Methoxy-Substituted Tyramine Derivatives Synthesis, Computational Studies and Tyrosinase Inhibitory Kinetics

Targeting tyrosinase for melanogenesis disorders is an established strategy. Hydroxyl-substituted benzoic and cinnamic acid scaffolds were incorporated into new chemotypes that displayed in vitro inhibitory effects against mushroom and human tyrosinase for the purpose of identifying anti-melanogenic ingredients. The most active compound 2-((4-methoxyphenethyl)amino)-2-oxoethyl (E)-3-(2,4-dihydroxyphenyl) acrylate (Ph9), inhibited mushroom tyrosinase with an IC50 of 0.059 nM, while 2-((4-methoxyphenethyl)amino)-2-oxoethyl cinnamate (Ph6) had an IC50 of 2.1 nM compared to the positive control, kojic acid IC50 16700 nM. Results of human tyrosinase inhibitory activity in A375 human melanoma cells showed that compound (Ph9) and Ph6 exhibited 94.6% and 92.2% inhibitory activity respectively while the positive control kojic acid showed 72.9% inhibition. Enzyme kinetics reflected a mixed type of inhibition for inhibitor Ph9 (Ki 0.093 nM) and non-competitive inhibition for Ph6 (Ki 2.3 nM) revealed from Lineweaver–Burk plots. In silico docking studies with mushroom tyrosinase (PDB ID:2Y9X) predicted possible binding modes in the catalytic site for these active compounds. Ph9 displayed no PAINS (pan-assay interference compounds) alerts. Our results showed that compound Ph9 is a potential candidate for further development of tyrosinase inhibitors.

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Molecular Docking, Synthesis, and Tyrosinase Inhibition Activity of Acetophenone Amide: Potential Inhibitor of Melanogenesis

BioMed Research International ◽

10.1155/2022/1040693 ◽

2022 ◽

Vol 2022 ◽

pp. 1-10

Author(s):

Yasir Nazir ◽

Hummera Rafique ◽

Sadia Roshan ◽

Shazia Shamas ◽

Zaman Ashraf ◽

...

Keyword(s):

Hydrogen Bond ◽

Cinnamic Acid ◽

Inhibitory Activity ◽

Reversible Inhibitor ◽

Binding Modes ◽

Mushroom Tyrosinase ◽

Cinnamic Acids ◽

Tyrosinase Inhibitory Activity ◽

In Silico Docking

Tyrosinase and its related proteins are responsible for pigmentation disorders, and inhibiting tyrosinase is an established strategy to treat hyperpigmentation. The carbonyl scaffolds can be effective inhibitors of tyrosinase activity, and the fact that both benzoic and cinnamic acids are safe natural substances with such a scaffolded structure, it was speculated that hydroxyl-substituted benzoic and cinnamic acid derivatives may exhibit potent tyrosinase inhibitory activity. These moieties were incorporated into new chemotypes that displayed in vitro inhibitory effect against mushroom tyrosinase with a view to explore antimelanogenic ingredients. The most active compound, 2-((3-acetylphenyl)amino)-2-oxoethyl(E)-3-(2,4-dihydroxyphenyl)acrylate (5c), inhibited mushroom tyrosinase with an IC50 of 0.0020 ± 0.0002 μ M , while 2-((3-acetylphenyl)amino)-2-oxoethyl 2,4-dihydroxybenzoate (3c) had an IC50 of 27.35 ± 3.6 μ M in comparison to the positive control arbutin and kojic acid with a tyrosinase inhibitory activity of IC50 of 191.17 ± 5.5 μ M and IC50 of 16.69 ± 2.8 μ M , respectively. Analysis of enzyme kinetics revealed that 5c is a competitive and reversible inhibitor with dissociation constant (Ki) value 0.0072 μM. In silico docking studies with mushroom tyrosinase (PDB ID 2Y9X) predicted possible binding modes in the enzymatic pocket for these compounds. The orthohydroxyl of the cinnamic acid moiety of 5c is predicted to form hydrogen bond with the active site side chain carbonyl of Asn 260 (2.16 Å) closer to the catalytic site Cu ions. The acetyl carbonyl is picking up another hydrogen bond with Asn 81 (1.90 Å). The inhibitor 5c passed the panassay interference (PAINS) alerts. This study presents the potential of hydroxyl-substituted benzoic and cinnamic acids and could be beneficial for various cosmetic formulations.

