Benzyl-Triazole Derivatives of Hydrazinecarbothiamide Derivatives as Potent Tyrosinase Inhibitors: Synthesis, Biological Evaluation, Structure-Activity Relationship and Docking Study

摘要

Skin and hair pigmentation, skin cancer, and enzymatic browning of plants and fruits are caused by tyrosinase, a di-copper oxidase. In the present work, we developed a novel series of substituted benzyl-1,2,3-triazole derivatives linked to hydrazinecarbothiamide via methoxyphenyl linker and assessed them for their tyrosinase inhibitory effects in the presence of L-dopa as substrates. The majority of the synthesized compounds inhibited tyrosinase at sub-micromolar concentrations. Compounds with 3,4-dichloro, 4-fluoro, and 3-chloro on the benzyl ring, respectively, exhibited exceptionally high potency against tyrosinase with IC_(50) values of 0.22, 0.22, and 0.24 μM in the presence of L-dopa as substrates, which is significantly lower than that of kojic acid as the positive control with an IC_(50) value of 9.64 μM. Result of kinetic assay demonstrated mixed type of inhibition by 9 g. The experimental findings of the potent compounds with the target enzyme, tyrosinase, were corroborated by molecular docking studies. The results of the molecular docking analysis showed the presence of critical pi-pi interactions between potent compounds and residues Phe264, and His263.