Structure-activity relationship investigation of coumarin-chalcone hybrids with diverse side-chains as acetylcholinesterase and butyrylcholinesterase inhibitors

Abstract

Chalcones containing tertiary amine side-chains have potent activity as acetylcholinesterase (AChE) inhibitors. However, the effects of the location of the tertiary amine groups as well as of other groups on AChE and butyrylcholinesterase (BChE) activity have not been reported. Here, we report the synthesis and testing of 36 new coumarin-chalcone hybrids (5d-7j, 9d-11f, 12k-13m) against AChE and BChE. The nature and position of the chalcone substituents had major effects on inhibitory activity as well as selectivity for AChE over BChE. Compounds with para-substituted chalcone fragments in which the substituents were choline-like had potent activity against AChE and poor activity against BChE, while ortho-substituted analogs exhibited an opposite effect. Replacement of the terminal amine groups by amide, alkyl or alkenyl groups abrogated activity. Compound 5e showed potent inhibitory activity [Formula: see text]) and good selectivity for AChE over BChE (ratio 27.4), and a kinetic study showed that 5e exhibited mixed-type inhibition against AChE. Computational docking results indicate that 5e binds to Trp 279, Tyr334 and Trp 84 in AChE, but only to Trp 82 in BChE. Overall, the results show that coumarin-chalcone hybrids with choline-like side-chains have promising activity and selectivity against AChE and be promising therapeutic leads for Alzheimer's disease.

Keywords: Chalcone; Cholinesterase inhibitors; Coumarin; Structure–activity relationship; Tertiary amine group.

FIGURE 1

Examples of chalcones and coumarins.

SCHEME 1

Synthesis of compounds 5d–7j. Reagents and conditions: (a) Piperidine, room temperature; (b) Piperidine, Hydroxybenzaldehyde, ethanol, reflux; (c) Cl(CH₂)₂NR/Br(CH₂)₂R, K₂CO₃, NaI, DMF, 56 °C.

Scheme 2

Synthesis of compounds 9d–11f. Reagents and conditions: (d) HNR₁R₂, NaAc, DCM, 0 °C to room temperature; (e) K₂CO₃, NaI, DMF, 56 °C.

Scheme 3

Synthesis of compounds 12k–13m. Reagents and conditions: (f) Acetic acid, TsOH, 70°C; (g) Cl(CH₂)₂NR₁R₂, K₂CO₃, NaI, acetone, reflux.