Halogenated aromatic thiosemicarbazones as potent inhibitors of tyrosinase and melanogenesis

Katarzyna Hałdys; Waldemar Goldeman; Michał Jewgiński; Ewa Wolińska; Natalia Anger-Góra; Joanna Rossowska; Rafał Latajka

doi:10.1016/j.bioorg.2019.103419

Halogenated aromatic thiosemicarbazones as potent inhibitors of tyrosinase and melanogenesis

Bioorg Chem. 2020 Jan:94:103419. doi: 10.1016/j.bioorg.2019.103419. Epub 2019 Nov 9.

Authors

Katarzyna Hałdys¹, Waldemar Goldeman², Michał Jewgiński³, Ewa Wolińska⁴, Natalia Anger-Góra⁵, Joanna Rossowska⁶, Rafał Latajka⁷

Affiliations

¹ Department of Bioorganic Chemistry, Wrocław University of Science and Technology, Wybrzeże Wyspiańskiego 27, 50-370 Wrocław, Poland. Electronic address: katarzyna.haldys@pwr.edu.pl.
² Department of Organic Chemistry, Wrocław University of Science and Technology, Wybrzeże Wyspiańskiego 27, 50-370 Wrocław, Poland. Electronic address: waldemar.goldeman@pwr.edu.pl.
³ Department of Bioorganic Chemistry, Wrocław University of Science and Technology, Wybrzeże Wyspiańskiego 27, 50-370 Wrocław, Poland. Electronic address: michal.jewginski@pwr.edu.pl.
⁴ Department of Bioorganic Chemistry, Wrocław University of Science and Technology, Wybrzeże Wyspiańskiego 27, 50-370 Wrocław, Poland. Electronic address: ewa.mrozinska@pwr.edu.pl.
⁵ Ludwik Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Science, Rudolfa Weigla 12, 53-114 Wrocław, Poland. Electronic address: natalia.anger@hirszfeld.pl.
⁶ Ludwik Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Science, Rudolfa Weigla 12, 53-114 Wrocław, Poland. Electronic address: joanna.rossowska@hirszfeld.pl.
⁷ Department of Bioorganic Chemistry, Wrocław University of Science and Technology, Wybrzeże Wyspiańskiego 27, 50-370 Wrocław, Poland. Electronic address: rafal.latajka@pwr.edu.pl.

PMID: 31761412
DOI: 10.1016/j.bioorg.2019.103419

Abstract

A set of 21 halogenated thiosemicarbazones (TSCs) have been synthesized and its inhibitory properties toward activity diphenolase of mushroom tyrosinase and their ability to inhibition of melanogenesis in B16F10 murine, melanoma cell line have been investigated. The molecular docking to the active site of the enzyme has been also performed to investigate the nature of enzyme-inhibitor interactions. The obtained outcomes allowed us to perform SAR analysis. TSC 6, 12 and 21 exhibited the most potent inhibitory properties showing IC₅₀ of 0.5, 0.9 and 0.8 µM, respectively. They revealed reversible and competitive manner of tyrosinase inhibition. According to SAR analysis, para-substituted acetophenone derivatives of thiosemicarbazones have the highest affinity to the enzyme among the investigated compounds. Melanin production in B16F10 cells was inhibited by all investigated compounds at the micromolar level. Suggested inhibition mechanism is based on the interaction between a sulfur atom of thiourea moiety of the thiosemicarbazones, and copper ions in the active site of the enzyme. These results might be useful in searching novel inhibitors of melanogenesis which could be used in the cosmetic and food industry.

Keywords: Kinetic studies; Melanogenesis; Molecular docking; Structure-activity relationships; Thiosemicarbazones; Tyrosinase.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Enzyme Inhibitors / pharmacology
Enzyme Inhibitors / therapeutic use*
Humans
Melanins / antagonists & inhibitors*
Melanins / biosynthesis
Molecular Docking Simulation / methods*
Molecular Structure
Monophenol Monooxygenase / drug effects*
Structure-Activity Relationship
Thiosemicarbazones / pharmacology
Thiosemicarbazones / therapeutic use*

Substances

Enzyme Inhibitors
Melanins
Thiosemicarbazones
Monophenol Monooxygenase