Green microwave synthesis of pyrazole chalcone molecular hybrids efficient route to advanced diabetes therapeutics with DNA intercalative properties

Abstract

Novel chalcone derivatives incorporating pyrazole moieties were synthesized via microwave assisted Claisen–Schmidt condensation and evaluated for their in vitro α-amylase and α-glucosidase inhibitory potential as therapeutic agents against diabetes mellitus, a rapidly escalating global health crisis. The microwave-assisted approach demonstrated remarkable synthetic advantages achieving excellent yields (80–85%) and enhanced product purity within minutes compared to conventional methods requiring over 24 hours. Five pyrazole-chalcone hybrids, L^I (C₁₉H₁₆N₂O), L^II (C₁₈H₁₄Cl₂N₂O), L^III (C₁₈H₁₄N₃O₃), L^IV (C₂₀H₁₆N₂O₂), and L^V (C₁₈H₁₅N₂O₂), were successfully synthesized from pyrazole ketone and different substituted aldehydes. Comprehensive structural characterization using FTIR, NMR, UV-Vis, fluorescence, cyclic voltammetry, and mass spectrometry confirmed successful target compound formation. In vitro enzyme inhibition studies revealed promising dose dependent activity with compounds L^IV (IC₅₀ = 212.5 µM) and L^II (IC₅₀ = 215.2 µM) demonstrating superior α-glucosidase inhibition compared to acarbose (IC₅₀ = 240.6 µM), while compound L^I exhibited potent α-amylase inhibitory activity (IC₅₀ = 501.9 µM). DNA binding studies indicated intercalative interactions with binding constants ranging from 10³ to 10⁴ M⁻¹. Molecular docking analysis revealed stable protein ligand complexes with compound L^II showing binding affinities of −6.15 kcal mol⁻¹ for α-glucosidase and −5.83 kcal mol⁻¹ for α-amylase, while DFT calculations indicated HOMO–LUMO energy gaps of 3.93–4.30 eV suggesting moderate chemical reactivity. The in silico drug-likeness and oral bioavailability profiles of pyrazole-chalcone fully comply with Lipinski's criteria and exhibit excellent ADMET properties. These comprehensive findings establish pyrazole chalcone hybrids as promising multifunctional molecular scaffolds with significant potential for next-generation antidiabetic therapeutics.