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Preliminary Screening of Selected Plant Extracts for Anti Tyrosinase Activity

Journal of Natural Remedies ◽

10.18311/jnr/2016/488 ◽

2016 ◽

Vol 16 (1) ◽

pp. 18 ◽

Cited By ~ 4

Author(s):

Vidyalakshmi Subramanian ◽

Dhamodharan Sahithya

Keyword(s):

Inhibitory Activity ◽

Kojic Acid ◽

Control Cell ◽

Punica Granatum ◽

Positive Control ◽

Tyrosinase Inhibition ◽

Tyrosinase Inhibitory Activity ◽

Cassia Angustifolia ◽

Important Approach

Tyrosinase inhibition is an important approach towards controlling hyper pigmentation. We aimed to screen alcoholic extracts of 11 plants extract for their tyrosinase inhibitory activity. These plants have been used traditionally in the treatment of skin ailments and for the improvement of skin complexion. The extracts were quantified for total phenols, alkaloids and tannins. In vitro tyrosinase inhibition was performed with kojic acid as the positive control. Cell viability was tested on B16 F0 melanoma cells. The extracts of Rosa berberifolia, Punica granatum and Casiia angustifolia showed more than 80% inhibition at 500 mg/ml concentration. Nine of the extracts were also shown to have a high phenolic content greater than 200 mg/g of the plant material. The tyrosinase inhibitory activity of the extracts of Cassia angustifolia, Punica granatum and Rosa berberifolia were comparable with that of the control, kojic acid. The three extracts also showed lesser than 50% cytotoxicity at the concentrations tested. From the screening assays, it is seen that three plants have appreciable tyrosinase inhibitory activity. Hence, these plants may be further evaluated for their use in cosmetics and hyper pigmentation.

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Preparation, COX-2 Inhibition and Anticancer Activity of Sclerotiorin Derivatives

Marine Drugs ◽

10.3390/md19010012 ◽

2020 ◽

Vol 19 (1) ◽

pp. 12

Author(s):

Tao Chen ◽

Yun Huang ◽

Junxian Hong ◽

Xikang Wei ◽

Fang Zeng ◽

...

Keyword(s):

Cytotoxic Activity ◽

Cancer Cells ◽

Inhibitory Activity ◽

Positive Control ◽

Human Lung Cancer ◽

Binding Modes ◽

Ic50 Values ◽

Cox 2 ◽

Inhibitory Agents

The latest research has indicated that anti-tumor agents with COX-2 inhibitory activity may benefit their anti-tumor efficiency. A series of sclerotiorin derivatives have been synthesized and screened for their cytotoxic activity against human lung cancer cells A549, breast cancer cells MDA-MB-435 using the MTT method. Among them, compounds 3, 7, 12, 13, 15, 17 showed good cytotoxic activity with IC50 values of 6.39, 9.20, 9.76, 7.75, 9.08, and 8.18 μM, respectively. In addition, all compounds were tested in vitro the COX-2 inhibitory activity. The results disclosed compounds 7, 13, 25 and sclerotiorin showed moderate to good COX-2 inhibition with the inhibitory ratios of 58.7%, 51.1%, 66.1% and 56.1%, respectively. Notably, compound 3 displayed a comparable inhibition ratio (70.6%) to the positive control indomethacin (78.9%). Furthermore, molecular docking was used to rationalize the potential of the sclerotiorin derivatives as COX2 inhibitory agents by predicting their binding energy, binding modes and optimal orientation at the active site of the COX-2. Additionally, the structure-activity relationships (SARS) have been addressed.

