A decade of research on cinnamic acid and its derivatives as potential anti-tyrosinase agents: A comprehensive review (2015–2025)

1. INTRODUCTION

Human skin, hair, and eye pigmentation are primarily determined by melanin, a key biopolymer produced in specialized organelles called melanosomes within melanocytes. Besides its role as a color determinant, melanin also plays an important role in protective functions, particularly in preventing DNA damage triggered by ultraviolet (UV) radiation [1]. Melanogenesis is affected when we are exposed to UV as one mechanism of body defense. Hyperpigmentation, unfortunately, can occur if there is overproduction of melanin. Generally, the biosynthesis of melanin is controlled by tyrosinase, which catalyzes the hydroxylation of L-tyrosine to L-DOPA. L-DOPA will subsequently be converted into dopaquinone through oxidation, which then forms dopachrome, and melanin eventually [2].

Tyrosinase is a copper-containing enzyme found widely distributed in plants, animals, fungi, and bacteria [3]. The role of tyrosinase is crucial in the biosynthesis of melanin, and its activity should be controlled to prevent excessive melanin accumulation. A variety of tyrosinase inhibitors – both natural and synthetic – have been identified, including hydroquinone, kojic acid, ascorbic acid, azelaic acid, and arbutin [4–6]. The clinical applications, however, are still limited due to their instability and the associated safety issues, including dermatitis, skin malignancies, cytotoxicity, and neurological complications [5,7,8]. To overcome these problems, there is a need for novel tyrosinase inhibitors with high efficacy and minimal health risks.

Based on this, cinnamic acid (3-phenylprop-2-enoic acid), a phenylpropanoid derivative mainly found in Cinnamomum cassia, has garnered considerable attention due to its promising noncytotoxic properties in human cells [9]. Studies indicate that cinnamic acid has a moderate tyrosinase inhibitory capacity, with IC₅₀ values ranging from 2014 to 1,000 µM (Table 1). Several modifications in the chemical scaffold of cinnamic acid to improve potency have been reported, such as substitutions on the phenyl ring (e.g., with hydroxyl, methoxy, chloro, and nitro groups), modifications of the carboxyl group via esterification and amide formation, and dimerization of cinnamic acid units with variations in cinnamoyl substitution and diamide linker length [10–13]. Unfortunately, the outcomes of these structural modifications have been inconsistent; some cases have shown improvement in activities, while others have shown small to no improvement. To date, the understanding of structure-activity relationships (SARs) remains insufficient, and further studies are needed to identify safe cinnamic acid derivatives with effective tyrosinase inhibitory activities.

Table 1. Anti-tyrosinase study of cinnamic acid as a single compound.

Various review articles have been published to study the role and inhibitory mechanism of tyrosinase, such as a recent study that focuses on ferulic acid and its analogues to examine the SAR of cinnamic acid derivatives [14] and another review that reported the activity of cinnamic acid derivatives inhibition was restricted to 4-hydroxycinnamate and 4-methoxycinnamate [13]. Based on these studies, the present review aims to provide a broader comparison, emphasizing structural modifications that improved inhibitory activities, outline the types of inhibition mechanisms, and analyze the SAR of cinnamic acid comprehensively to support the rational design of safer and more effective tyrosinase inhibitors.

2. METHODS

The review articles collection in this study was conducted by searching for suitable references in international journals through Google Scholar, PubMed, and Scopus databases published within the last 10 years (2015–2025) (Fig. 1). Boolean Operators performed the search by using the following keywords: (“cinnamic acid derivatives” OR “Cinnamic acid” OR “Phenylpropanoic acid”) AND (“tyrosinase inhibition” OR “tyrosinase inhibitor”) AND (activity OR “melanin inhibition” OR “anti-melanogenesis” OR “skin whitening”). Inclusion criteria for the articles: full text or the articles must be completely accessible, published in English, published in the last 10 years, and explaining cinnamic acid or its derivatives, accompanied by in vitro experiments on tyrosinase inhibition activity. Exclusion criteria for the articles: Articles reported in languages other than English, unrelated research, duplicate articles, and nonfull-text articles. The collected articles were then analyzed, and an extensive comparison was conducted among the articles.

Figure 1. Reference sources used in the review (2015–2025). [Click here to view]

3. RESULTS AND DISCUSSION

3.1 Tyrosinase and melanin synthesis pathway

Melanin is a natural dark pigment providing the color to human skin, hair, and eyes, and has the function of a bodily defence against UV radiation, thereby contributing to skin and ocular health. Nonetheless, overproduction of melanin may cause hyperpigmentation, including melasma, lentigo, and neoplastic melanocyte, as well as cosmetic problems [1,5]. Melanin biosynthesis is mainly regulated by tyrosinase. This particular enzyme also plays a crucial role in the food processing industry, as it causes enzymatic browning of fruits and vegetables, which ultimately deteriorates the quality and economic value of the products [10,15].

Melanogenesis is an intricate process where three main enzymes are involved: tyrosinase, TYRP1, and TYRP2, and tyrosinase is responsible for controlling the speed of the whole process of melanin production (the rate-limiting enzyme). As shown in Figure 3, tyrosinase catalyzes the conversion of L-tyrosine to L-DOPA (monophenolase activity). L-DOPA will subsequently be oxidized to dopachrome (diphenolase activity). Further reactions of dopachrome will ultimately generate melanin [2,16]. There are two main pathways in melanin biosynthesis: the pheomelanin pathway, where dopachrome reacts with thiol-containing molecules such as glutathione or L-cysteine through Michael-type addition (producing red-yellow pigment), and the eumelanin pathway, where dopachrome is converted into eumelanin in the absence of thiols (producing brown-black pigment). Both pheomelanin and eumelanin contribute to the human skin color, and the intensity of the color is determined by the relative proportions of the two [17,18].

