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

Abstract

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 oligomers. We also demonstrate that the Aβ binding site of these hybrids differs from that of Pittsburgh Compound B (PIB).Molecules 2020, 25, 77 2 of 32 Despite extensive research efforts, the causative factors of AD remain unclear [18]. However, various characteristics, such as low levels of acetylcholine (ACh), accumulation of amyloid-β (Aβ) deposits, tau (τ) protein aggregation, oxidative stress, inflammation, metal ion imbalance, and breakdown of homeostatic systems, play crucial roles in AD progression [19][20][21][22][23][24][25]. Currently, most of the primary therapeutic options for treating AD are based on AChEIs [26][27][28][29][30][31]. Low levels of acetylcholine (ACh) can lead to cognitive and memory deficits. The two types of cholinesterases present in the central nervous system, acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), are capable of hydrolyzing ACh [32][33][34][35]. In healthy brains, BChE plays a secondary role to AChE, but as AD progresses the activity and expression of BChE in the brain increases [36]. Although developing inhibitors against these enzymes alone will not lead to a cure, combining their effect with another hallmark of AD progression, such as Aβ peptide accumulation, could potentially be beneficial. The accumulation of Aβ peptides in the cerebral cortex of the brain has been suggested as a part of AD pathogenesis [37,38]. Thus, additionally preventing the aggregation of Aβ and/or disrupting the existing Aβ plaques are potential therapeutic approaches for treating AD [22,[39][40][41].There are currently reports in the literature investigating new scaffolds with two or more pharmacophores connected to each other through a linker aimed at interacting with more than one biological target [42][43][44][45][46][47][48][49][50][51]. Previously, our group as well as others studied donepezil, the current drug of choice for treating AD with its AChE and BChE inhibiting capacity [52][53][54][55][56][57]. In addition, we explored the use of chalcone derivatives as AChE inhibitors as well as Aβ peptide and metal-Aβ complex-targeting compounds [58,59]. Here, we ...

Therapeutic Potential of Multifunctional Derivatives of Cholinesterase Inhibitors

“…Chandrika et al [ 142 ] described synthesis and biological tests of two series of bifunctional donepezil derivatives against AD. They contained 1,3- or 1,4-chalcone-donepezil hybrids.…”

New Chalcone Derivatives as Anticancer and Antioxidant Agents: Synthesis, Molecular Docking Study and Biological Evaluation

“…Many synthesized chemical compounds have shown various biological activities [2][3][4][5][6][7][8][9]. Among those compounds, chalcones and their derivatives have received increasing attention from researchers because of their various activities, such as anti-bacterial [10][11][12], antifungal [13,14], anti-cancer [15][16][17], anti-Alzheimer [18,19], anti-inflammatory [20,21], and antioxidant [22][23][24], in addition to their importance in the industrial field [25][26][27].…”

Synthesis, Biological Evaluation, and In Silico Studies of New Acetylcholinesterase Inhibitors Based on Quinoxaline Scaffold

“…X-ray crystallography of tacrine-Torpedo califonica (TcAChE) complex revealed strong interactions between tacrine and the Catalytic Anionic Site (CAS) at the bottom of deep and narrow AChE active site gorge [18,19]. Many compounds were reported as the possible candidate/lead for AChE inhibitors such as coumarins [20], flavonoids derivatives [20], flavonolignans [21], chalcones [22], quinolines [23], quinoxalines [24,25] and others. Among the possible leads, quinoxaline has been used as a molecular scaffold for the design of some acetylcholinesterase inhibitors [24][25][26][27][28][29][30].…”