Design and Synthesis of Morroniside Derivatives Targeting H ₂ O ₂ ‐Induced Oxidative Stress: Antioxidant‐Triggered Neuroprotective Effect

Oxidative stress drove neuronal damage by disrupting redox homeostasis and played a crucial role in the progression of neurological disorders. Natural antioxidants garnered significant interest as potential therapeutics. Morroniside exhibited promising antioxidant activity but had low bioavailability and poor lipid solubility, limiting its therapeutic application. To address these limitations, a series of alkyl and benzenesulfonate ester derivatives were designed and synthesized. Their antioxidant activities were evaluated using multiple in vitro assays. Structure–activity relationship (SAR) analysis indicated that both the type and position of substituents influenced antioxidant activity. Subsequently, the six most active derivatives were selected and evaluated for cytotoxicity and antioxidant capacity in hydrogen peroxide (H ₂ O ₂ )‐induced PC12 cells. The results identified derivative 4b as the most promising candidate, demonstrating acceptable cytotoxicity and strong protective effects. Furthermore, 4b significantly increased superoxide dismutase (SOD) activity while reducing intracellular reactive oxygen species (ROS) and malondialdehyde (MDA) levels. Mechanistic studies suggested that 4b exerted antioxidant effects through modulation of the nuclear factor erythroid 2‐related factor 2 (Nrf2) signaling pathway. These findings demonstrated that sulfonate ester modification was an effective strategy to improve the antioxidant activity of morroniside, and derivative 4b was identified as a promising antioxidant and neuroprotective candidate.