Figure 2. Structure of cinnamic acid. [Click here to view]

Figure 3. The mechanism of tyrosinase inhibition by cinnamic acid derivatives. [Click here to view]

Melanin biosynthesis can be inhibited through three main strategies: reducing tyrosinase activity, downregulating microphthalmia-associated transcription factor, or absorbing UV radiation. Among these, suppression of tyrosinase enzymatic function represents the most widely employed approach in pigmentation-related studies. Tyrosinase inhibitors act through four principal mechanisms of enzyme inhibition: competitive, noncompetitive, mixed type, and uncompetitive [9,19].

3.1.1. Competitive type

Competitive inhibition occurs when the structure of the inhibitor resembles the natural substrate of tyrosinase, such as L-tyrosine or L-DOPA, allowing the inhibitor and the natural substrate to compete for binding at the active site of tyrosinase. The examples of cinnamic acid derivatives with this type of inhibition are listed in Table 2. As an example of competitive inhibitors, caftaric acid (compound 8) found in grape as hydroxycinnamic acid derivative which contains hydroxyl groups at positions 3 and 4 (Fig. 4), 6’-O-caffeoylarbutin (compound 9), isolated from Quezui tea, paeonol with a 1,3-dioxypropyl linker (compound 11), cinnamic amide derivatives (compounds 41-42), and hydroxy-substituted 2-[(4-acetylphenyl)amino]-2-oxoethyl derivatives (compound 44), all show competitive inhibitions. In addition, several cinnamate analogues—including substituted vanillyl derivatives (compound 15), dimeric compounds (23–25), and hydroxycinnamic acid derivatives from Lepechinia meyenii (compound 31)—exert similar effect. Their structural similarity to tyrosinase substrates is the key factor enabling competitive binding.

Figure 4. Structure of the compounds 1-16. [Click here to view]

Table 2. Inhibition study of tyrosinase from cinnamic acid derivatives.

