5-Substituted isatin thiosemicarbazones as inhibitors of tyrosinase: Insights of substituent effects

Run Cheng; Wenyan Shi; Qingyun Yuan; Ruiren Tang; Yujie Wang; Di Yang; Xin Xiao; Jianping Zeng; Jingwen Chen; Yanqing Wang

doi:10.1016/j.saa.2021.119669

5-Substituted isatin thiosemicarbazones as inhibitors of tyrosinase: Insights of substituent effects

Spectrochim Acta A Mol Biomol Spectrosc. 2021 Jul 5:255:119669. doi: 10.1016/j.saa.2021.119669. Epub 2021 Mar 9.

Authors

Run Cheng¹, Wenyan Shi², Qingyun Yuan³, Ruiren Tang⁴, Yujie Wang², Di Yang², Xin Xiao², Jianping Zeng², Jingwen Chen⁵, Yanqing Wang⁶

Affiliations

¹ College of Chemistry and Chemical Engineering, Central South University, Changsha 410000, PR China; School of Chemistry and Chemical Engineering, Building Materials Research Academy, Yancheng Institute of Technology, Jianjun East Rd. 211, Yancheng 224051, PR China.
² School of Chemistry and Chemical Engineering, Building Materials Research Academy, Yancheng Institute of Technology, Jianjun East Rd. 211, Yancheng 224051, PR China.
³ School of Chemistry and Chemical Engineering, Building Materials Research Academy, Yancheng Institute of Technology, Jianjun East Rd. 211, Yancheng 224051, PR China; School of Chemistry and Chemical Engineering, Jiangsu University, Xuefu Rd. 301, Zhenjiang 212013, PR China.
⁴ College of Chemistry and Chemical Engineering, Central South University, Changsha 410000, PR China.
⁵ School of Chemistry and Chemical Engineering, Building Materials Research Academy, Yancheng Institute of Technology, Jianjun East Rd. 211, Yancheng 224051, PR China. Electronic address: jwchen@ycit.edu.cn.
⁶ College of Chemistry and Environmental Engineering, Institute of Environmental Toxicology and Environmental Ecology, Yancheng Teachers University, Xiwang Avenue South Rd. 2, Yancheng 224007, PR China. Electronic address: wyqing76@126.com.

PMID: 33812239
DOI: 10.1016/j.saa.2021.119669

Abstract

Seven isatin-thiosemicarbazone analogues bearing different substituents (R) attached at C-5 of the indoline ring, TSC-ISA-R (R = -H, -CH₃, -OCH₃, -OCF₃, -F, -Cl and -NO₂), were synthesized and evaluated as inhibitors of mushroom tyrosinase (TYR). The inhibitory behaviour and performance of TSC-ISA-R were investigated spectroscopically in relation to the substituent modifications through examining their inhibition against the diphenolase activity of TYR using L-DOPA as a substrate. The IC₅₀ values of TSC-ISA-R were determined to be in the range of 81-209 μM. The kinetic analysis showed that TSC-ISA-R were reversible and mixed type inhibitors. Three potential non-covalent interactions rather than complexation including the binding of TSC-ISA-R with free TYR, TYR-L-DOPA complex, and with substrate L-DOPA were found to be involved in the inhibition. The substituent modifications affected these interactions by varying the characters of the resulting TSC-ISA-R in different degrees. The thiosemicarbazido moiety of each TSC-ISA-R contributed predominantly to the inhibition, and the isatin moiety seemed to play a regulatory role in the binding of TSC-ISA-R to the target molecules. The results of theoretical calculations using density functional theory method indicated a different effect of -R on the electron distribution in HOMO of TSC-ISA-R. The LUMO-HOMO energy gap of TSC-ISA-R almost accords with the trend of their experimental inhibition potency.

Keywords: Inhibition mechanism; Isatin thiosemicarbazone derivatives; Substituent effects; Tyrosinase inhibitors.

MeSH terms

Agaricales*
Enzyme Inhibitors / pharmacology
Isatin*
Kinetics
Monophenol Monooxygenase / metabolism
Thiosemicarbazones* / pharmacology

Substances

Enzyme Inhibitors
Thiosemicarbazones
Isatin
Monophenol Monooxygenase