Thiourea derivatives

According to relevant studies,cistanche is a common herb that is known as "the miracle herb that prolongs life". Its main component is cistanoside, which has various effects such as antioxidant, anti-inflammatory, and immune function promotion. The mechanism between cistanche and skin whitening lies in the antioxidant effect of cistanche glycosides. Melanin in human skin is produced by the oxidation of tyrosine catalyzed by tyrosinase, and the oxidation reaction requires the participation of oxygen, so the oxygen-free radicals in the body become an important factor affecting melanin production. Cistanche contains cistanoside, which is an antioxidant and can reduce the generation of free radicals in the body, thus inhibiting melanin production.

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Phenylthiourea (PTU) is one of the most well-known tyrosinase inhibitors studied in the literature89–91. The sulfur atom of PTU binds to both copper ions at the active site of tyrosinase and blocks the enzyme activity. Professor Jung et al. recently explored the SAR of PTU derivatives on mushroom tyrosinase92,93. Although the effects of PTU derivatives were primarily evaluated for their melanogenesis inhibition in B16 melanoma cells, later it was confirmed that it was due to inhibition of tyrosinase activity. The SAR studies have highlighted the important structural requirements for both melanogenesis and tyrosinase inhibition (Figure 9(a)): (i) direct connection of p-planar structure to thiourea (24a–24b), (ii) hydrophobic substituent at the para- or meta-position of the phenyl ring was accepted (24c–24d), substituent at the ortho-position was not tolerated (24e), suggested that C2-substituted phenyl may hinder the complex formation of thiourea with copper ions at the active site of tyrosinase. Moreover, (iii) free 3-amino hydrogens were important for tyrosinase inhibition but not for the melanogenesis inhibition on B16 cells, 1,3-disubstituted derivatives showed greater potency in melanogenesis inhibition (24f). These findings suggested that 1,3-disubstituted derivatives act through a pathway different from the tyrosinase catalytic activity to prevent melanogenesis. Molecular docking analysis of 1-phenylthiourea and 1,3,-diphenyl thiourea revealed that the direct connection of planar phenyl to thiourea unit and free 3-NH2 was a prerequisite for the tyrosinase activity (Figure 10).

On the other hand, Crinton et al reported a series of N-hydroxy-N0 -phenyl urea derivatives, replacing sulfur with oxygen and 3-NH2 with N-hydroxylamine in PTU91. The results showed the reported derivatives were more potent, in particular, N-hydroxy-N0 -phenyl urea (25a) showed 6 times more potent than PTU. In contrast, N-hydroxy-N0 -phenylthiourea (25b) derivatives showed no inhibition, suggesting that the chelating ability of N-hydroxyurea is important for the tyrosinase inhibition (Figure 9(a)).

Apart from synthetic or natural sources, screening is another alternative strategy to find new inhibitors. Mainly screening of drugs that are clinically approved has become increasing for many biological targets. The data associated with an existing drug will reduce the time and cost associated with the intellectual rights for developing novel pharmaceutics. This approach has several advantages; including availability, lower cost, and safety/tolerability. Phenylthiourea has long been known as a tyrosinase inhibitor89–91,94. The chemical similarity analysis performed by ligand-based virtual or HTS screening identified ethionamide (26a) and its analogs (26c–26e), including prothionamide (26b), as tyrosinase inhibitors95 (Figure 9(a)). Ethionamide is an approved second-line antituberculosis drug used for the treatment of multi-drug-resistant tuberculosis. In contrast, isoniazid, a structural analog, and the first-line antituberculosis drug was a poor inhibitor of tyrosinase. In B16 cells, inhibitors pyridine-2-carbothioamide and thiobenzamide substantially reduced the melanin content by 44% and 37%, respectively. After an extensive structural analysis, the SAR data suggest that carbothioamide was a central moiety for the development of new and potent tyrosinase inhibitors.

In a recent study, the researchers retrieved the thiourea-derived drugs in clinical use and investigated their effect on tyrosinase activities by using enzyme- and cell-based assays96. It was observed that the antithyroid agents methimazole 27a, 97 carbimazole 27b, 97 thiouracils 27c, 97 methylthiouracil 27d97, and propylthiouracil 27e97 inhibited mushroom tyrosinase (Figure 9(b)). In addition, kinetic studies assigned thiourea-containing drugs as non-competitive inhibitors. The SAR studies explained that thiourea itself inhibits tyrosinase enzyme activity in a concentration-dependent manner. This shows the inhibitory activity of thiourea analogs must be originated from the sulfur and the nitrogen atoms.