Compounds	Assay type (Substrate Used)	Compound No.	Inhibitory activity	Mechanism	Key finding	Reference
Cinnamic acid-eugenol ester	In vitro (L-DOPA)	1	IC50: 3.07 ± 0.28 µM	Mixed type, reversible	Modification patterns on the aromatic ring substituents and the hybrid of cinnamic acid and eugenol enhance the tyrosinase inhibitory activity.	[22]
		2	IC50: 5.95 ± 1.46 µM	-
		3	IC50: 16.28 ± 1.52 µM	-
Ester of cinnamic acid with paeonol or thymol	In vitro (L-DOPA)	4	IC50: 2.0 µM	Noncompetitive, reversible	Modification of phenyl ring substituents and hybrids of cinnamic acid and paeonol or the tyrosinase inhibitory potential of thymol was observed to exceed that of kojic acid and its parent compound.	[10]
		5	IC50: 8.3 µM	Mixed type, reversible
		6	IC50: 10.6 µM	Mixed type, reversible
Cinnamic acid-4-hydroxyphenyl	In vitro (L-DOPA)	7	IC50: 5.7 ± 0.3 µM	Noncompetitive, reversible	The substitution of groups and the difference in the position of substituents on the phenyl ring affect the increase and decrease of inhibition activity.	[54]
Polyphenol esters (caffeic acid, coumaric, ferulic) from grapes with tartaric acid	In vitro (L-tyrosine)	8	IC50: 30 µM	Competitive type	Caftaric acid is more potent than the others due to the difference in position on the phenyl ring. Caftaric acid has hydroxyl groups at positions 3 and 4.	[33]
6'-O-Caffeoylarbutin from quezui tea	In vitro (L-tyrosine and L-DOPA	9	Monophenolase: IC50: 1.114 ± 0.035 µM Diphenolase: IC50: 95.198 ± 1.117 µM	Diphenolase: Competitive type, reversible	It shows higher antimelanin activity than beta arbutin, toxicity tests indicate that doses above 28056 mg/kg body weight in rats show toxic symptoms.	[21]
Cinnamic acid with paeonol with a linker of 1,3-dioxipropyl	In vitro (L-DOPA)	10	IC50: 20.7 µM	Mixed type	Compounds 11 and 12 have higher security on the B16F10 cells. Compound 11 has a stronger inhibition activity than kojic acid and arbutin.	[55]
		11	IC50: 13.9 µM	Competitive type
		12	IC50: 15.16 µM	Mixed type
Substituted vanillyl cinnamic acid analogs	In vitro (L-DOPA)	13	IC50: 268.5 µM	Mixed type, reversible	Nonmethoxy substitution at the C-3 position of the benzene ring provides better activity. The three compounds have stronger activity than kojic acid.	[52]
		14	IC50: 213.2 µM	Mixed type, reversible
		15	IC50: 413.6 µM	Competitive type, reversible
Derivative of N-(2-morpholinoethyl) cinnamide	In vitro (L-DOPA)	16	IC50: 15.2 ± 0.6 µM	Mixed type	The effectiveness of inhibition is closely related to the electronic nature and positional orientation of substituents on the phenyl moiety. The 3-Cl group is the most potent, but when moved to the 4-Cl position, it reduces activity, whereas when moved to the 2-Cl position, it loses activity entirely.	[43]
Hydroxyl-substituted cinnamic acid derivatives based on amide	In vitro (L-DOPA)	17	IC50: 0.0020 ± 0.0002 µM	Reversible	Hydroxyl substituents on the phenyl ring at positions 2 and 4 have the strongest inhibition. The addition of hydroxyl/chlorine groups at position 4 decreases activity.	[39]
Cinnamide derivatives	In vitro (L-tyrosine)	18	Inhibition in 25 µM mushroom tyrosinase 93.72% ± 0.25%	-	The three compounds have much higher inhibition than kojic acid at 25 µM of tyrosinase fungus. The compound with the 2,4-dihydroxyphenyl group shows the strongest inhibition. All three compounds inhibit melanin production without cytotoxicity.	[31]
	B16F10 (L-DOPA)	19	Inhibition in 25 µM mushroom tyrosinase 78.97% ± 0.16%	-
		20	Inhibition in 25 µM mushroom tyrosinase 59.09% ± 1.4%	-
Methoxy-substituted tyramine derivatives based on amide	In vitro (L-DOPA) and L-DOPA Human (Sel A375)	21	IC50 mushroom: 0.00005950 ± 0.00000225 µM Human: 94.59% ± 8.071%	Mixed type	Substituents on the phenyl ring with 2,4-dihydroxy show very strong activity on tyrosinase from mushroom and human. Substitution with 2-hydroxy, 4-hydroxy, and 4-chloro decreases the inhibition activity.	[38]
		22	IC50 mushroom: 0.00204 ± 0.000087 µM Human: 92.24% ± 7.985%	Noncompetitive type
Dimeric cinnamoyl analog (DCAs)	Not mentioned	23	IC50: 4.6 ± 0.04 µM	Competitive type	Because its structure mimics that of the tyrosine binding region, the p-hydroxybenzyl group exhibits strong competitive inhibition.	[11]
		24	IC50: 3.4 ± 0.06 µM	Competitive type
		25	IC50: 6.5 ± 0.03 µM	Competitive type
Derivatives of acetamide triazole	Not mentioned	26	Inhibition in 40 µM 44.87% ± 6.66%	-	The combination of methyl groups (steric effect) and nitro groups (electron-withdrawing) can enhance potency.	[56]
N-hydroxycinnamyl amino acid derivatives	In vitro (L-tyrosine)	27	Inhibition ± 45%	-	Compound 27 showed the most significant inhibition compared to ferulic acid. The inhibitory activity of the tyrosinase from the acetylferuloyl amino acid ester was more effective than that of the feruloyl amino acid amide derived from the acetyl group, and both correlated with the alkyl chain in the structure.	[46]
		28	Inhibition ± 42%	-
		29	Inhibition ± 40%	-
Derivative (E)-2,3-Diphenylacrylate	In vitro (L-tyrosine)	30	Inhibition in 25 µM 76.43% ± 3.53%	-	The presence of the (E)-β-phenyl-α,β-unsaturated carbonyl group in certain derivatives is closely associated with their capacity to inhibit tyrosinase.	[48]
Hydroxycinnamic acid derivatives isolated from Lepechinia meyenii	In vitro (L-Tyrosine and L-DOPA)	31	Monophenolase: IC50: 0.30 µM Diphenolase: IC50: 0.62 µM	Monophenolase: noncompetitive type Diphenolase: competitive type	Compound 31 is more active than compound 32, while the hydroxyl group at position 3 reduces activity. The increase in molecular weight of compound 33 decreases activity.	[34]
		32	Monophenolase: IC50: 1.50 µM Diphenolase: IC50: 2.30 µM	Monophenolase: noncompetitive type Diphenolase: mixed type
		33	Monophenolase: IC50: 4.14 µM Diphenolase: IC50: 8.59 µM	Monophenolase: noncompetitive type Diphenolase: noncompetitive type
Para-substituted cinnamic acid derivatives	In vitro (L-Tyrosine and L-DOPA)	34	Monophenolase: IC50: 0.477 µM Diphenolase: IC50: 0.229 µM	Noncompetitive, reversible type	The three compounds are effective as tyrosinase inhibitors. Compound 34 does not bind Cu but interacts with other active sites, while compounds 35 and 36 bind Cu.	[44]
		35	Monophenolase: IC50: 0.980 µM Diphenolase: IC50: 0.252 µM	Mixed type, reversible
		36	Monophenolase: IC50: 0.521 µM Diphenolase: IC50: 0.381 µM	Mixed type, reversible
Cinnamamide derivatives	In vitro (L-tyrosine)	37	Inhibition at 25 µM was 95.74% ± 0.12% IC50: 0.06 ± 0.01 µM	-	The highest inhibitory activity was found in compound 37. All compounds had a 2,4-OH substitution on the phenyl ring and produced the best inhibition of each series of compounds made. Variations in the amide section showed an increase in the activity of cinnamide as a tyrosinase inhibitor.	[12]
		38	Inhibition at 25 µM was 94.39% ± 0.25% IC50: 0.14 ± 0.00 µM	-
		39	Inhibition at 25 µM was 94.11% ± 1.38% IC50: 0.12 ± 0.00 µM	-
		40	Inhibition at 25 µM was 93.78% ± 1.42% IC50: 0.16 ± 0.01 µM	-
Cinnamic amide derivatives	In vitro (L-tyrosine)	41	Inhibition at 25 µM was 96.20% ± 1.44% IC50: 11.2 ± 3.0 nM	Competitive type	The highest inhibitory activity was found in compound 41. Compounds containing a 2,4-OH substitution on the phenyl ring showed the best activity in each series of derivatives. Variations in the amide section showed an increase in the activity of cinnamide as a tyrosinase inhibitor.	[32]
		42	Inhibition at 25 µM was 93.70% ± 1.48% IC50: 25.6 ± 2.0 nM	Competitive type
Analog thymol with cinnamic acid	In vitro (L-DOPA)	43	Inhibition at 25 µM was 93.4% IC50: 15.2 ± 0.42 µM	Mixed type, reversible	The most potent activity among the other thymol analog derivatives. The presence of a 4-hydroxyl group on the phenyl ring of cinnamic acid increases tyrosinase inhibitory activity. Other compound variations, such as 4-H and 4-Cl substitutions, do not significantly increase activity and are still weaker than kojic acid.	[37]
Hydroxy substituted 2-[(4-acetylphenyl)amino]-2-oxoethyl derivatives	In vitro (L-DOPA)	44	IC50: 0.0089 ± 0.0004 µM	Competitive type	The presence of a hydroxyl group on the phenyl ring, particularly at the 2,4-dihydroxyl position in compound 44, plays a key role in enhancing its tyrosinase inhibitory activity. Substitution of 4-Cl on the phenyl ring resulted in a higher increase in activity compared to kojic acid. Compound 44 works by forming a stable complex with the target protein.	[41]
		45	IC50: 8.2 ± 1.7 µM	Mixed type
Vanillin derivatives with substituted 4-hydroxyphenylpropene groups	In vitro (L-DOPA)	46	IC50: 16.13 ± 0.94 µM	Mixed type, reversible	In compound 46, the hydroxy-substituted cinnamate group is more active than the hydroxy-substituted benzoate group. The hydroxyl group on the phenyl ring of cinnamic acid plays a role in the formation of a complex between the ligand and the target protein. The inhibitory value is almost comparable to that of kojic acid.	[36]
Coumarin-cinnamic acid derivates with oxime linkage	In vitro (L-DOPA)	47	IC50: 3.04 ± 0.01 µM	Noncompetitive, reversible type	Cinnamic acid coumarin derivatives are more active than benzoic acid coumarin. Compound 47 is the most potent compound among the other derivatives. The addition of substituents to the phenyl group such as CH3, Cl, Br, F, OCH3, NO2 increases the activity, with the highest activity being with the OH substituent.	[57]
hydroxylated amide derivatives of cinnamic acid	In vitro (L-DOPA) and human (cell A375)	48	IC50 of mushrooms: 0.15 ± 0.01 µM Human tyrosinase inhibition at 50 µg/mL: 91.87% ± 8.43%	Noncompetitive, irreversible	Compound 48 has the best tyrosinase inhibitory activity. The addition and position of the hydroxyl group on the phenyl ring affect tyrosinase activity. With a ratio of 2,4-dihydroxyl>4-H>4-hydroxy>2-Hydroxy. Compound 48 inhibits the enzyme by binding to its binuclear active site.	[58]