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Novel Anti-Melanogenic Compounds, (Z)-5-(Substituted Benzylidene)-4-thioxothiazolidin-2-one Derivatives: In Vitro and In Silico Insights

Molecules ◽

10.3390/molecules26164963 ◽

2021 ◽

Vol 26 (16) ◽

pp. 4963

Author(s):

Heejeong Choi ◽

Il Young Ryu ◽

Inkyu Choi ◽

Sultan Ullah ◽

Hee Jin Jung ◽

...

Keyword(s):

Active Site ◽

Kojic Acid ◽

Docking Simulation ◽

Tyrosinase Activity ◽

In Vitro Assays ◽

Mushroom Tyrosinase ◽

Tyrosinase Inhibitors ◽

Melanin Contents ◽

Human Tyrosinase

To confirm that the β-phenyl-α,β-unsaturated thiocarbonyl (PUSTC) scaffold, similar to the β-phenyl-α,β-unsaturated carbonyl (PUSC) scaffold, acts as a core inhibitory structure for tyrosinase, twelve (Z)-5-(substituted benzylidene)-4-thioxothiazolidin-2-one ((Z)-BTTZ) derivatives were designed and synthesized. Seven of the twelve derivatives showed stronger inhibitory activity than kojic acid against mushroom tyrosinase. Compound 2b (IC50 = 0.47 ± 0.97 µM) exerted a 141-fold higher inhibitory potency than kojic acid. Kinetic studies’ results confirmed that compounds 2b and 2f are competitive tyrosinase inhibitors, which was supported by high binding affinities with the active site of tyrosinase by docking simulation. Docking results using a human tyrosinase homology model indicated that 2b and 2f might potently inhibit human tyrosinase. In vitro assays of 2b and 2f were conducted using B16F10 melanoma cells. Compounds 2b and 2f significantly and concentration-dependently inhibited intracellular melanin contents, and the anti-melanogenic effects of 2b at 10 µM and 2f at 25 µM were considerably greater than the inhibitory effect of kojic acid at 25 µM. Compounds 2b and 2f similarly inhibited cellular tyrosinase activity and melanin contents, indicating that the anti-melanogenic effects of both were due to tyrosinase inhibition. A strong binding affinity with the active site of tyrosinase and potent inhibitions of mushroom tyrosinase, cellular tyrosinase activity, and melanin generation in B16F10 cells indicates the PUSTC scaffold offers an attractive platform for the development of novel tyrosinase inhibitors.

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Synthesis and Heme Polymerization Inhibitory Activity (HPIA) Assay of Chalcone, Flavone and Flavanone Derivatives

Materials Science Forum ◽

10.4028/www.scientific.net/msf.948.109 ◽

2019 ◽

Vol 948 ◽

pp. 109-114

Author(s):

Novia Suryani ◽

Sabirin Matsjeh ◽

Respati Tri Swasono

Keyword(s):

Inhibitory Activity ◽

Antimalarial Activity ◽

Positive Control ◽

Potential Candidate ◽

Base Catalyst ◽

Antimalarial Agent ◽

Chloroquine Diphosphate ◽

Antimalarial Compounds

Chalcone, flavone, and flavanone had been synthesized as candidate of the antimalarial compounds. The chalcone 1was synthesised from 2,4-dihydroxyacetophenone and 4-metoxybenzaldehyde as starting materials using base catalyst KOH via Claisen-Schmidt Condensation. The synthesis flavone 2was carried out by cyclization of chalcone 1using I2 in DMSO, while the flavanone 3was produced by cyclization of chalcone 1using NaOAc as a base catalyst. An in vitro antimalarial activity of the compound 1, 2and 3have been evaluated with the chloroquine diphosphate as a positive control in various concentration, and this assay was carried out according to the Basilico method. The IC50value of compound 1, 2, 3and a positive control were 0.25; 0.62; 1.33 and 0.35 mM, respectively. The result showed that chalcone1with the lowestIC50value is a potential candidate as an antimalarial agent.