In another study, a class of novel N-aryl-N0 -substituted phenylthiourea derivatives was evaluated on the diphenolase activity of mushroom tyrosinase98. The results showed few 4,5,6,7-tetrahydro- 2-[[(phenylamino)thioxomethyl]amino]-benzo[b]thiophene-3-carboxylic acid derivatives (28a–28d, (Figure 9(b))) exhibited moderate inhibitory potency on diphenolase activity of tyrosinase. When the scaffold of 4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylic acid was replaced with 2–(1,3,4-thiadiazol-2-yl)thio acetic acid, the inhibitory activity of compounds (e.g. 29a–29d, Figure 9(b)) 98 against tyrosinase was improved. Especially, 29d (IC50=6.13 lM) exhibited more potent inhibitory activity than kojic acid (IC50=33.3 lM).

Since 1885, saccharin, 1,2-benzisothiazole-3-one-1,1-dioxide is a well-known heterocyclic compound and used as a sweetener in the form of its sodium salt. Besides, it is reported for many biological targets and thus can be viewed as a privileged scaffold. Recently, a novel series of 6-(phenylurenyl/thionyl) conjugated saccharin derivatives were evaluated for inhibitory effects on the diphenolase activity of banana tyrosinase enzyme99. The results showed that all the compounds inhibited the tyrosinase activity. Among them, 6–(3-chlorophenylurenyl) saccharin 30a (Ki= 5.85 lM) and 6–(3-iodophenylthiourenyl) saccharin 30b (Ki=3.95 lM) was found to be the most active compounds. The SAR studies showed 6-(phenylthiourenyl) saccharin derivatives exhibited higher inhibitory activity than 6-(phenylurenyl) saccharin derivatives. An electron-withdrawing group at the 3-position of phenylurenyl/thiourenyl-ring increased in activity, in particular, the halogen series showed higher inhibitory activities.

Thiosemicarbazone-type inhibitors

Thiosemicarbazones occupy one of the major classes of tyrosinase inhibitors due to their classical structural unit and the ability to chelate copper ions at the active site of the tyrosinase enzyme. Recently, a huge number of thiosemicarbazones by different research groups have been reported99–101 as potent tyrosinase inhibitors.

The SAR studies revealed that the thiosemicarbazide scaffold was a key unit for determining the tyrosinase inhibitory activity because it was able to effectively complex the two copper ions at the active site of tyrosinase. To improve the activity, a series of 4/3-aminoacetophenones and derived thiosemicarbazones were reported for their inhibitory activity of mushroom tyrosinase102. Results from the biological evaluation, the acylamino compounds (31a–31g, Figure 11) exhibited more potent tyrosinase inhibitors than kojic acid (IC50=28.5 lM), and in contrast, the aminophenol (31 h and 31i) showed activation of tyrosinase activity. Compound 31d was found to be the most active compound with an IC50 value of 0.291 lM. The studies with SAR analysis also revealed that the thiosemicarbazide group played a very vital role in tyrosinase inhibition, acylamino moieties crucial for enhancing the tyrosinase inhibitory activity and the acylamide substituent at 4-position on the phenyl ring increased the tyrosinase inhibitory potency. Moreover, the inhibition mechanism and kinetics study revealed that compound 31a was reversible and a noncompetitive inhibitor.

In continuing to search for potent compounds as highly efficient tyrosinase inhibitors, and understanding the SARs of thiosemicarbazone compounds, a series of novel 4-alkoxy- and 4-acyloxy-phenyl ethylene thiosemicarbazone analogs (32a–32i, Figure 11) were synthesized and evaluated for tyrosinase inhibitory activity103. The results showed that most of the inhibitors displayed remarkable potency in inhibiting tyrosinase with an IC50 value lower than 1.0 lM. In particular, compound 32d exhibited a remarkable tyrosinase inhibitory potency compared to other analogs from this series. The SAR studies revealed that the thiosemicarbazone moiety played a key role in determining the tyrosinase inhibitory activity. The length of the methylene linker between the phenyl ring and the thiosemicarbazone moiety (32f–g) did not influence the tyrosinase inhibitory potency. The introduction of thiocarbonohydrazide moiety (32 h–32i) was unfavorable for the tyrosinase inhibitory activity.

