Antioxidant and Cytoprotective Effects of Novel Hydrazone-Chalcone Hybrids Against Hydrogen Peroxide-Induced Oxidative Stress
DOI:
https://doi.org/10.5281/zenodo.22664579Keywords:
hydrazone-chalcone hybrid, oxidative stress, DPPH/ABTS/FRAP, cytoprotection, hydrogen peroxideAbstract
Background: Oxidative stress driven by excess reactive oxygen species contributes to a broad range of chronic pathologies, and
molecules that combine two independently validated antioxidant pharmacophores are of continuing interest as cytoprotective
leads.
Objective: We designed and evaluated a series of hydrazone-chalcone hybrids in which a common chalcone-carbohydrazide core
was condensed with seven structurally varied aromatic aldehydes, to test whether the electronic and hydrogen-bonding character
of the hydrazone-forming ring predicts both cell-free antioxidant potency and cytoprotection against hydrogen peroxide-induced
oxidative stress.
Methods: Hybrids HC-1 to HC-7 were synthesized by Claisen-Schmidt condensation followed by hydrazide formation and
acid-catalyzed hydrazone closure, and characterized by NMR, FT-IR and HRMS. Antioxidant activity was assessed by DPPH, ABTS
and FRAP assays. Cytoprotection was evaluated in human dermal fibroblasts challenged with 400 uM H2O2, using MTT viability,
DCFH-DA fluorescence for intracellular reactive oxygen species, and a thiobarbituric acid reactive substances assay for
malondialdehyde.
Results: The catechol-substituted hybrid HC-3 was the most potent compound across all assays (DPPH IC50 9.8 +/- 1.1 uM; viability
EC50 6.4 +/- 0.9 uM), followed by the hindered-phenol hybrid HC-7 and the vanillin-type hybrid HC-4. The unsubstituted and
nitro-substituted analogues were essentially inactive. Cell-free DPPH potency correlated reasonably well with cytoprotective EC50
across the series (r = 0.87), though the dimethylamino hybrid HC-5 protected cells somewhat better than its chemical-assay
ranking predicted.
Conclusion: Hydroxylation pattern and electronic character of the hydrazone-forming aryl ring are the principal determinants of
antioxidant and cytoprotective activity in this hybrid series, and the catechol-substituted hybrid HC-3 warrants further
mechanistic and in vivo evaluation as a cytoprotective lead.
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