scholarly journals Monosubstituted Acetophenone Thiosemicarbazones as Potent Inhibitors of Tyrosinase: Synthesis, Inhibitory Studies, and Molecular Docking

2021 ◽  
Vol 14 (1) ◽  
pp. 74
Author(s):  
Katarzyna Hałdys ◽  
Waldemar Goldeman ◽  
Natalia Anger-Góra ◽  
Joanna Rossowska ◽  
Rafał Latajka
Keyword(s):  
Molecular Docking ◽  
Active Site ◽  
Melanoma Cell Line ◽  
Inhibitory Concentration ◽  
Copper Ions ◽  
Tyrosinase Inhibitor ◽  
Melanin Production ◽  
B16f10 Cells ◽  
Tyrosinase Inhibitors ◽  
Murine Melanoma Cell Line

A set of 12 monosubstituted acetophenone thiosemicarbazone derivatives (TSCs) were synthesized and their inhibitory properties toward tyrosinase activity were tested. Moreover, their ability to inhibit melanogenesis in the B16F10 murine melanoma cell line was studied. In order to investigate the nature of interactions between the enzyme and the inhibitors, molecular docking to the active site was performed. TSCs 5, 6, 8, and 9 revealed a half maximal inhibitory concentration (IC50) below 1 µM. Compound 6 turned out to be the most potent tyrosinase inhibitor. All investigated compounds showed reversible inhibition of competitive or mixed type. The para-substituted TSCs had higher affinity for the enzyme as compared to their ortho- and meta-analogues. All investigated compounds inhibited melanin production in B16F10 cells at the micromolar level. Molecular docking showed that the sulfur atom of the thiourea moiety penetrates the active site and interacts with copper ions. The above outcomes might be helpful in the design of new tyrosinase inhibitors in the food and cosmetic industries.

scholarly journals Anti-tick effect and cholinesterase inhibition caused by Prosopis juliflora alkaloids: in vitro and in silico studies

2020 ◽  
Vol 29 (2) ◽  
Author(s):  
Hélimar Gonçalves de Lima ◽  
Francianne Oliveira Santos ◽  
Acidália Carine Vieira Santos ◽  
Gisele Dias da Silva ◽  
Rafaela Jesus dos Santos ◽  
...  
Keyword(s):  
Molecular Docking ◽  
Active Site ◽  
Inhibitory Concentration ◽  
Interaction Mechanism ◽  
Docking Studies ◽  
Prosopis Juliflora ◽  
Cholinesterase Inhibition ◽  
In Silico Studies ◽  
Pi Interactions

Abstract We investigated the in vitro acaricide activity of the methanolic extract (ME) and alkaloid-rich fraction (AF) of Prosopis juliflora on Rhipicephalus microplus and correlated this effect with acetylcholinesterase (AChE) inhibition. The acaricide activity was evaluated using adult and larval immersion tests. Also, we studied the possible interaction mechanism of the major alkaloids present in this fraction via molecular docking at the active site of R. microplus AChE1 (RmAChE1). Higher reproductive inhibitory activity of the AF was recorded, with effective concentration (EC50) four times lower than that of the ME (31.6 versus 121 mg/mL). The AF caused mortality of tick larvae, with lethal concentration 50% (LC50) of 13.8 mg/mL. Both ME and AF were seen to have anticholinesterase activity on AChE of R. microplus larvae, while AF was more active with half-maximal inhibitory concentration (IC50) of 0.041 mg/mL. The LC-MS/MS analyses on the AF led to identification of three alkaloids: prosopine (1), juliprosinine (2) and juliprosopine (3). The molecular docking studies revealed that these alkaloids had interactions at the active site of the RmAChE1, mainly relating to hydrogen bonds and cation-pi interactions. We concluded that the alkaloids of P. juliflora showed acaricide activity on R. microplus and acted through an anticholinesterase mechanism.

scholarly journals Discovery of [1,2,4]Triazole Derivatives as New Metallo-β-Lactamase Inhibitors

Molecules ◽  
2019 ◽  
Vol 25 (1) ◽  
pp. 56
Author(s):  
Chen Yuan ◽  
Jie Yan ◽  
Chen Song ◽  
Fan Yang ◽  
Chao Li ◽  
...  
Keyword(s):  
Public Health ◽  
Molecular Docking ◽  
Active Site ◽  
Inhibitory Concentration ◽  
Hydrophobic Interactions ◽  
Global Public Health ◽  
Triazole Derivatives ◽  
Potent Inhibition ◽  
Zinc Coordination