Peptide type inhibitors

To discover new tyrosinase inhibitors, recent attention has been drawn to applying peptide sequences for tyrosinase inhibition. Several tyrosinase inhibitory peptides such as dipeptides104, cyclic peptides105, short-sequence oligopeptides106, and kojic acid tripeptide compounds107, have been investigated. Especially, oligopeptides have proven to be effective tyrosinase inhibitors. Two oligopeptides P3, an octapeptide (Arg-Ala-Asp-ser-Arg-Ala-Asp-Cys), and a decapeptide P4 (Tyr-Arg-ser-Arg-Lys-Tyr-Ser-Ser-Trp-Tyr) showed substantial inhibitory effects on mushroom and human tyrosinase with IC50 value of 123 and 40 lM, compared with hydroquinone. These oligopeptides did not show any effect on melanocyte cytotoxicity108. After successful formulation into topical cream and favorable clinical results, a decapeptide P4 also known as decapeptide-12 has been commercialized as the main active ingredient in a skin-lightening product109.

In a recent study, Hsiao et al. discovered that dipeptide-like compound (A5) and tripeptides RCY and CRY effectively inhibit the tyrosinase activity109. Especially, a novel tripeptide CRY showed the most striking inhibitory potency against mushroom tyrosinase (IC50=6.16 lM). This tripeptide is more potent than the known oligopeptides and comparable with kojic acid-tripeptides. CRY and RCY used the thiol group of the cysteine residue to coordinate with Cu ions at the active site of tyrosinase, thereby showing low tyrosinase activity. In another study, the cysteine-containing dipeptides were reported to inhibit the tyrosinase activity in an effective manner110. The authors suggested that these cysteine-containing dipeptides could directly block the active site of tyrosinase and thereby leading to potent inhibition. In particular, N-terminal cysteine-containing dipeptides markedly outperform the C-terminal and the cysteine-containing dipeptides, CE, CS, CY, and CW show comparative bioactivities and tyrosine-containing dipeptides are substrate-like inhibitors. In addition, these dipeptides do not show significant cytotoxicity in melanocytes, and CA and PD attenuated 5.6 and 16.5% melanin content, respectively, at 100 lM (Table 1).

Li et al. reported a set of hydroxypyridinone-L-phenylalanine conjugates (33a and 33b) starting from kojic acid (Figure 12) 111 for their inhibitory activities on tyrosinase. Evaluation against tyrosinase activity revealed that one of the compounds ((S)-(5-(benzyloxy)-1-octyl-4-oxo-1,4- dihydropyridine-2-yl)methyl 2-amino-3- phenylpropionate, (33b) showed IC50 values 12.6 and 4.0 lM for mycophenolate and diphenolase activities, respectively. Moreover, these conjugates were mixed-type inhibitors, suggesting they could bind to both the free enzyme and the enzyme-substrate complexes.

In another study, hydroxypyridinone-L-amino acid conjugates were designed and evaluated for their inhibitory activities on mushroom tyrosinase112. Among the investigated compounds, only two compounds exhibited both mycophenolate (34, IC50=1.95 lM; 35, IC50=2.79 lM) and diphenolase inhibitory (34, IC50=8.97 lM; 35, IC50=26.20 lM) activity of tyrosinase (Figure 12). Moreover, compounds 34 and 35 were identified to be reversible and mixed-type inhibitors.

Miscellaneous mushroom tyrosinase inhibitors

Recently, the extracts and isolated compounds from natural sources have attracted much attention as tyrosinase inhibitors and have been accepted as popular skin whitening agents113–123. To find a safe and effective whitening substance, Chen et al., screened several natural products from herbal plants and isolated compounds 36 and 37 from the rhizome of Gastrodia elata, as mushroom tyrosinase inhibitors124. Subsequent SAR studies have identified analogs 38–40 (Figure 13). Bis(4-hydroxy benzyl) sulfide 36 showed outstanding inhibitory potency against tyrosinase with an IC50 value of 0.5 lM and Ki value of 58 nM. The compound 37 connected through an ether linkage shows a 713-fold decrease in the inhibitory ability (IC50=378.11 lM) indicating the sulfur atom is very important in chelating with the copper ions and contributes to a greater inhibition tyrosinase activity. On the other hand, shortening the carbon linker, which connects the sulfur to benzene rings, results in moderate tyrosinase inhibition of 38. The removal of hydroxyl group, 39 leads to poor tyrosinase inhibition, indicating that two hydroxyl groups are important. With the methoxy substitution, an analog of 36, reduces potency to an IC50 value of 40.02 lM, suggesting that hydrogen bond interactions were more favorable than the hydrophobic interactions provided by methoxide groups.