3.1.2. Noncompetitive type

In contrast to competitive inhibition, inhibitors in noncompetitive inhibition do not have a similarity to the structure of the natural substrates of tyrosinase and bind to a different site on the enzyme. The interaction between the enzyme and the inhibitor caused a loss of activity, which could occur with either the free enzyme or the enzyme-substrate complex. Cinnamic acid derivatives are reported to act through this mechanism and demonstrate noncompetitive inhibition, including cinnamic acid esters of paeonol or thymol (compound 4), cinnamic acid-4-hydroxyphenyl (compound 7), and hydroxycinnamic acids such as p-coumaric (compound 31) and rosmarinic acids (compound 33), 4-chlorocinnamate (compound 34), and some amide or oxime-linked derivatives (compound 47).

3.1.3. Mixed type

In mixed inhibition, the inhibitors have different binding affinities, both with the free enzyme and enzyme-substrate complex, at a site other than the catalytic center. Table 2 lists some cinnamic acid derivatives reported with this mechanism. The examples include cyanamate-eugenol ester (compound 1), cinnamic acid esters of paeonol or thymol (compounds 5-6), and paeonol derivatives with a 1,3-dioxypropyl linker (compounds 10 and 12), substituted vanillyl cinnamate analogues (compounds 13-14), N-(2-morpholinoethyl) cinnamamide (compound 16), caffeic acid (compound 32), and a range of para-substituted and amide derivatives (compounds 35, 36, 43, 45, and 46), all of which consistently display mixed type inhibition.

3.1.4. Uncompetitive type

Uncompetitive inhibition occurs when the inhibitors bind exclusively to the enzyme-substrate complex, forming an inactive ternary complex, rather than to the free enzyme [20]. However, in the present review, no cinnamic acid derivatives were identified as uncompetitive inhibitors.

Besides the four types of inhibition mentioned above, enzyme inhibitors are also categorized into two groups according to the nature of their binding: reversible and irreversible [21]. Reversible binding of inhibitors is noncovalent, and the interaction is only temporary; the enzyme activity will recover once the binding complex dissociates [22]. In contrast, irreversible inhibitors form covalent bonds, resulting in a permanent decrease in enzymatic function.

