Design, synthesis, biological activity and in silico evaluation of phenylthiazole derivatives as multifunctional...

Excessive melanin accumulation causes hyperpigmentation, a skin pathophysiology that highlights the need for safe and multifunctional skin-whitening agents. Building on the reported tyrosinase inhibitory potential of phenylthiazole derivatives, a series of compounds was designed and synthesized to investigate the structural determinants of their multi-functional activities. The biological evaluation included mushroom tyrosinase (mTYR) inhibition, as well as anti-melanogenic, anti-inflammatory, and antioxidant assays. Among the series, compound 3c exhibited the most potent multi-functional profile, showing mTYR inhibition (IC₅₀ = 30.8 ± 2.7 µM) with a mixed-type inhibitory mechanism (K_i = 20 µM), a 34% reduction in melanin content at 40 µM, significant nitric oxide inhibition (IC₅₀ = 33.7 ± 2.0 µM), and strong antioxidant activity (SC₅₀ = 29.0 ± 0.8 µM). Density Functional Theory (DFT) calculations and predicted physicochemical properties indicate that 3c possesses favorable molecular stability and promising potential for skin penetration. Molecular docking and molecular dynamics (MD) simulations further demonstrated that 3c stably occupies the active pocket of human tyrosinase-related protein 1 (TYRP1, PDB ID: 5M8M), forming key interactions with Zn²⁺-coordinating residues and maintaining a stable energetic profile. Collectively, these findings indicate that 3c exhibits the most balanced multi-functional activity within the series and holds promise as a lead compound for topical skin-whitening applications.