Compound 36 treated with 50 lM reduced 20% melanin content in the human melanocytes system without significant cytotoxicity. In addition, the zebrafish in vivo assay reveals that 36 effectively reduces melanogenesis with no adverse effect. Moreover, the acute oral toxicity study confirmed that compound 36 was free of discernable cytotoxicity in mice. Thus compound 36 is a potential candidate for developing a safe and effective pharmacological agent for skin whitening. Recently, Ai et al., screened a chemical library using a virtual screening approach and identified a compound 41 as a potent mushroom tyrosinase inhibitor125, with an IC50 value of 8 lM and yielded a 29%±17.64% blockage of melanin biosynthesis in B16 cells at a concentration of 0.002% that was equal to 27.5 lathes.

The SAR studies examined around structure 41 showed the aromaticity of the ring B of compound 41 appears essential for activity, as the replacement of ring B with cyclohexyl ring (compound 42b) losses the inhibitory activity of melanin synthesis in B16 cells. On the other hand, the substitution at the 4-position of ring A had a negligible effect on the inhibitory activity (42a–42d). These compounds were dose-dependent and inhibited melanin synthesis in B16 cells. However, further development of compound 41, leads to a potential formulation problem and is eliminated as a candidate for cosmetic purposes. A further substructural analysis identified a compound 43 exhibited 79%±5.34% inhibition on melanin biosynthesis of B16 cells at a concentration of 0.001% (33.6 lM). These two compounds 41 and 43 possess good biochemical properties and satisfy Lipinski’s “rule of five” and exhibited a substantial inhibitory effect on melanin synthesis in B16 cells. This melanin synthesis inhibition was shown not to affect cellular viability, which further underscores the potential commercial utility of these compounds.

It was reported that vanillin and vanillic acid isolated from Origanum vulgare may serve as agents for antimelanogenesis126. Based on this background, a series of vanillin esters incorporating benzoic acid, cinnamic acid, and piperazine have been reported for tyrosinase inhibitory activity127. The results showed that compounds 44a–44d exhibited good to excellent inhibition of mushroom tyrosinase activity (Figure 14). In particular, 44b exhibited the most potent inhibitory activity with an IC50 value of 16.13 lM. From the structural point of view, the substituted cinnamic acid esters and hydroxyl substitution played an important role in tyrosinase inhibition. The kinetic studies revealed compound 44b was a mixed-type tyrosinase inhibitor with Ki 13 lM and Ki 0 53 lM and formed a reversible enzyme-inhibitor complex.

In another study, 2-hydroxytyrosol 45 (2-HT)128 was found to inhibit mushroom tyrosinase with an IC50 value of 13.0 lmol/L which was equally potent as kojic acid (IC50=14.8 lmol/L). Furthermore, 2-HT dose-dependently inhibited tyrosinase activity (IC50=32.5 lmol/L) in the cell-free extract of B16 melanoma cells and a-MSH-stimulated melanin formation in intact B16 melanoma cells. Methimazole (2-mercapto-1-methylimidazole) derivatives were reported to inhibit mushroom tyrosinase129. 2-Mercaptoimidazole (46a), mercapto-1-methylimidazole (46b), and tert-butyl 3-methyl-2-sulfanylidene-2,3-dihydro-1H-imidazole- 1-carboxylate (46c) significantly inhibited tyrosinase activity exhibiting an IC50 value of 4.11 mM, and 1.43 mM and 1.45 mM, respectively, (Figure 14). Kinetic analysis indicated that compounds 46a and 46b as competitive tyrosinase inhibitors, while 46c was a non-competitive tyrosinase inhibitor. Further, in vitro analysis on B16 cells, compounds of 46a–46c exerted a potent inhibitory effect on intracellular melanin production without influencing the cytotoxicity.

A series of triazole Schiff’s base derivatives have been demonstrated for their inhibitory activity against mushroom tyrosinase activity130. The results showed from the biological evaluation that only three compounds 47a–47c exhibit potent inhibitory effects with IC50 values of 12.5, 7.0, and 1.5 lM (Figure 14). Kinetic analysis revealed that inhibitors are reversible and mixed type. Fluorescence quenching and copper interaction studies confirmed the interaction of inhibitors with tyrosinase and chelation ability with copper ions in the active site. From a structural point of view, the substitution at the 2-position of the benzene ring showed superior activity (47c) than the 3-position (47b). A novel series of thymol analogs incorporating hydroxylated benzoic acids and cinnamic acids were reported as mushroom tyrosinase inhibitors131. In general, the cinnamic acid-derived thymol derivatives showed better tyrosinase inhibition than the benzoic acid derivatives, exemplified by the comparison of 48a (IC50 15.20 lM) versus 48b (IC50 91.5 lM).