The emergence and spread of metallo-β-lactamase (MBL)-mediated resistance to β-lactam antibacterials has already threatened the global public health. A clinically useful MBL inhibitor that can reverse β-lactam resistance has not been established yet. We here report a series of [1,2,4]triazole derivatives and analogs, which displayed inhibition to the clinically relevant subclass B1 (Verona integron-encoded MBL-2) VIM-2. 3-(4-Bromophenyl)-6,7-dihydro-5H-[1,2,4]triazolo [3,4-b][1,3]thiazine (5l) manifested the most potent inhibition with an IC50 (half-maximal inhibitory concentration) value of 38.36 μM. Investigations of 5l against other B1 MBLs and the serine β-lactamases (SBLs) revealed the selectivity to VIM-2. Molecular docking analyses suggested that 5l bound to the VIM-2 active site via the triazole involving zinc coordination and made hydrophobic interactions with the residues Phe61 and Tyr67 on the flexible L1 loop. This work provided new triazole-based MBL inhibitors and may aid efforts to develop new types of inhibitors combating MBL-mediated resistance.

scholarly journals Anti-TB Evaluation of Novel 2,3-Dihydroquinazolin-4(1H)-Ones and in Silico Studies of The Active Compounds

2021 ◽  
Author(s):  
Apurba Dutta ◽  
Priyanka Trivedi ◽  
Dipshikha Gogoi ◽  
Pankaj Chetia ◽  
Vinita Chaturvedi ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Molecular Docking ◽  
Minimum Inhibitory Concentration ◽  
Active Site ◽  
In Silico ◽  
Inhibitory Concentration ◽  
Acyl Carrier Protein ◽  
Carrier Protein ◽  
In Silico Studies

Abstract In vitro anti-tubercular activity of a series of 15 novel 2,3-dihydroquinazolin-4(1H)-one analogues were evaluated against Mycobacterium tuberculosis H37Ra (ATCC 25177 strain). Among the series, seven compounds showed moderate to good anti-TB activity with minimum inhibitory concentration (MIC) values ranging from 25.0-12.5 μg/mL. Further, in silico experiments were carried out to identify the probable ligand-protein interaction. Molecular docking of the target compounds into the active site of enzymes 1DQY Antigen 85C from Mycobacterium Tuberculosis and 2NSD Enoyl Acyl Carrier Protein Reductase reveals notable information on the possible binding interactions.

Natural Tyrosinase Inhibitors: Role of Herbals in the Treatment of Hyperpigmentary Disorders

2019 ◽  
Vol 19 (10) ◽  
pp. 796-808 ◽  
Author(s):  
Kamal Uddin Zaidi ◽  
Sharique A. Ali ◽  
Ayesha Ali ◽  
Ishrat Naaz
Keyword(s):  
Critical Role ◽  
Enzymatic Browning ◽  
Melanin Production ◽  
Natural Sources ◽  
Pigmentary Disorders ◽  
Normal Manner ◽  
Abnormal Accumulation ◽  
Current Article ◽  
Tyrosinase Inhibitors

Cutaneous pigmentation plays critical role in determining the color of skin along with photo protection of skin from dreadful effects of ultraviolet radiations. Conversely, abnormal accumulation of melanin is responsible for hyper pigmentary disorders such as melasma, senile lentigines and freckles. Because of the visible nature of dermatologic diseases, they have a considerable psychosomatic effect on affected patients. Tyrosinase inhibitors are molecules that interrelate in some way with the enzyme to prevent it from working in the normal manner. Past many decades witnessed the quest for the development of natural tyrosinase inhibitors due to imperative role played by tyrosinase in the process of melanogenesis and fungi or fruit enzymatic browning. Mechanism of pigmentation is characterized by the intact process of the synthesis of specialized black pigment within melanosomes. Melanin is synthesized by a cascade of enzymatic and chemical reactions. For this reason, melanin production is mainly controlled by the expression and activation of tyrosinase. In the current article, we discussed tyrosinase inhibitors from the natural sources, which can be an essential constituent of cosmetics products and depigmenting agents for the treatment of hyperpigmentory disorders.

