Development of antioxidant-enhanced hyaluronan derivatives functionalized with cinnamaldehyde and...

This study aims to improve the pharmaceutical properties of hyaluronan (HA) by conjugating it with cinnamaldehyde and pyrogallol-4-carboxaldehyde to prepare novel compounds, designated HA-Cin and HA-Pyr, respectively. The development of both compounds was verified through elemental analysis, ¹H NMR, FT-IR, and UV-Vis spectroscopy, showing the distinct features of HA-Cin and HA-Pyr compared to native HA. Antioxidant assessment demonstrated that HA-Pyr exhibited the most potent radical scavenging activity, inhibiting ABTS^•+ and DPPH^• radicals by 76.23 ± 3.3% and 68.18 ± 3.5%, respectively, at a concentration of 1.5 mg/mL. Additionally, HA-Cin exerted moderate DPPH^• radicals scavenging activity of 34.1 ± 2.1%, whereas native HA revealed minimal scavenging activity against ABTS^•+ and DPPH^• radicals, reporting 10.37 ± 0.5% and 4.14 ± 0.7%, respectively, at a similar concentration. Remarkably, in silico examination of absorption, distribution, metabolism, excretion, and toxicity (ADMET) exhibited safety profiles for HA-Cin and HA-Pyr, indicating non-hepatotoxic, non-carcinogenic, non-mutagenic, and non-cytotoxic properties, along with a short half-life and low clearance rate. These findings were emphasized using cytotoxicity assessment against fibroblast cells, manifesting the biocompatibility of both HA derivatives. Molecular docking findings further revealed stronger interaction and higher binding affinities of HA-Cin and HA-Pyr at the active site of cytochrome c peroxidase compared to native HA, reporting binding energies of -17.01 kcal/mol and - 19.02 kcal/mol, respectively, while native HA showed a binding affinity of -15.59 kcal/mol, corroborating the antioxidant results. These findings propose the potential use of HA-Cin and HA-Pyr in fabricating innovative wound dressings for chronic wound management.