Recently, the effect of picrionoside A 49 isolated from the leaves of Korean ginseng (P. ginseng C.A. Mayer) was examined132 and it has inhibited mushroom tyrosinase activity with an IC50 value of 9.8 lM, about 6.8 to 10-fold higher than kojic acid and arbutin, respectively (Figure 14). In melan-Ab cells, 49 reduced 17.1% melanin content in a dose-dependent manner without inducing cell viability. In addition, Picrionoside A-treated zebrafish showed a remarkable inhibitory effect on the body’s pigmentation. Taken together these results show that Picrionoside A may be an effective skin-whitening agent133. In the course of screening, melanogenesis inhibitors in Streptomyces bikiniensis, it was found that S-(-)-10,11-dihydroxyfarnesoic acid methyl ester (dhFAME, 50), an insect juvenile hormone produced by Beauveria bassiana CS1029 134 directly inhibited the tyrosinase activity. In addition, 50 significantly reduce the melanin content, inhibited the cellular tyrosinase activity as well as the intracellular accumulation of cAMP levels in melan-a cells without inducing the cell viability.

A new class of potent tyrosinase inhibitors was identified by structure-based virtual screening prediction135. The structure of mushroom tyrosinase (PDB ID: 2Y9X) was used as a template for molecular dynamics (MD) simulation. Initially, an ensemble of 10 000 structures using molecular dynamics simulation was generated. Consequent screenings yielded the top 61 molecules for evaluation against mushroom tyrosinase activity and the selective inhibitors (51a–51e) are indicated in Figure 14. The results show that the moieties of tetrazole and triazole were able to interact with the di-copper catalytic center of the tyrosinase. In particular, tetrazole compound 51b exhibits the strongest activity. The authors found that many compounds displayed a good reduction in melanin production in B16 melanoma cells with no cytotoxicity. Specifically, a thiosemicarbazone-containing compound 51e reduced melanin content by 55%. The results provide valuable insight into the modulation of the functions of type-3 copper enzymes.

Captopril ([2S]-N-[3-mercapto-2-methylpropionyl]-L-proline) is an angiotensin-converting enzyme inhibitor136,137 which is widely used in the treatment of hypertension and heart failure. To identify novel and effective tyrosinase inhibitors, the inhibitory effect of captopril (52) was experimented with for tyrosinase inhibitory activity. The result showed that 52 inhibited tyrosinase activity with an IC50 value of 590 lg/mL (Figure 14) 138. Further, in vitro studies in B16 cells, 52 was found to inhibit the tyrosinase activity139,140 in a dose-dependent manner that leads to the inhibition of melanin formation without cytotoxicity.

Human tyrosinase inhibitors

Although a huge number of tyrosinase inhibitors were available and several of them with potent inhibitory activities were discussed earlier, almost all the inhibitors were evaluated against mushroom tyrosinase. To find novel inhibitors against human tyrosinase, Yoshimori et al demonstrated thujaplicins (52–54; a, b, and c isomers, Figure 15) for their inhibitory effects on both mushroom tyrosinase and human tyrosinase (Tyr), with comparison141. The results showed that brand c-thujaplicins (53 and 54) effectively inhibited the human tyrosinase activity in a dose-dependent manner with IC50 values of 8.98 and 1.15 lM, respectively. Especially, c-thujaplicin 54 was extremely superior to kojic acid (IC50=17 lM). The SAR studies revealed the position of isopropyl on the tropolone scaffold was the determinant factor for the potency of thujaplicines. The potency of thujaplicins is in the following order: c > b > a-thujaplicin.