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Moracin VN, A New Tyrosinase and Xanthine Oxidase Inhibitor from the Woods of Artocarpus heterophyllus

Natural Product Communications ◽

10.1177/1934578x1701200623 ◽

2017 ◽

Vol 12 (6) ◽

pp. 1934578X1701200

Author(s):

Tho Huu Le ◽

Hai Xuan Nguyen ◽

Truong Van Nhat Do ◽

Phu Hoang Dang ◽

Nhan Trung Nguyen ◽

...

Keyword(s):

Kinetic Study ◽

Xanthine Oxidase ◽

Inhibitory Activity ◽

Competitive Inhibition ◽

Kojic Acid ◽

Positive Control ◽

Oxidase Inhibitor ◽

Xanthine Oxidase Inhibitor ◽

Artocarpus Heterophyllus ◽

Isolated Compound

Bioactivity-guided fractionation of the woods extract of Artocarpus heterophyllus collected in Vietnam revealed that a new 2-arylbenzofuran, moracin VN (1) together with two known compounds were isolated. Compound 1 possessed the inhibitory activity on tyrosinase with IC50 value of 0.82 μM, more potent than the positive control kojic acid (IC50, 44.6 μM). Compound 1 also showed moderate inhibitory activity on xanthine oxidase with IC50 value of 22.8 μM. The kinetic study of tyrosinase was performed on moracin VN (1) showed non-competitive inhibition with Ki value of 2.40 μM.

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Inhibitory effects of bioaccessible anthocyanins and procyanidins from apple, red grape, cinnamon on α-amylase, α-glucosidase and lipase

International Journal for Vitamin and Nutrition Research ◽

10.1024/0300-9831/a000652 ◽

2020 ◽

pp. 1-9

Author(s):

Pınar Ercan ◽

Sedef Nehir El

Keyword(s):

Inhibitory Activity ◽

Digestive Enzymes ◽

Positive Control ◽

Anthocyanin Content ◽

Inhibitory Effects ◽

Total Anthocyanin ◽

Total Anthocyanin Content ◽

Before And After ◽

Red Grape

Abstract. The goals of this study were to determine and evaluate the bioaccessibility of total anthocyanin and procyanidin in apple (Amasya, Malus communis), red grape (Papazkarası, Vitis vinifera) and cinnamon (Cassia, Cinnamomum) using an in vitro static digestion system based on human gastrointestinal physiologically relevant conditions. Also, in vitro inhibitory effects of these foods on lipid (lipase) and carbohydrate digestive enzymes (α-amylase and α-glucosidase) were performed with before and after digested samples using acarbose and methylumbelliferyl oleate (4MUO) as the positive control. While the highest total anthocyanin content was found in red grape (164 ± 2.51 mg/100 g), the highest procyanidin content was found in cinnamon (6432 ± 177.31 mg/100 g) (p < 0.05). The anthocyanin bioaccessibilities were found as 10.2 ± 1%, 8.23 ± 0.64%, and 8.73 ± 0.70% in apple, red grape, and cinnamon, respectively. The procyanidin bioaccessibilities of apple, red grape, and cinnamon were found as 17.57 ± 0.71%, 14.08 ± 0.74% and 18.75 ± 1.49%, respectively. The analyzed apple, red grape and cinnamon showed the inhibitory activity against α-glucosidase (IC50 544 ± 21.94, 445 ± 15.67, 1592 ± 17.58 μg/mL, respectively), α-amylase (IC50 38.4 ± 7.26, 56.1 ± 3.60, 3.54 ± 0.86 μg/mL, respectively), and lipase (IC50 52.7 ± 2.05, 581 ± 54.14, 49.6 ± 2.72 μg/mL), respectively. According to our results apple, red grape and cinnamon have potential to inhibit of lipase, α-amylase and α-glucosidase digestive enzymes.

