Green microwave synthesis of pyrazole chalcone molecular hybrids efficient route to advanced diabetes therapeutics...

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.