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

Abstract

Due to the multifaceted pharmacological activities of chalcones, these scaffolds have been considered one of the most privileged frameworks in the drug discovery process. Structurally, chalcones are α, β-unsaturated carbonyl functionalities with two aryl or heteroaryl units. Amongst the numerous pharmacological activities explored for chalcone derivatives, the development of novel chalcone analogs for the treatment of Alzheimer's disease (AD) is among the research topics of most interest. Chalcones possess numerous advantages, such as smaller molecular size, opportunities for further structural modification thereby altering the physicochemical properties, cost-effectiveness, and convenient synthetic methodology. The present review highlights the recent evidence of chalcones as a privileged structure in AD drug development processes. Different classes of chalcone-derived analogs are summarized for the easy understanding of the previously reported analogs as well as the importance of certain functionalities in exhibiting cholinesterase inhibition. In this way, this review will shed light on the medicinal chemistry fraternity for the design and development of novel promising chalcone candidates for the treatment of AD.

Keywords: acetylcholinesterase; butyrylcholinesterase; chalcones; structure activity relationships.

Figure 1

Pathophysiology of Alzheimer’s disease (AD).

Figure 2

Chemical structures of clinically used drugs for AD.

Figure 3

Structure and numbering of chalcone scaffold.

Figure 4

Chalcone derivatives with simple substitutions by Aslan et al. [38].

Figure 5

Chalcone derivatives with simple substitutions by Hasan et al. [39].

Figure 6

Chalcone derivatives with simple substitutions by Mphahlele et al. [40].

Figure 7

Chalcone derivatives with simple substitutions by Fosso et al. [41].

Figure 8

Chalcones inspired from Flavokawain Mannich bases.

Figure 9

Mannich bases-derived chalcone reported by Zhang et al.

Figure 10

4-amino chalcone derivatives reported by Gurdere et al.

Figure 11

2′-amino chalcones derivatives reported by Sakata et al.

Figure 12

Structural refinement involved the modification of simple amino to cyclic morpholine derivatives.

Figure 13

Structural refinement involved the modification of simple amino to cyclic piperazine derivatives.

Figure 14

Chemical structures of chalcone imide derivatives.

Figure 15

Chemical structures of chalcone sulphonamide derivatives.

Figure 16

Ether-substituted chalcone derivatives reported by Liu et al.

Figure 17

Fluoro-chalcone-substituted amino alkyl derivatives.

Figure 18

Open-chain amino alkyl chalcone derivative.

Figure 19

Chalcone–carbamate hybrid analogs.

Figure 20

Chalcone benzyl piperidine derivatives.

Figure 21

Chalcone derivatives reported by Rampa et al.

Figure 22

O-alkylamine-substituted chalcone derivatives reported by Sang et al.

Figure 23

Chalcone-O-alkylamine derivatives reported by Bai et al.

Figure 24

Chlorochalcones with tertiary amine side chain.

Figure 25

Benzofuran-based chalconoid-containing N-benzylpyridinium motif.

Figure 26

Chemical structures of donepezil–chalcone hybrid derivatives.

Figure 27

Chemical structures of rivastigmine–chalcone hybrid derivatives.

Figure 28

Chemical structures of flurbiprofen Mannich derivative–chalcone hybrid derivatives.

Figure 29

N-substituted-4-phenothiazine chalcone derivatives.

Figure 30

Chemical structures of 4-amino chalcone-rivastigmine derivatives.

Figure 31

Flavonoid-inspired chalcone derivatives.

Figure 32

Ferulic acid-inspired chalcone derivatives.

Figure 33

Chemical structure of chalcone and chalcone epoxide.

Figure 34

Chemical structure of bis-etherified bis-chalcone.

Figure 35

Chemical structures of 4-hydroxy chalcones and bis-chalcone derivatives.

Figure 36

Chemical structures of tris-chalcone derivatives.

Figure 37

Fluorine-substituted tris-chalcone derivatives.

Figure 38

Chemical structures of chalcone-O-carbamate derivatives.

Figure 39

Chemical structures of chalcones reported by Bag et al.

Figure 40

Chemical structures of coumarin–chalcone hybrid analogs.

Figure 41

Piperidyl–thienyl and 2-pyrazoline derivatives of chalcone.

Figure 42

Chemical structures of quinolone-substituted chalcone derivatives.

Figure 43

Structural modification of quinolone-substituted chalcone derivatives.

Figure 44

Chemical structures of triazole-chalcone derivatives.

Figure 45

Chemical structures of benzodioxole chalcone derivatives.

Figure 46

Chemical structures of Schiff bases-appended chalcone derivatives.

Figure 47

Chemical structures of chalcone oxime ether derivatives.

Figure 48

Summary of SAR points in ChE inhibition.