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Synthesis and Evaluation of the Antitumor Activity of Novel 1-(4-Substituted phenyl)-2-ethyl Imidazole Apoptosis Inducers In Vitro

Molecules ◽

10.3390/molecules25184293 ◽

2020 ◽

Vol 25 (18) ◽

pp. 4293

Author(s):

Zhen-Wang Li ◽

Chun-Yan Zhong ◽

Xiao-Ran Wang ◽

Shi-Nian Li ◽

Chun-Yuan Pan ◽

...

Keyword(s):

Antitumor Activity ◽

Tumor Cells ◽

Antiproliferative Activity ◽

Antitumor Agent ◽

Positive Control ◽

Selectivity Index ◽

Time Dependent ◽

Potential Candidate ◽

Dependent Manner

Novel imidazole derivatives were designed, prepared, and evaluated in vitro for antitumor activity. The majority of the tested derivatives showed improved antiproliferative activity compared to the positive control drugs 5-FU and MTX. Among them, compound 4f exhibited outstanding antiproliferative activity against three cancer cell lines and was considerably more potent than both 5-FU and MTX. In particular, the selectivity index indicated that the tolerance of normal L-02 cells to 4f was 23–46-fold higher than that of tumor cells. This selectivity was significantly higher than that exhibited by the positive control drugs. Furthermore, compound 4f induced cell apoptosis by increasing the protein expression levels of Bax and decreasing those of Bcl-2 in a time-dependent manner. Therefore, 4f could be a potential candidate for the development of a novel antitumor agent.

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Ingol and Ingenol-Type Diterpenes from Euphorbia trigona Miller with Keratinocyte Inhibitory Activity

Plants ◽

10.3390/plants10061206 ◽

2021 ◽

Vol 10 (6) ◽

pp. 1206

Author(s):

Reham Hammadi ◽

Norbert Kúsz ◽

Csilla Zsuzsanna Dávid ◽

Zoltán Behány ◽

László Papp ◽

...

Keyword(s):

Liquid Chromatography ◽

Cytotoxic Activity ◽

Inhibitory Activity ◽

High Performance ◽

Skin Condition ◽

Positive Control ◽

Active Species ◽

The European Union ◽

Ingenol Mebutate

Ingenol mebutate, isolated from Euphorbia peplus, is an ingenane-type diterpenoid, primarily used for the topical treatment of actinic keratosis, a premalignant skin condition. The aim of our work was to investigate other Euphorbia species to find structurally similar diterpenes that can be used as alternatives to ingenol mebutate. Pharmacological investigation of Euphorbia candelabrum, Euphorbia cotinifolia, Euphorbia ramipressa, and Euphorbia trigona revealed the potent keratinocyte (HPV-Ker cell line) inhibitory activity of these spurge species. From the methanolic extract of the aerial parts of Euphorbia trigona Miller, the most active species, five ingol (1–5) and four ingenane-type diterpenoids (6–9) were isolated by various chromatographic separation techniques, including open column chromatography, vacuum liquid chromatography, thin-layer chromatography, and high-performance liquid chromatography. The structures of the compounds were determined by NMR spectroscopic analysis and by comparison of the assignations with the literature data. The cytotoxic activity of the compounds against keratinocytes was tested in vitro by using ingenol mebutate as a positive control. Among the isolated compounds, two ingenane derivatives (6 and 7) exhibited remarkably stronger cytotoxic activity (IC50 values 0.39 μM and 0.32 μM, respectively) on keratinocytes than ingenol mebutate (IC50 value 0.84 μM). These compounds could serve as starting materials for further investigations to find alternatives to Picato® (with active substance ingenol mebutate), which was withdrawn from marketing authorization in the European Union.

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