Reversible inhibitors were mainly attributed to cinnamic acid derivatives (Table 2). Such as: cinnamic acid esters with eugenol (compound 1), cinnamic acid esters with paeonol or thymol (compounds 4–6), cinnamic acid-4-hydroxyphenyl (compound 7), 6’-O-caffeoylarbutin (compound 9), disubstituted vanillyl cinnamate analogs (compounds 13–15), hydroxyl-substituted cinnamic acid amides (compound 17), para-substituted cinnamic acid derivatives (compounds 34–36), vanillin derivatives with substituted 4-hydroxyphenylpropene groups (compound 46), coumarin–cinnamic acid derivatives with oxime linkage (compound 47) are among the reversible inhibitors. In addition, several cinnamaldehyde derivatives, such as α-bromo-, α-chloro-, and α-methylcinnamaldehyde, have been reported as reversible inhibitors [23]. Only one compound, described as an irreversible inhibitor, is the hydroxylated amide derivative of cinnamic acid (compound 48). This compound in particular will hopefully help guide the rational design of new derivatives as much as possible.

From a more general standpoint, to gain a deeper understanding of the inhibitory properties of cinnamic acid derivatives, it is beneficial to compare the inhibitory mechanism of cinnamic acid with that of established tyrosinase inhibitors, such as hydroquinone and kojic acid. The three compounds exhibit distinct mechanisms of inhibition: cinnamic acid demonstrates mixed inhibition, allowing it to attach to both free enzymes and enzyme-substrate complexes [9]. In contrast, kojic acid forms complexes with Cu⁺ ions at the active site, thereby inhibiting the tautomerization process of DOPA into 5,6-dihydroxyindole-2-carboxylic acid [24]. Meanwhile, hydroquinone resembles L-tyrosine closely enough to bind competitively to tyrosinase, which obstructs substrate binding and ultimately interferes with melanin biosynthesis [25].

3.2 The potency of cinnamic acid and its derivatives as anti-tyrosinase

Cinnamic acid is commonly found in the essential oils of Cinnamomum cassia and in balsamic resins such as styrax [10]. It is also widely distributed in vegetables, fruits, and grains, and can be obtained either from natural sources or through chemical synthesis [26,27].

Chemically, cinnamic acid has the molecular formula C₉H₈O₂ (C₆H₅CH=CHCOOH) and a molecular weight of 148.15 g/mol. Structurally, cinnamic acid exists in two geometric isomeric forms, trans-cinnamate and cis-cinnamate, with melting points of 133°C and 68°C, respectively. Among these, the trans is more thermodynamically stable and predominantly found in nature. Several derivatives of cinnamic acid are also abundant in plants, including p-coumaric acid, caffeic acid, ferulic acid, and sinapic acid [28,29]. In addition to these fundamental properties, studies have also demonstrated that cinnamic acid, as a single compound, exhibits a mild tyrosinase inhibitory capacity, with various IC₅₀ values reported and summarised in Table 1. Besides its role as a tyrosinase inhibitor, cinnamic acid also has various pharmacological effects, such as antiviral, anti-inflammatory, antibacterial, antitumor, and antileishmaniasis [26,30].

Cinnamic acid consists of three basic structures: a phenyl ring, an unsaturated double bond, and a carboxylic acid group (Fig. 2). The phenyl ring is the one with six carbons that form an aromatic ring and is located at the head of the cinnamic acid. Modifications to the phenyl ring are most often conducted to obtain derivatives with better activity. Different substituents can be attached to the phenyl ring, such as hydroxyl, methoxy, methyl, halogens (F, Cl, Br), nitro, or other conjugated groups. The phenyl ring is connected to the carboxylic acid group by an unsaturated double bond, which usually adopts the (E)-configuration [20,31]. This geometry is typical of cinnamic acid and forms an important structural motif known as the β-phenyl-α,β-unsaturated carbonyl [20,32]. At the opposite end of the molecule, the carboxylic acid group often serves as a site for modification. Transformations into ester or amide derivatives are common strategies to improve anti-tyrosinase activity [5,22].

Cinnamic acid derivatives may be obtained from both natural and synthetic sources. Unripe grape juice, a natural source, contains cinnamic acid derivatives. According to one study, which isolated and evaluated the inhibitory effects of caftaric acid (compound 8) on tyrosinase, caftaric acid demonstrated high activity with an IC₅₀ value of 30 µM. The molecule contains hydroxyl groups at the 3- and 4-positions of the phenolic ring, derived from caffeic acid. Kinetic analysis revealed that caftaric acid inhibits tyrosinase in a concentration-dependent manner, with lower concentrations acting as competitive inhibitors. However, this mechanism alters at elevated concentrations, as demonstrated by Lineweaver-Burk plot analysis [33].

Another investigation isolated 6’-O-Caffeoylarbutin (compound 9) from quenzui tea, which shows tyrosinase inhibitory activity both as an anti-monophenolase (IC₅₀ = 1.114 ± 0.035 µM), with 7,500-fold higher potency compared to β-arbutin, and as an anti-diphenolase (IC₅₀ = 95.198 ± 1.117 µM) [21]. 6’-O-Caffeoylarbutin is a β-arbutin derivative modified with caffeic acid group addition and contains the same dihydroxy group as caftaric acid. The higher potency of this compound is attributed to the presence of a dihydroxy structure in the caffeic acid part, which appears to enhance interaction with the enzyme. Previous studies have suggested that the intrinsic fluorescence of tyrosinase may be decreased when caffeic acid is added, indicating a binding between the molecule and the enzyme’s active site [21].

