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Design, Synthesis, and Biological Evaluation of Triazole-Piperazine Derivatives Bearing Carbodithioate Functionalities As Potent Tyrosinase Inhibitors to Reduce Hyperpigmentation Publisher



Meshkani M ; Sayahi MH ; Taherkhani AM ; Dastyafteh N ; Nikfar P ; Bagheri F ; Safapoor S ; Rastegar H ; Larijani B ; Mahdavi M ; Iraji A
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Source: ChemistrySelect Published:2026


Abstract

Tyrosinase, a copper-containing enzyme, plays a crucial role in melanogenesis by catalyzing the oxidation of tyrosine to melanin. Excessive melanin production leads to hyperpigmentation disorders, prompting the search for effective tyrosinase inhibitors. Herein, we report the design, synthesis, and biological evaluation of a series of triazole-piperazine derivatives as tyrosinase inhibitors. The synthetic procedures involve a multi-step reaction including Boc protection/deprotection, carbodithioate formation, and click reaction to yield the final compounds with high purity. The structures of the compounds were confirmed using different techniques, including 1H and 13C NMR, mass spectrometry, and IR spectroscopy. The synthesized compounds were then evaluated for their inhibitory activity against tyrosinase, with IC50 values ranging from 24.71 ± 2.00 µM to >100 µM. Structure-activity relationship (SAR) analysis revealed the important role of electron-withdrawing and lipophilic substitutions for potency. Molecular docking and dynamics studies further confirmed key interactions with the active site residues and the copper cofactor. This study highlights the potential of triazole-piperazine derivatives as promising candidates against hyperpigmentation and related disorders. © 2026 Wiley-VCH GmbH.
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