To understand the inhibitory mechanism, the binding mode of c-thujaplicin was predicted using a homology model of hTYR. It showed the carbonyl and hydroxyl group of the c-thujaplicin chelate with two copper ions at the active site of hTYR. Tropolone scaffolds of thujaplicin form stacking interaction with the imidazole ring of His367 and hydrophobic interaction with isopropyl of Val377. The isopropyl group of thujaplicin forms hydrophobic interaction with Ile368. In addition, the results from comparative studies on the inhibitory effects of the other thujaplicins (a and b) indicated that van der Waals (VdW) clashes of the isopropyl group of a-thujaplicin with Val377 and S380 might reduce the inhibitory activity against hTYR. The main reason for the higher inhibitory activity of c–thujaplicin against hTYR among thujaplicins is considered to be the hydrophobic interaction of the isopropyl group with Ile368. In contrast, in many, the Val377, and Ser380 are replaced with proline (P257) and alanine (A260), respectively, therefore it can be considered that there are little VdW clashes of the isopropyl group of a-thujaplicin with A260 and P257 (Figure 16). This explains why the inhibitory effect of a-thujaplicin against mTYR (IC50=9.53 lM) is more than two orders of magnitude stronger than hTYR (IC50>1000 lM). Accordingly, it was suggested that the difference between Ala260 in mTYR and Ser380 in hTYR dramatically affects the inhibitory profile of a-thujaplicin.

Wang and coworkers have recently found the natural products linderanolide B (55) and suboxide A (56) isolated from the stems of Cinnamomum were proved to have good in vitro inhibitory abilities of mushroom tyrosinase at low doses (Figure 15) 142. Both compounds showed cell viability of human keratinocytes, melanocytes, and fibroblasts treated with various concentrations of two compounds. Treatment at a low dose (0.01–1.0 lM) did not show significant cytotoxicity to human skin cells. The study revealed both compounds could reduce 50% of human tyrosinase activities at a dose of 1 lM after 48-h treatment and effectively inhibited (40% reduction) the melanin formation in HEMn-MP cells. Both 55 and 56 showed a remarkable inhibitory potential on zebrafish in vivo pigmentation even at low doses without observable toxicity. Therefore these two compounds are effective novel tyrosinase inhibitors to be considered as skin-whitening agents. In another study, Kolbe et al. examined the inhibitory effects of kojic acid, hydroquinone, and arbutin with the other well-known class of compound 4-butyl resorcinol (57) on human tyrosinase as well as inhibition of the production of MelanoDermTM skin model culture143. In 1995, 4-butyl resorcinol introduced a resorcinol derivative that has an inhibitory effect on both tyrosinase144 and TRP-1145,146. The results showed that 4-butyl resorcinol proved to be a highly effective inhibitor of human tyrosinase with an IC50 value of 21 lmol/L and complete inhibition at concentrations above 100 lmol/L. 4-Butyl resorcinol exhibited 20 times more potent inhibitory activity than kojic acid, which showed an IC50 of 500 lmol/L, and maximum inhibition (89%) was achieved at 5.6 mmol/L concentration. Arbutin and hydroquinone are poor inhibitors of human tyrosinase with IC50 values in the millimolar range, that is, 6500 lmol/L for arbutin and 4400 lmol/L for hydroquinone. However, none of both have completely inhibited human tyrosinase.

In the melanoDerm skin model, arbutin showed only marginal efficacy on melanin production with an IC50 value of 500 lmol/L, while kojic acid inhibited with an IC50 of 400 mol/L. Interestingly, hydroquinone inhibited melanin production with an IC50 value below 40 lmol/L, which is probably due to different mechanisms of tyrosinase inhibition. 4-Butyl resorcinol was the most potent inhibitor with an IC50 of 13.5 mol/L. The in vivo efficacy of 4-butyl resorcinol was confirmed in clinical studies. Patients with age spots on the forearm were treated twice daily two age spots with a formula containing 4-n-butyl resorcinol (57), 4-hexylresorcinol (58), and 4-phenylethylresorcinol (59). Within 8 weeks, 4-butyl resorcinol (57) significantly reduced the appearance of age spots while 4-hexylresorcinol and 4-phenylethylresorcinol showed significant effects after 12 weeks. A second study showed that 4-butylresorcinol was more effective than 4-hexylresorcinol and 4-phenylmethylsorcinol. The resulting clinical output on hyperpigmentation reveals that 4-butyl resorcinol could be a valuable active compound for the management of pigmentation disorders. 4-butyl resorcinol has been used for the treatment of melasma. In all published literature, 4-butyl resorcinol 0.1% cream showed rapid efficacy, safety, and tolerability when it is used for the melasma treatment147,148. A recent study reported that 4-butyl resorcinol 0.3% cream is safe, effective, and well tolerated in Indian patients with melisma149.

For more info: david.deng@wecistanche.com  WhatApp:86 13632399501