Lepechinia meyenii derived another cinnamic acid derivative containing p-coumaric acid (compound 31), caffeic acid (compound 32), and rosmarinic acid (compound 33) [34], all of which exhibited stronger inhibitory activity than kojic acid towards monophenolase and diphenolase. Compound 31 (IC₅₀ = 0.30 µM for monophenolase, ~100-fold vs. kojic acid; 0.62 µM for diphenolase, ~60-fold vs. kojic acid) showed excellent power, which is considered due to the para-hydroxyl substitution. However, the inhibition was slow and reversible, as indicated by the kinetic analysis of the enzyme-inhibitor complex transiently formed, resulting in residual enzyme [35]. Compound 32 (IC₅₀: monophenolase, 1.50 mM; diphenolase, 2.30 mM) has an additional hydroxyl group at the meta-position forming a catechol group and exhibits significantly lower activity compared to compound 31 (Fig. 5). Compound 33 (IC₅₀ = 4.14 µM for monophenolase; 8.59 µM for diphenolase) features a 3,4-dihydroxyphenyl lactate moiety, which is predicted to weaken its activity, possibly due to steric hindrance. The literature mechanical analysis of these hydroxycinnamic acids does not have direct interaction with the catalytic copper ions, but it is supposed that they bind to the outer coordination site of oxytyrosinase in a similar way that substrates do and deactivate the enzyme [34].

Figure 5. Structure of the compounds 17-40. [Click here to view]

In general, tyrosinase inhibitory activities found in natural cinnamic acid derivatives are promising, as are the corresponding synthetic derivatives that allow for structural modifications to improve bioactivity, stability, and selectivity. Modifications reported include esterification, amide formation, and dimerization, increasing some synthetic cinnamic acid derivatives inhibitory capacity comparable, approximately equivalent to that of kojic acid, such as vanillin (compound 46), thymol (compound 43), and the ester analogues (compound 6) [10,36,37], and even noticeably enhanced the inhibitory capacity for some other compounds such as paeonol esters (compound 4, ~16-fold; compound 5, ~4-fold increase relative to kojic acid), dimeric cinnamoyl analogs (compound 24, ~3-fold increase relative to arbutin), eugenol esters (compound 1, ~5-fold increase relative to kojic acid), and coumarin–oxime derivatives (compound 47, ~5-fold increase relative to kojic acid), underscoring their potential as potent tyrosinase inhibitors [10,11,22].

One study synthesized and evaluated a series of five triamine-cinnamic acid derivatives for their inhibitory activity against tyrosinase (Fig. 5). Among them, compound 21 (IC₅₀ = 5.95 × 10^-5 µM; ~280,000-fold vs. kojic acid) and 22 (IC₅₀ = 2.04 × 10^-³ µM; ~8,181-fold vs. kojic acid) demonstrated their remarkable activities against mushroom tyrosinase [38]. Both compounds also exhibited excellent inhibition, ranging from 92% to 96%, against human tyrosinase in A375 melanoma cells. In a further study by the same group, a hydroxyl-substituted cinnamic acid amide derivative was synthesized. Compound 17 (IC₅₀ = 2.0 × 10^-³ µM) contains hydroxyl groups at the ortho (2-) and para (4-) positions of the phenyl ring, exhibiting superior inhibition relative to kojic acid (~8,000-fold) [39]. The compounds 21, 22, and 17 obviously pass the Pan-assay interference compounds (PAINS) screening, with no false positive results due to structural issues that nonspecifically interact with other biological targets mimicking the desired response, and supporting these compounds’ potential as effective tyrosinase inhibitor candidates [40].

Other related derivatives found in compound 44 (Fig. 6), a hydroxy-substituted 2-[(4-acetylphenyl)amino]-2-oxoethyl derivative, a potent tyrosinase inhibitor (IC₅₀ = 0.0089 ± 0.0004 µM; ~1.9-fold more active than kojic acid) [41]. A cinnamic amide derivative (compound 41) also displayed potent inhibitory activity with an IC₅₀ of 11.2 ± 3.0 nM (~2.7-fold more active than kojic acid) [32].

Figure 6. Structure of the compound 41-48. [Click here to view]

The very low IC₅₀ values of these compounds, especially those in the nanomolar range, reveal the potential inhibitory activities of synthetic cinnamic acid derivatives compared to those previously reported for natural ones. The most active activities are mainly accomplished by chemical synthesis and structure modification, which offer specific variations of substituents and functional groups for potential favor in the active site with enhanced inhibitory activity.

3.3 SAR of cinnamic acid derivatives

This section summarizes cinnamic acid derivatives that have structural modifications at key positions to affect their tyrosinase inhibitory activities (Table 2 provides details of the inhibition studies). Several prominent SAR patterns were highlighted that may be utilized in designing derivatives with enhanced properties (Fig. 7).

Figure 7. SAR of cinnamic acid. [Click here to view]

3.3.1. Phenyl ring modification

Phenyl ring modification with substituents such as hydroxyl, methoxy, methyl, halogen, and nitro groups is often used to improve the inhibitory capability of the molecule.

3.3.1.1. Hydroxyl substitution

Substitutions on the phenyl ring most often influence tyrosinase inhibitory activity due to the resemblance to the natural substrate (L-tyrosine and L-DOPA) and mimic their binding to the enzyme [39]. Several studies indicate that hydroxyl groups at the ortho and para positions (2,4-dihydroxyphenyl) yield the most potent derivatives. For instance, compound 17 (IC₅₀ = 2.0 ± 0.2 nM; ~8,500-fold vs. kojic acid) and compound 21 (IC₅₀ = 0.0595 ± 0.0023 nM; ~280,500-fold vs. kojic acid) demonstrated exceptional potency. On the other hand, meta-para substitution (3,4-dihydroxyphenyl) also produced active compounds, such as compound 9 (IC₅₀ = 1.114 ± 0.035 µM; ~7,500-fold vs. β-arbutin) and compound 32 (IC₅₀ = 1.50 µM; ~20-fold vs. kojic acid), but with generally lower activity than ortho-para substitution.

