Design and Development of a Novel Chalcone Derivative as an Anticholinesterase Inhibitor for Possible Treatment of Dementia

Abstract

BackgroundCognitive decline (e.g., memory loss), which mainly occurs in the elderly, is termed dementia. In the present study, we intended to explore the cholinesterase inhibitory activity of some novel synthesized chalcones, together with their effect on β-amyloid anti-aggregation.Material/MethodsA novel class of chalcone derivatives have been synthesized and characterized by FT-IR, 1H-NMR, 13C-NMR, and mass and elemental analysis. These derivatives were later used for the determination of acetylcholinesterase (AChE) inhibitory and β-amyloid anti-aggregation activity.ResultsThe results of the study showed that among the developed compounds, 8g inhibits AChE more prominently than BuChE, as suggested by a selectivity index (SI) of 2.88. Furthermore, the most potent compound, 8g, showed considerable action in inhibition of β-secretase and Aβ aggregation, but not as prominent as that of curcumin as a standard.ConclusionsIn conclusion, our study revealed a novel class of chalcone derivatives as a selective inhibitor of AChE with considerably action against β-secretase and Aβ aggregation. Our results may be useful in developing AD drug therapy and warrant further investigation to generate more advanced analogues.

The State of The Art on Acetylcholinesterase Inhibitors in the Treatment of Alzheimer’s Disease

“…Chalcone is an aromatic ketone that forms the central core for a variety of important biological compounds, collectively known as chalcones or chalconoids. Such compounds are selective AChE inhibitors and also possess anti-Aβ aggregation properties, 68 thus they were selected as promising scaffolds for the development of new drugs for AD treatment.…”

Structural Modifications on Chalcone Framework for Developing New Class of Cholinesterase Inhibitors

“…Para-substituted derivatives demonstrated a potent inhibition, wherein compound 19 showed potent inhibition against both enzymes with an SI value of 2.88 towards AChE. Electron-donating substituents such as methyl and methoxy groups showed better prominent inhibition than the electron-withdrawing halogens (-Cl, -F) [54]. In another study by Sang et al, a multi-design strategy was adopted, wherein O-alkyla mine functionalities were incorporated into the chalcones (Figure 22) [56].…”

“…The incorporation of 10 methylene units resulted in a decremental activity, while a 3 to 7 spacer demonstrated beneficial ChEs inhibitory potential. All of the screened compounds showed nanomolar potency (0.52 to 51.8 nM), which was much higher than those of standards, rivastigmine (AChE IC 50 A series of chalcone-benzyl piperidine derivatives was synthesized using an alkyl amine linker and the effect of various substituents on the ChE inhibitory activity was evaluated (Figure 20) [54]. The unsubstituted benzyl counterpart of the benzyl piperidine resulted in poor ChEs inhibition, highlighting the importance of substitution on the latter.…”

“…A series of chalcone–benzyl piperidine derivatives was synthesized using an alkyl amine linker and the effect of various substituents on the ChE inhibitory activity was evaluated ( Figure 20 ) [ 54 ]. The unsubstituted benzyl counterpart of the benzyl piperidine resulted in poor ChEs inhibition, highlighting the importance of substitution on the latter.…”

Synthesis and Structure of Some Chalcones Containing Acetamide Group

“…On the other hand, compounds containing phenoxy-N-arylacetamide scaffold were reported showing many of the same potential bioactivities such as virus inhibitory including HCMV (Babkov et al, 2015), HIV-1 RT (Sankaran et al, 2011), antimicrobial (Berest et al, 2011Nguyen et al, 2016;Rajurkar et al, 2014;Williams et al, 2015), antioxidant (Autore et al, 2010;Rajurkar et al, 2014), anticancer (Adimule et al, 2014Rani et al, 2014), antiinflammatory (Adimule et al, 2014Rajurkar et al, 2014), analgesic, antipyretic (Adimule et al, 2014Rani et al, 2015), and enzyme inhibitory (Atkinson et al, 2019;Kilic-Kurt et al, 2015;Ölgen et al, 2008;Raghavendra et al, 2012;Singh et al, 2017;Zhao et al, 2017).…”