Novel Piperazine Amides of Cinnamic Acid Derivatives as Tyrosinase Inhibitors

2018 ◽  
Vol 16 (1) ◽  
pp. 36-44 ◽  
Author(s):  
Zehra Tuğçe Gür ◽  
Fatma Sezer Şenol ◽  
Suhaib Shekfeh ◽  
İlkay Erdoğan Orhan ◽  
Erden Banoğlu ◽  
...  
Keyword(s):  
Cinnamic Acid ◽  
Active Site ◽  
Agaricus Bisporus ◽  
Biological Activities ◽  
Docking Simulation ◽  
Cinnamic Acid Derivatives ◽  
In Silico Docking ◽  
Amide Derivatives ◽  
Tyrosinase Inhibitors ◽  
Further Development

Background: A series of novel cinnamic acid piperazine amide derivatives has been designed and synthesized, and their biological activities were also evaluated as potential tyrosinase inhibitors. Methods: Compounds 9, 11 and 17 showed the most potent biological activity (IC50 = 66.5, 61.1 and 66 µM, respectively). In silico docking simulation was performed to position compound 11 into the Agaricus bisporus mushroom tyrosinase’s active site to determine the putative binding interactions. Results and Conclusion: The results indicated that compound 11 could serve as a promising lead compound for further development of potent tyrosinase inhibitors.

Structure-Based Design, Synthesis, Biological Evaluation and Molecular Docking Study of 4-Hydroxy-N'-methylenebenzohydrazide Derivatives Acting as Tyrosinase Inhibitors with Potentiate Anti-Melanogenesis Activities

2020 ◽  
Vol 16 (7) ◽  
pp. 892-902 ◽  
Author(s):  
Aida Iraji ◽  
Mahsima Khoshneviszadeh ◽  
Pegah Bakhshizadeh ◽  
Najmeh Edraki ◽  
Mehdi Khoshneviszadeh
Keyword(s):  
Molecular Docking ◽  
Active Site ◽  
Competitive Inhibition ◽  
Docking Study ◽  
Biological Evaluation ◽  
Primary Response ◽  
Ratio Method ◽  
Molecular Docking Study ◽  
Metal Chelating

Background: Melanogenesis is a process of melanin synthesis, which is a primary response for the pigmentation of human skin. Tyrosinase is a key enzyme, which catalyzes a ratelimiting step of the melanin formation. Natural products have shown potent inhibitors, but some of these possess toxicity. Numerous synthetic inhibitors have been developed in recent years may lead to the potent anti– tyrosinase agents. Objective: A number of 4-hydroxy-N'-methylenebenzohydrazide analogues with related structure to chalcone and tyrosine were constructed with various substituents at the benzyl ring of the molecule and evaluate as a tyrosinase inhibitor. In addition, computational analysis and metal chelating potential have been evaluated. Methods: Design and synthesized compounds were evaluated for activity against mushroom tyrosinase. The metal chelating capacity of the potent compound was examined using the mole ratio method. Molecular docking of the synthesized compounds was carried out into the tyrosine active site. Results: Novel 4-hydroxy-N'-methylenebenzohydrazide derivatives were synthesized. The two compounds 4c and 4g showed an IC50 near the positive control, led to a drastic inhibition of tyrosinase. Confirming in vitro results were performed via the molecular docking analysis demonstrating hydrogen bound interactions of potent compounds with histatidine-Cu+2 residues with in the active site. Kinetic study of compound 4g showed competitive inhibition towards tyrosinase. Metal chelating assay indicates the mole fraction of 1:2 stoichiometry of the 4g-Cu2+ complex. Conclusion: The findings in the present study demonstrate that 4-Hydroxy-N'- methylenebenzohydrazide scaffold could be regarded as a bioactive core inhibitor of tyrosinase and can be used as an inspiration for further studies in this area.

Evaluation of Cytotoxic and Tyrosinase Inhibitory Activities of 2-phenoxy(thiomethyl) pyridotriazolopyrimidines: In Vitro and Molecular Docking Studies

2020 ◽  
Vol 20 (14) ◽  
pp. 1714-1721
Author(s):  
Hatem A. Abuelizz ◽  
El Hassane Anouar ◽  
Mohamed Marzouk ◽  
Mizaton H. Hasan ◽  
Siti R. Saleh ◽  
...  
Keyword(s):  
Molecular Docking ◽  
Kojic Acid ◽  
Docking Studies ◽  
Breast Adenocarcinoma ◽  
Amino Acid Residues ◽  
New Class ◽  
Structure Activity ◽  
Tyrosinase Inhibitors ◽  
Mcf 7

Background: The use of tyrosinase has confirmed to be the best means of recognizing safe, effective, and potent tyrosinase inhibitors for whitening skin. Twenty-four 2-phenoxy(thiomethyl)pyridotriazolopyrimidines were synthesized and characterized in our previous studies. Objective: The present work aimed to evaluate their cytotoxicity against HepG2 (hepatocellular carcinoma), A549 (pulmonary adenocarcinoma), MCF-7 (breast adenocarcinoma) and WRL 68 (embryonic liver) cell lines. Methods: MTT assay was employed to investigate the cytotoxicity, and a tyrosinase inhibitor screening kit was used to evaluate the Tyrosinase (TYR) inhibitory activity of the targets. Results: The tested compounds exhibited no considerable cytotoxicity, and nine of them were selected for a tyrosinase inhibitory test. Compounds 2b, 2m, and 5a showed good inhibitory percentages against TYR compared to that of kojic acid (reference substance). Molecular docking was performed to rationalize the Structure-Activity Relationship (SAR) of the target pyridotriazolopyrimidines and analyze the binding between the docked-selected compounds and the amino acid residues in the active site of tyrosinase. Conclusion: The target pyridotriazolopyrimidines were identified as a new class of tyrosinase inhibitors.