Introduction to a hydroxyl group at position 2 of the 4-hydroxyl derivative creates a potent activity [31], whereas addition of a hydroxyl group at position 3 reduces activity. Compound 31, with a single 4-hydroxyl group, has vigorous activity (for monophenolase, IC₅₀ = 0.30 µM; ~100-fold vs. β-arbutin; and for diphenolase, IC₅₀ = 0.62 µM; ~60-fold vs. kojic acid) compared to that of compound 32 (for monophenolase IC₅₀ = 1.50 µM; ~20-fold vs. kojic acid; and for diphenolase, IC₅₀ = 2.30 µM; ~20-fold vs. kojic acid) with a 3,4-dihydroxyl group [34]. The evidence is also supported by another study, where compound 1 with a 3,4-dihydroxyl group displayed the highest inhibitory activity compared to the others (IC₅₀ = 3.07 ± 0.28 µM; ~5-fold more potent than kojic acid) [22]. Hydroxyl substituent positions are essential in determining the inhibitory activities of molecules with final potency; however, it still depends on the broader structural context of the derivative [42].

3.3.1.2. Nonhydroxyl substitution

Other groups, such as methoxy, chlorine, fluorine, and nitro, have also been reported. Compound 16 (IC₅₀ = 15.2 ± 0.6 µM, equivalent to kojic acid), with a 3-chloro with a chloro group in position 3, has the highest activity among the analogues, which will have a reduced activity if the group is relocated to the para position or even lose the activity when the group is relocated to the ortho position [43]. In another study, compound 34 with a 4-chloro substitution (for monophenolase, IC₅₀ = 0.477 µM and for diphenolase, IC₅₀ = 0.229 µM) was more active than its corresponding 4-ethoxy (compound 35) and 4-nitro (compound 36) substitution compounds, although not compared with the positive control (kojic acid) [44]. Another investigation reported that 4-fluoro substitution enhanced activity as in compound 5 (IC₅₀ = 8.3 µM; ~4-fold vs. kojic acid) [10]. This finding is consistent with subsequent reports indicating that the 4-fluoro derivative was the most favourable among fluorine-substituted analogues, as well as the 4-nitro analogue, although still less potent than kojic acid [43]. In the same study, further examination was conducted of methoxy and methyl substitutions. The results showed that the methoxy substitution at any position did not improve activity. On the other hand, a 3-methyl derivative showed moderate potency, but substitution at positions 2 and 4 rendered the compounds inactive.

3.3.2. Carboxylate modifications: esterification, amidation, and heterocycles

Free carboxyl group in cinnamic acid brings little influence on tyrosinase inhibition, and the high polarity may reduce the ability to reach melanocytes in the basal epidermis [10,20]. To produce more potent inhibitors, it is suggested that chemical modifications be made to the carboxyl group through esterification, amidation, or heterocyclic derivatization.

Esterification: A large number of studies have reported that ester derivatives are more active than cinnamic acid as the parent compound. Compound 1, for instance, exhibited approximately fivefold higher inhibitory activity than kojic acid (IC₅₀ = 3.07 ± 0.28 µM). This compound was synthesized via esterification with eugenol. Similarly, paeonol and thymol esters displayed significantly improved inhibition, with compound 4 (IC₅₀ = 2.0 µM; ~16-fold vs. kojic acid) and compound 6 (IC₅₀ = 10.6 µM; ~3-fold vs. kojic acid), respectively [10]. Furthermore, one of the cinnamic acid–benzenediol esters displayed notable activity (IC₅₀ = 24.01 μg/ml), indicating that esterification has a positive effect on biological performance [45]. Additional examples include cinnamic acid-4-hydroxyphenyl (compound 7), caftaric acid (compound 8), substituted vanillyl analogues (compounds 13-15), and coumarin-cinnamic acid oxime derivatives (compound 47). Collectively, esterification improves the balance between tyrosinase affinity and lipophilicity, enhancing skin permeability [20].

Amidation: An amide converted from a carboxyl group will also improve inhibitory potency and lipophilicity for cinnamic acid derivatives. For example, N-(2-morpholinoethyl)cinnamamide (compound 16, IC₅₀ = 15.2 ± 0.6 µM) showed comparable activity to kojic acid [43]. Furthermore, cinnamamide analogues (compounds 18-20: inhibition of 59.09%–93.72% at 25 µM) and N-hydroxycinnamyl amino acid derivatives (compounds 27-29: inhibition of 40%–45%) compared to kojic acid inhibition of 18.81% ± 1.25% showed potential inhibitory activities on fungal tyrosinase enzyme [31,46]. In one of the latest studies, a series of cinnamides linked to 1-aryl piperazines was reported, among which 3-nitrocinnamoyl and 2-chloro-3-methoxycinnamoyl (IC₅₀ = 0.12 and 0.16 μM, respectively) far exceeding the potency of kojic acid (IC₅₀ = 17.76 μM) [47]. The formation of amide appears to facilitate skin permeation and increases the likelihood of reaching melanocytes [20].

