A neohesperidin dihydrochalcone–pyruvic acid deep eutectic solvent: a novel tyrosinase inhibitor for enhanced transdermal delivery

Abstract

A novel therapeutic deep eutectic solvent (THEDES) comprising neohesperidin dihydrochalcone (NHDC) and pyruvic acid (PA) was synthesized in this study 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. The THEDES system enhanced skin permeation by 5.3-fold in vitro compared to free NHDC and exhibited superior antioxidant activity (DPPH IC₅₀: 35.99 µg mL⁻¹; ABTS IC₅₀: 21.88 µg mL⁻¹). TYR inhibition assays revealed enhanced efficacy, with a mushroom TYR IC₅₀ of 2.93 mg mL⁻¹ (vs. NHDC's 7.04 mg mL⁻¹), 64.6% higher melanin suppression, and 23.6% greater intracellular TYR inhibition. Molecular docking identified stronger TYR binding affinity for the THEDES (ΔG = −10.8 kcal mol⁻¹, which is 1.5 kcal mol⁻¹ lower than that of 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.