In vitro and in silico insights into tyrosinase inhibitors with (E)-benzylidene-1-indanone derivatives

Hee Jin Jung,Sang Gyun Noh,Yujin Park,Dongwan Kang,Pusoon Chun,Hae Young Chung,Hyung Ryong Moon

doi:10.1016/j.csbj.2019.07.017

Abstract

Tyrosinase is a key enzyme responsible for melanin biosynthesis and is effective in protecting skin damage caused by ultraviolet radiation. As part of ongoing efforts to discover potent tyrosinase inhibitors, we systematically designed and synthesized thirteen (E)-benzylidene-1-indanone derivatives (BID1–13) and determined their inhibitory activities against tyrosinase. Among the compounds evaluated, BID3 was the most potent inhibitor of mushroom tyrosinase (IC50 = 0.034 µM, monophenolase activity; IC50 = 1.39 µM, diphenolase activity). Kinetic studies revealed that BID3 demonstrated a mixed type of tyrosinase inhibition with Ki value of 2.4 µM using l-DOPA as a substrate. In silico molecular docking simulations demonstrated that BID3 can bind to the catalytic and allosteric sites of tyrosinase to inhibit enzyme activity which confirmed in vitro experimental studies between BID3 and tyrosinase. Furthermore, melanin contents decreased and cellular tyrosinase activity was inhibited after BID3 treatment. These observations revealed that BID3 is a potent tyrosinase inhibitor and potentially could be used as a whitening agent for the treatment of pigmentation-related disorders.

Highlights

Melanin is synthesized by melanocytes in the vassal layer of the epidermis generally refers to the family of pigments commonly known for protecting mammalian skin from damage caused by harmful UV radiation by scavenging free radicals or dispersing incoming UV light [1]
Target (E)-2-benzylidene-1-indanone derivatives were synthesized employing acidic (1 M HCl in acetic acid) conditions. These reactions generated the target (E)-2-benzylidene-1indanone derivatives in yields of 32.8–99.1%. It appears that only the E-isomers of 2-benzylidene-1-indanones were generated due to the A-strain known as the 1,3-allylic strain
Based on IC50 values via the L-tyrosine and L-DOPA pathway, BID3 demonstrated the most potent tyrosinase inhibitory activity we further studied the mechanism underlying this inhibitory effect

Summary

Introduction

Melanin is synthesized by melanocytes in the vassal layer of the epidermis generally refers to the family of pigments commonly known for protecting mammalian skin from damage caused by harmful UV radiation by scavenging free radicals or dispersing incoming UV light [1]. Abundant generation of melanin can cause visible hyperpigmentation of the epidermis, which may be obvious as melasma, freckles, age spots, or senile lentigines [2]. When L-tyrosine is the substrate, the product of tyrosinase catalyzed reaction is DOPA-quinone, which is converted to melanin [3]. These steps are crucial for the protection of skin against UV damage. New tyrosinase inhibitors exhibiting drug-like and skin-whitening properties are required to inhibit excessive skin pigmentation

Methods

Results

Conclusion