Heterocycles: Heterocycle compounds, including piperidine, pyrrolidine, piperazine, triazole, and morpholine, are usually introduced via amide linkages. The cinnamic acid carboxyl group can be converted to an amide, and a morpholine heterocyclic ring can then be added, resulting in a more favourable interaction with the enzyme tyrosinase (compounds 16 and 37) [12,43]. Further piperidine-substituted (compounds 19-20, 59.09%–78.97% inhibition) and pyrrolidine derivatives (compound 18, 93.72% ± 0.25% inhibition) also proved more effective at 25 µM than were kojic acid (18.81% ± 1.25% inhibition) [31]. Derivatives containing cyclopentylamine (compound 39, IC₅₀ = 0.12 ± 0.00 µM; ~250-fold vs. kojic acid) and cyclohexylamine (compound 40, IC₅₀ = 0.16 ± 0.01 µM; ~200-fold vs. kojic acid) were equally effective with similar high potency [12]. Heterocyclic substitution at the carboxylate group, broadly speaking, increases the tyrosinase inhibitory capacity by increasing lipophilicity and promoting favourable enzyme-substrate interaction.

3.3.3. Dimeric modification

Some studies investigated structural modifications, such as substituent addition or removal, and some others explored the conversion of monomeric into dimeric structures of the molecule. Dimeric derivatives connected through diamide linkages are potential as tyrosinase inhibitors [11]. One with most potent activity is compound 24 (IC₅₀ = 3.4 ± 0.06 µM; ~3.06-fold vs. arbutin), followed by compound 23 (4.6 ± 0.04 µM; ~2.26-fold) and compound 25 (6.5 ± 0.03 µM; ~1.6-fold). The resulting data can also be attributed to the folded conformational advantages conducive to the spatial orientation and binding affinity of the substrate at the active site of the enzymes [11].

3.3.4. Geometric configuration modification

The geometric configuration was also studied on tyrosinase inhibition as (E)- and (Z)-2,3-diphenylacrylate derivatives (compounds 14 and 1, respectively) [48]. The (E)-configuration exhibited a strong tyrosinase inhibition (compound 30, 76.43% ± 3.53% inhibition at 25 µM, compared to kojic acid of 21.56% ± 2.93% inhibition). It is suggested that the β-phenyl-α,β-unsaturated carbonyl system has a favorable binding site to the enzyme through (E)-configuration, making it an effective substrate for the binding site on the enzyme. Conversely, the (Z)-isomer exhibited little activity, further suggesting that geometric organization was essential for the inhibition of tyrosinase [48].

3.3.5. Combination modifications

Comparative studies have investigated the combination of ferulic acid and 4-hydroxycinnamic acid, which differ only by a methoxy group at the 3-position of the phenyl ring in ferulic acid [49], on the inhibition of tyrosinase. This combination yielded highly effective tyrosinase inhibition (90.44%), far beyond the efficacy of each compound alone (12.15% for 4-hydroxycinnamic acid and 22.17% for ferulic acid). This effect is believed to result from complementary mechanisms: 4-hydroxycinnamic acid mimics L-DOPA, facilitating the formation of a tyrosinase-L-DOPA complex. The ferulic acid further binds to this complex, strengthening the inhibitory action. Therefore, a combination of modifications may become a strategic approach to significantly improve biological activities and properties of a molecule as tyrosinase inhibitors [49,50].

4. CONCLUSION

This article provides comprehensive review based on recent findings on cinnamic acid and its derivatives, promising to be potential candidates for more effective tyrosinase inhibitors. In-depth SAR analysis reveals a crucial framework for enhancing the potential tyrosinase inhibitory activity. Modifications (introduction of hydroxyl, halogen, and methoxy groups); alterations at the carboxyl site (esterification or amide formation); dimerization; and retention of (E)-β-phenyl-α,β-unsaturated carbonyl motif all significantly influence on the tyrosinase inhibitory activity. The type of inhibition depends on the molecular structure; specific cinnamic acid derivatives may exhibit competitive, noncompetitive, or mixed-type inhibition. In order to have potent and effective tyrosinase inhibitors, structural modification of cinnamic acid can be used as a strategic approach. Further research is essential to optimize these compounds for potential therapeutic and cosmetic applications..

5. AUTHOR CONTRIBUTIONS

All authors made substantial contributions to conception and design, acquisition of data, or analysis and interpretation of data; took part in drafting the article or revising it critically for important intellectual content; agreed to submit to the current journal; gave final approval of the version to be published; and agreed to be accountable for all aspects of the work. All the authors are eligible to be author as per the International Committee of Medical Journal Editors (ICMJE) requirements/guidelines.

6. FINANCIAL SUPPORT

This project was supported by the International Research Collaboration-LPPM-UMP (grant number: A.11-III/159-S.Pj./LPPM/III/2022).

7. CONFLICTS OF INTEREST

The authors report no financial or any other conflicts of interest in this work.

8. ETHICAL APPROVALS

This study does not involve experiments on animals or human subjects.

9. DATA AVAILABILITY

All data generated and analyzed are included in this research article.

10. PUBLISHER’S NOTE

All claims expressed in this article are solely those of the authors and do not necessarily represent those of the publisher, the editors and the reviewers. This journal remains neutral with regard to jurisdictional claims in published institutional affiliation.

11. USE OF ARTIFICIAL INTELLIGENCE (AI)-ASSISTED TECHNOLOGY

The authors declare that they have not used artificial intelligence (AI)-tools for writing and editing of the manuscript, and no images were manipulated using AI.

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