published:2020


Abstract

To discover multifunctional agents for the treatment of Alzheimer's disease (AD), a new series of 1,2,3-triazole-chromenone derivatives were designed and synthesized based on the multi target-directed ligands approach. The in vitro biological activities included acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) inhibition as well as anti-Aβ aggregation, neuroprotective effects, and metal-chelating properties. The results indicated a highly selective BuChE inhibitory activity with an IC50 value of 21.71 μM for compound 10h as the most potent compound. Besides, compound 10h could inhibit self-induced Aβ1–42 aggregation and AChE-induced Aβ aggregation with 32.6% and 29.4% inhibition values, respectively. The Lineweaver–Burk plot and molecular modeling study showed that compound 10h targeted both the catalytic active site (CAS) and peripheral anionic site (PAS) of BuChE. It should be noted that compound 10h was able to chelate biometals. Thus, the designed scaffold could be considered as multifunctional agents in AD drug discovery developments. [Figure not available: see fulltext.] © 2020, The Author(s).
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