Optimization of Polyphenol Extraction from Two Ziziphus Species via Central Composite Design-Response Surface Methodology: In Vitro Screening for Antioxidant, Antidiabetic, and Anti-Glycation Potentials

Polyphenols are widely available in medicinal plants and show promising pharmacological activity for many chronic diseases like diabetes mellitus. This study is aimed at optimizing the polyphenols from Ziziphus mauritiana and Ziziphus spina-christi using central composite design–response surface methodology (CCD–RSM) and evaluating their antioxidant, antidiabetic, and anti-glycation potentials. The key extraction parameters used for the optimal yield and biological evaluation were ethanol concentration, extraction time, solid-to-liquid ratio, and temperature. Total phenolic content (TPC) was maximized at intermediate ethanol concentrations (50–70% v/v), moderate extraction times (20–40 min), solid-to-liquid ratios of 20–25 g/mL, and temperatures between 40.0 and 60.0°C, and TPC obtained with optimal conditions was 120.59 mg GAE/g DW for Z. mauritiana and 104.77 mg GAE/g DW for Z. spina-christi. For the optimized extracts, Z. mauritiana showed significantly higher DPPH and ABTS (131.73 ± 7.23 mg and 271.62 ± 6.23 mg VCEAC/g DE) activities than Z. spina-christi (DPPH: 111.29 ± 4.34 mg; ABTS: 236.71 ± 8.23 mg VCEAC/g DE), while Z. spina-christi exhibited greater FRAP activity compared to Z. mauritiana (149.17 ± 6.23 mg and 123.53 ± 5.23 mg VCEAC/g DE, respectively). Z. spina-christi also had higher flavonoid and tannin content. In vitro assays revealed moderate α-amylase inhibition (IC₅₀ 112.30–176.20 µg/mL) and prominent anti-glycation effects (IC₅₀ 118–146 µg/mL), suggesting potential for managing oxidative stress and diabetes-related complications. This study underscores the phytotherapeutic potential of Ziziphus species and highlights CCD–RSM as an effective tool for optimizing bioactive compound extraction.