Neohesperidin Dihydrochalcone-Pyruvic Acid Deep Eutectic Solvent: A Novel Tyrosinase Inhibitor for Enhanced Transdermal Delivery

Abstract

This study synthesizes a novel therapeutic deep eutectic solvent (THEDES) comprising neohesperidin dihydrochalcone (NHDC) and pyruvic acid (PA) to overcome NHDC’s poor solubility and optimize its transdermal delivery as a tyrosinase (TYR) inhibitor. The NHDC: PA (1:3 mol/mol) complex demonstrated optimal hydrogen bonding, validated by FT-IR, NMR, TGA, and computational modeling. THEDES enhanced skin permeation by 5.3-fold in vitro compared to free NHDC and exhibited superior antioxidant activity (DPPH IC50: 35.99 μg/mL; ABTS IC50: 21.88 μg/mL). TYR inhibition assays revealed enhanced efficacy: mushroom TYR IC50 at2.93 mg/mL (vs. NHDC’s 7.04 mg/mL), 64.6% higher melanin suppression, and 23.6% greater intracellular TYR inhibition. Molecular docking identified stronger TYR binding affinity for THEDES (ΔG = −10.8 kcal/mol; 1.5 kcal/mol lower than NHDC). Safety assessments confirmed biocompatibility and non-irritant properties. The THEDES system thus provides a transdermally efficient, bioactive, and safe platform for TYR-targeted depigmentation therapies.