Combining Chalcones with Donepezil to Inhibit Both Cholinesterases and Aβ Fibril Assembly.

Autor: Thamban Chandrika N; Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, KY 40536-0596, USA., Fosso MY; Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, KY 40536-0596, USA., Tsodikov OV; Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, KY 40536-0596, USA., LeVine Iii H; Center on Aging, School of Medicine, University of Kentucky, Lexington, KY 40536-0230, USA.; Department of Molecular and Cellular Biochemistry, School of Medicine, University of Kentucky, Lexington, KY 40536-0230, USA., Garneau-Tsodikova S; Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, KY 40536-0596, USA.
Jazyk: angličtina
Zdroj: Molecules (Basel, Switzerland) [Molecules] 2019 Dec 24; Vol. 25 (1). Date of Electronic Publication: 2019 Dec 24.
DOI: 10.3390/molecules25010077
Abstrakt: The fact that the number of people with Alzheimer's disease is increasing, combined with the limited availability of drugs for its treatment, emphasize the need for the development of novel effective therapeutics for treating this brain disorder. Herein, we focus on generating 12 chalcone-donepezil hybrids, with the goal of simultaneously targeting amyloid-β (Aβ) peptides as well as cholinesterases (i.e., acetylcholinesterase (AChE) and butyrylcholinesterase (BChE)). We present the design, synthesis, and biochemical evaluation of these two series of novel 1,3-chalcone-donepezil ( 15a - 15f ) or 1,4-chalcone-donepezil ( 16a - 16f ) hybrids. We evaluate the relationship between their structures and their ability to inhibit AChE/BChE activity as well as their ability to bind Aβ peptides. We show that several of these novel chalcone-donepezil hybrids can successfully inhibit AChE/BChE as well as the assembly of N -biotinylated Aβ (1-42) oligomers. We also demonstrate that the Aβ binding site of these hybrids differs from that of Pittsburgh Compound B (PIB).
Competing Interests: The authors declare no conflict of interest.
Databáze: MEDLINE
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