Novel Chalcone Derivatives as α-Amylase and α-Glucosidase Inhibitors: Solvent-Free Synthesis, Spectral Characterization, and Enzyme Kinetics

Abstract

Ten new chalcone derivatives (C1′–C10′) were synthesized with potassium hydroxide as a base catalyst in a Claisen–Schmidt condensation reaction performed in solvent-free mechanochemical conditions.  The clean and efficient green protocol yielded excellent yields of bright yellow to orange crystalline solids, as verified by melting-point analysis and thin-layer chromatography (TLC).  HR-ESI mass spectrometry, FTIR, and ^1H/^13C NMR structure determination all validated the successful formation of the α,β-unsaturated carbonyl system.

Based on biological research, chalcones suppressed enzymes metabolizing carbohydrates in a dose-dependent fashion. Halogenated analogues C3′ and C6′ had a competitive inhibition pattern and IC₅₀ values (55–60 µg/mL) comparable to or superior to that of acarbose in inhibiting α-amylase.  Nitro-substituted C4′ and trifluoromethyl-substituted C7′ inhibited α-glucosidase more effectively than acarbose with mixed-type inhibition and IC₅₀ = 35–40 µg/mL. Aromatic ring substitution were favored in α-glucosidase inhibition while halogens boosted α-amylase inhibition, based on structure–activity relationship (SAR) studies. These results prove the promise of the substituted chalcones as dual α-amylase/α-glucosidase inhibitors and the influence of substituent effects in altering enzyme interaction. The research gives a structural basis for optimisation of chalcone derivatives in the future as promising antidiabetic drugs.