Structure-Activity Relationships of Thiazolyl Resorcinols, Potent and Selective Inhibitors of Human Tyrosinase

International Journal of Molecular Sciences
Tobias MannLudger Kolbe

Abstract

Tyrosinase inhibitors are of great clinical interest as agents for the treatment of hyperpigmentary disorders; however, most compounds described in the literature lack clinical efficiency due to insufficient inhibitory activity against human tyrosinase (hTyr). Recently, we reported that thiazolyl resorcinols (4-resorcinylthiazol-2-amines and -amides) are both selective and efficacious inhibitors of hTyr in vitro and in vivo. Here, we measured dose-activity profiles of a large number of thiazolyl resorcinols and analogous compounds to better understand the molecular basis of their interaction with hTyr. We show that both the resorcinyl moiety and the thiazole ring must be intact to allow efficient inhibition of hTyr, while the substituents at the thiazole 2-amino group confer additional inhibitory activity, depending on their size and polarity. The results of molecular docking simulations were in excellent agreement with the experimental data, affording a rationale for the structural importance of either ring. We further propose that a special type of interaction between the thiazole sulfur and a conserved asparagine residue is partially responsible for the superior inhibitory activity of thiazolyl resorcinols against hTyr.

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Citations

May 8, 2020·Natural Product Research·Akhtar AtiyaUma Ranjan Lal
Feb 9, 2019·Journal of Enzyme Inhibition and Medicinal Chemistry·Samaneh ZolghadriAli Akbar Saboury
Dec 19, 2018·International Journal of Molecular Sciences·Alessandra Napolitano, Shosuke Ito
Jul 26, 2018·International Journal of Molecular Sciences·Raffaella MicilloConchi Olivares
Aug 7, 2020·Journal of Cosmetic Dermatology·Vasanop VachiramonKumutnart Chanprapaph
Aug 9, 2021·European Journal of Medicinal Chemistry·Jin LiGuan Wang
Aug 14, 2020·Journal of Medicinal Chemistry·Brayan RoulierRomain Haudecoeur

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Methods Mentioned

BETA
X-ray
acylation
glycosylation
Assay

Software Mentioned

Molegro Virtual Docker ( MVD
Tasser suite
SigmaPlot
Scifinder
Molegro Virtual Docker ( MVD )
MVD
Tasser
Phyre2
Moldock
LigPlot

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