Chalcone and its analogs: Therapeutic and diagnostic applications in Alzheimer's disease

Abstract

Chalcone [(E)-1,3-diphenyl-2-propene-1-one], a small molecule with α, β unsaturated carbonyl group is a precursor or component of many natural flavonoids and isoflavonoids. It is one of the privileged structures in medicinal chemistry. It possesses a wide range of biological activities encouraging many medicinal chemists to study this scaffold for its usefulness to oncology, infectious diseases, virology and neurodegenerative diseases including Alzheimer's disease (AD). Small molecular size, convenient and cost-effective synthesis, and flexibility for modifications to modulate lipophilicity suitable for blood brain barrier (BBB) permeability make chalcones a preferred candidate for their therapeutic and diagnostic potential in AD. This review summarizes and highlights the importance of chalcone and its analogs as single target small therapeutic agents, multi-target directed ligands (MTDLs) as well as molecular imaging agents for AD. The information summarized here will guide many medicinal chemist and researchers involved in drug discovery to consider chalcone as a potential scaffold for the development of anti-AD agents including theranostics.

Keywords: Alzheimer’s disease; Amyloid beta inhibition; Chalcone; Cholinesterase inhibitors; Molecular probes; Multi-target directed ligands; Neuroinflammation; Theranostic.

Figure 1.

Structure of chalcone and its form (A), major possible modifications (B) and clinically used and/or tested chalcone-based drugs (C).

Figure 2.

Biosynthesis of chalcone and its subsequent conversion to natural flavonoids.

Figure 3.

Structures of clinically approved drugs for the treatment of AD.

Figure 4.

Chalcone-Rivastigmine/Donepezil hybrids.

Figure 5.

Halogenated and non-halogenated alkyl amine derivatives of chalcones.

Figure 6.

Chalcone derivative with alkylamine functional groups.

Figure 7.

Chalcone derivative with di O-alkylamine substituents.

Figure 8.

Tetramethyl pyrazine derivatives of chalcone.

Figure 9.

Quinoline and piperidyl derivatives as cholinesterase inhibitors.

Figure 10.

Chalcones derivatives with imide, coumarin and aniline functional groups as cholinesterase inhibitors.

Figure 11.

Arylidene indanones (rigid analogs of chalcones) as cholinesterase inhibitors.

Figure 12.

Other rigid analogs of chalcones as cholinesterase inhibitors.

Figure 13.

Examples of potent BACE-1 inhibitors that enter clinical trials.

Figure 14.

BACE-1 inhibitors: (a) natural chalcone and (b) synthetic derivatives.

Figure 15.

Aβ aggregation inhibitors: (a) compounds that entered clinical trials and (b) natural and synthetic chalcone-based compounds.

Figure 16.

Structure of tau-based inhibitors in clinical trials

Figure 17.

Structures of (a) tau aggregation and (b) kinase inhibitors containing α,-β unsaturated carbonyl group

Figure 18.

Natural and synthetic chalcone derivatives as anti-neuroinflammation agents

Figure 19.

Rigid analogs (chromanone, aurone) of chalcone and flurbiprofen-chalcone hybrids as multifunctional agents in AD.

Figure 20.

FDA approved PET imaging probe for amyloid (Aβ) and tau proteins (NFTs)

Figure 21.

Radiolabeled chalcone derivatives (¹²⁵I, ¹⁸F, ¹¹C and ^99mTc) as a molecular probe for detection of amyloid beta plaques.

Figure 22.

Radiolabeled conformationally constrained chalcone derivatives (aurone and indanone) as a molecular probe for detection of amyloid beta plaques

Figure 23.

Chalcone based fluorescent probe for imaging Aβ aggregates

Figure 24.

Representative phenothiazine based (101 and 102), and curcumin based (CRANAD-58 and 17) NIR fluorescence probe with theranostic potential.