The Molecular and Enzyme Kinetic Basis for Altered Activity of Three Cytochrome P450 2C19 Variants Found in the Chinese Population

2020 ◽  
Vol 13 (3) ◽  
pp. 233-244
Author(s):  
Amelia Nathania Dong ◽  
Nafees Ahemad ◽  
Yan Pan ◽  
Uma Devi Palanisamy ◽  
Beow Chin Yiap ◽  
...  
Keyword(s):  
Cytochrome P450 ◽  
Molecular Docking ◽  
Active Site ◽  
Chinese Population ◽  
Accessible Surface Area ◽  
Solvent Accessible Surface Area ◽  
In Vitro Assays ◽  
Access Channel ◽  
Cytochrome P450 2C19

Background: There is a large inter-individual variation in cytochrome P450 2C19 (CYP2C19) activity. The variability can be caused by the genetic polymorphism of CYP2C19 gene. This study aimed to investigate the molecular and kinetics basis for activity changes in three alleles including CYP2C19*23, CYP2C19*24 and CYP2C19*25found in the Chinese population. Methods: The three variants expressed by bacteria were investigated using substrate (omeprazole and 3- cyano-7-ethoxycoumarin[CEC]) and inhibitor (ketoconazole, fluoxetine, sertraline and loratadine) probes in enzyme assays along with molecular docking. Results: All alleles exhibited very low enzyme activity and affinity towards omeprazole and CEC (6.1% or less in intrinsic clearance). The inhibition studies with the four inhibitors, however, suggested that mutations in different variants have a tendency to cause enhanced binding (reduced IC50 values). The enhanced binding could partially be explained by the lower polar solvent accessible surface area of the inhibitors relative to the substrates. Molecular docking indicated that G91R, R335Q and F448L, the unique mutations in the alleles, have caused slight alteration in the substrate access channel morphology and a more compact active site cavity hence affecting ligand access and binding. It is likely that these structural alterations in CYP2C19 proteins have caused ligand-specific alteration in catalytic and inhibitory specificities as observed in the in vitro assays. Conclusion: This study indicates that CYP2C19 variant selectivity for ligands was not solely governed by mutation-induced modifications in the active site architecture, but the intrinsic properties of the probe compounds also played a vital role.

scholarly journals Inhibitory Effects of Cycloheterophyllin on Melanin Synthesis

Molecules ◽  
2021 ◽  
Vol 26 (9) ◽  
pp. 2526
Author(s):  
Joong-Hyun Shim
Keyword(s):  
Functional Materials ◽  
Tyrosinase Activity ◽  
Melanin Synthesis ◽  
Activity Assay ◽  
Inhibitory Effects ◽  
Melanin Production ◽  
Messenger Ribonucleic Acid ◽  
B16f10 Cells ◽  
Cell Line Cell ◽  
Tyrosinase Related Protein

This study was performed to clarify the inhibitory effects of cycloheterophyllin on melanin synthesis. In order to elucidate the inhibitory effects of cycloheterophyllin on the B16F10 cell line, cell viability, messenger ribonucleic acid (mRNA) expressions, tyrosinase activity assay, and melanin production assay were measured. The effects of cycloheterophyllin on tyrosinase-related protein 1 (TYRP1)/TYRP2/tyrosinase (TYR)/microphthalmia-associated transcription factor (MITF) mRNA expressions and melanin content were determined. Quantitative real-time RT-PCR showed that cycloheterophyllin decreased the mRNA expression level of TYRP1/TYRP2/TYR/MITF genes and melanin production contents than α-MSH-treated B16F10 cells. The tyrosinase activity assay revealed that cycloheterophyllin decreased the melanin production in the B16F10 cells. These data show that cycloheterophyllin increases the whitening effects in the B16F10 cells; thus, cycloheterophyllin is a potent ingredient for skin whitening. Thus, further research on the mechanism of action of cycloheterophyllin for the development of functional materials should be investigated.

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