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

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.

Effective Tyrosinase Inhibition by Thiamidol Results in Significant Improvement of Mild to Moderate Melasma

“…However, the clinical efficacy of current tyrosinase inhibitors is limited due to the fact that they were typically selected based on their ability to inhibit mushroom tyrosinase (Chang, 2009;Lee et al, 2016). In recent studies, Thiamidol was characterized as an especially potent inhibitor of human tyrosinase (Mann et al, 2018a(Mann et al, , 2018b. In vitro, Thiamidol was superior to frequently used inhibitors of hyperpigmentation such as arbutin, kojic acid, and hydroquinone.…”

“…Thus, it is evident that an effective and safe topical inhibitor of human skin hyperpigmentation is lacking. Recently, more than 50,000 compounds were screened for their ability to inhibit a recombinant human tyrosinase (Cordes et al, 2013) and Thiamidol (isobutylamido-thiazolyl-resorcinol) was identified as an especially potent inhibitor of human tyrosinase (Mann et al, 2018a(Mann et al, , 2018b. In vitro, Thiamidol was superior to frequently used inhibitors of hyperpigmentation, such as arbutin, kojic acid, and hydroquinone.…”

A comprehensive review on tyrosinase inhibitors

“…So far, several azole derivatives (Figure 13) have been studied for their tyrosinase inhibitory activity 388 . The discovered new types of inhibitors included DL-3(5-benzazolyl) alanines and alpha-methyldopa analogs 389 , aryl pyrazoles 390 , heterocyclic hybrids based on pyrazole and thiazolidinone scaffolds 391 , 3,5-diaryl-4,5-dihydro-1H 392 and 3,5-diaryl pyrazole derivatives 393 , pyrazolo[4,3-e][1,2,4]triazine sulfonamides and sildenafil 394–396 , 1,3-oxazine-tetrazole 397 , indole-spliced thiadiazole 398 , benzimidazole-1,2,3-triazole hybrids 399 , 1,2,3-triazole-linked coumarinopyrazole conjugates 400 , isoxazolone derivatives 401 5(4H)-oxazolone derivative 402 , imidazolium ionic liquids 403 , thiazolyl resorcinols 404 have demonstrated the inhibitory effect on tyrosinase. Furthermore, some thiazolidine derivatives have been evaluated for their tyrosinase inhibitory activity including azo-hydrazone tautomeric dyes substituted by thiazolidinone moiety 405 , (Z)-5-(2,4-dihydroxybenzylidene) thiazolidine-2,4-dione 406 , 5-(substituted benzylidene) thiazolidine-2,4-dione derivatives 407 , (2RS,4R)-2-(2,4-dihydroxyphenyl)thiazolidine-4-carboxylic acid 408 , 2-(substituted phenyl) thiazolidine-4-carboxylic acid derivatives 409 and (Z)-5-(3-hydroxy-4-methoxybenzylidene)-2-iminothiazolidin-4-one 410 .…”

Thiamidol containing treatment regimens in facial hyperpigmentation: An international multi‐centre approach consisting of a double‐blind, controlled, split‐face study and of an open‐label, real‐world study

“…So far, most tyrosinase inhibitors lack clinical efficacy [13] because they were identified by testing on mushroom and not on human tyrosinase [8,14,15]. The purification of soluble variants of human tyrosinase [16] allowed the identification of Thiamidol (isobutylamido thiazolyl resorcinol) as its most potent inhibitor [11,17,18] out of 50 000 screened compounds.…”