Design and computational evaluation of E-stilbene-bearing 1,3,4-oxadiazole derivatives as potential tyrosinase...

A series of E-stilbene-bearing 1,3,4-oxadiazole derivatives (4a-b and 5a-f) was synthesized via the Mizoroki-Heck reaction and evaluated as inhibitors of tyrosinase, a vital enzyme involved in melanin biosynthesis. The synthesized compounds were structurally confirmed through NMR spectroscopy (¹H NMR, ¹³C NMR), infrared spectroscopy (FT-IR), and mass spectrometry. Nearly all derivatives exhibited inhibitory effects against tyrosinase with IC₅₀ values ranging from 0.32 ± 0.03 µM to 6.28 ± 0.05 µM. Among them, compounds 5d and 5b illustrated the most significant inhibitory activity, with IC₅₀ values of 0.32 ± 0.03 µM and 0.76 ± 0.01 µM, respectively. Molecular docking against tyrosinase (PDB: 2Y9X) revealed strong binding affinities (-10.0 kcal mol^-1 and -8.5 kcal mol^-1) exceeding those of the standard inhibitors kojic acid and ascorbic acid. Molecular dynamics simulation (100 ns), DFT analysis, and ADMET predictions further supported the stability, reactivity, and favorable pharmacokinetic behavior of the active compounds. These findings indicate that E-stilbene-based 1,3,4-oxadiazole derivatives hold significant potential as promising scaffolds for the development of new tyrosinase inhibitors for potential dermatological and cosmetic applications.