Synthesis and tyrosinase inhibitory activities of 4-oxobutanoate derivatives of carvacrol and thymol.
Ontology highlight
ABSTRACT:
SUBMITTER: Brotzman N
PROVIDER: S-EPMC7059125 | biostudies-literature | 2019 Jan
REPOSITORIES: biostudies-literature
Publications
Synthesis and tyrosinase inhibitory activities of 4-oxobutanoate derivatives of carvacrol and thymol.
Brotzman Nicholas N Xu Yiming Y Graybill Allison A Cocolas Alexander A Ressler Andrew A Seeram Navindra P NP Ma Hang H Henry Geneive E GE
Bioorganic & medicinal chemistry letters 20181108 1
Carvacrol (1) and thymol (2) were converted to their alkyl 4-oxobutanoate derivatives (7-20) in three steps, and evaluated for tyrosinase inhibitory activity. The compounds showed structure-dependent activity, with all alkyl 4-oxobutanoates, except 7 and 20, showing better inhibitory activity than the precursor 4-oxobutanoic acids (5 and 6). In general, thymol derivatives exhibited a higher percent inhibitory activity than carvacrol derivatives at 500 μM. Derivatives containing three-carbon and ...[more]
Similar Datasets
Project description:The present work describesthe development of highly potent mushroom tyrosinase inhibitor better than the standard kojic acid. Carvacrol derivatives 4a-f and 6a-d having substituted benzoic acid and cinnamic acidresidues were synthesized with the aim to possess potent tyrosinase inhibitory activity.The structures of the synthesized compounds were ascertained by their spectroscopic data (FTIR, 1HNMR, 13CNMR and Mass Spectroscopy).Mushroom tyrosinase inhibitory activity of synthesized compounds was determined and it was found that one of the derivative 6c possess higher activity (IC50 0.0167?M) than standard kojic acid (IC50 16.69?M). The derivatives 4c and 6b also showed good tyrosinase inhibitory activity with (IC50 16.69?M) and (IC50 16.69?M) respectively.Lineweaver-Burk and Dixon plots were used for the determination of kinetic mechanism of the compounds 4c and 6b and 6c. The kinetic analysis revealed that compounds 4c and 6b showed mixed-type inhibition while 6c is a non-competitive inhibitor having Ki values19 ?M, 10 ?M, and 0.05 ?Mrespectively. The enzyme inhibitory kinetics further showed thatcompounds 6b and 6c formed irreversible enzyme inhibitor complex while 4c bind reversibly with mushroom tyrosinase.The docking studies showed that compound 6c have maximum binding affinity against mushroom tyrosinase (PDBID: 2Y9X) with binding energy value (-7.90 kcal/mol) as compared to others.The 2-hydroxy group in compound 6c interacts with amino acid HIS85 which is present in active binding site. The wet lab results are in good agreement with the dry lab findings.Based upon our investigation we may propose that the compound 6c is promising candidate for the development of safe cosmetic agent.
| S-EPMC5441849 | biostudies-literature
Project description: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.
| S-EPMC8122972 | biostudies-literature
Project description:In the present study, new Schiff's base derivatives: (Z)-4-amino-5-(2-(3- fluorobenzylidene)hydrazinyl)-4H-1,2,4-triazole-3-thiol (Y1), (Z)-3-((2-(4-amino-5- mercapto-4H-1,2,4-triazol-3-yl)hydrazono)methyl)phenol (Y2), (Z)-2-((2-(4-amino-5- mercapto-4H-1,2,4-triazol-3-yl)hydrazono)methyl)phenol (Y3) and 3-((Z)-(2-(4- (((E)-3-hydroxybenzylidene)amino)-5-mercapto-4H-1,2,4-triazol-3-yl)hydrazono)methyl)phenol (Y4) were synthesized and their structures were characterized by LC-MS, IR and 1H NMR. The inhibitory effects of these compounds on tyrosinase activites were evaluated. Compounds Y1, Y2 and Y3 showed potent inhibitory effects with respective IC50 value of 12.5, 7.0 and 1.5 ?M on the diphenolase activities. Moreover, the inhibition mechanisms were determined to be reversible and mixed types. Interactions of the compounds with tyrosinase were further analyzed by fluorescence quenching, copper interaction, and molecular simulation assays. The results together with the anti-tyrosinase activities data indicated that substitution on the second position of benzene ring showed superior ant-ityrosinase activities than that on third position, and that hydroxyl substitutes were better than fluorine substitutes. In addition, two benzene rings connecting to the triazole ring would produce larger steric hindrance, and affect the bonding between tyrosinase and inhibitors to decrease the inhibitory effects. The anti-tyrosinase effects of these compounds were in contrast to their antioxidant activities. In summary, this research will contribute to the development and design of antityrosinase agents.
| S-EPMC4589318 | biostudies-literature
Project description:In this study, a series of coumarin derivatives were synthesized and their inhibitory effects on the activity of mushroom tyrosinase were evaluated. As a result of measuring the inhibition of tyrosinase activity of these derivatives, the compounds 3e (1.05 μM), 3f (0.83 μM), 3h (0.85 μM), 3i (1.05 μM), and 3k (0.67 μM) of the geranyloxycoumarin derivatives were highly active at a concentration of 0.8%. The geranyloxycoumarin derivatives exhibited better activity than the hydroxycoumarin derivatives. Among the geranyloxycoumarin derivatives, compound 3k was two times more active than arbutin, a positive control, at a concentration of 0.4%. The above results suggest that geranyloxycoumarin derivatives have great potential for application as functional cosmetic ingredients with tyrosinase-inhibiting activity.
| S-EPMC8073051 | biostudies-literature
Project description:The anticoccidial activity of thymol, carvacrol, and saponins was assessed in an in vitro model of coccidiosis. Eimeria spp. sporozoites were collected from field samples, characterized, and used for 2 different invasion assays on Madin-Darby Bovine Kidney cells (MDBK). The cells were challenged with 5 × 104 sporozoites without (control) or with various treatments: saponins (10 ppm), thymol, and carvacrol (7 ppm each) or a combination of saponins, thymol, and carvacrol at 2 doses; MIX 1 (saponins 5 ppm, thymol 3.5 ppm, and carvacrol 3.5 ppm) and MIX 2 (saponins 10 ppm, thymol 7 ppm, and carvacrol 7 ppm). The treated cells were incubated at 37°C for 24 h (invasion assay 1) and for 2, 24, and 48 h (invasion assay 2). The efficiency of invasion was determined by counting the sporozoites left in the supernatant that were not able to invade the cells, whereas intracellular Eimeria DNA was detected by qPCR to confirm the data. Data were analyzed with ANOVA, and differences were considered significant when P value was ?0.05. Data from invasion assay 1 showed that the thymol and carvacrol-containing blends significantly reduced invasion, especially in combination with saponins at the highest dose. Saponins alone did not have a strong inhibiting activity but acted synergistically with the other molecules. Interestingly, in invasion assay 2, it was found that the effect of the highest dose of the blend of saponins, thymol, and carvacrol was already visible at 2 h postinfection, whereas the other treatments were significantly successful at 24 h postinfection. The invasion assay protocol was designed to screen molecules in vitro starting from field fecal samples, and it can represent a potential tool in Eimeria research. Moreover, this study shows that invasion in MDBK cells by Eimeria sporozoites is inhibited in presence of thymol, carvacrol, and saponins, thus highlighting the anticoccidial potential of these compounds.
| S-EPMC7647770 | biostudies-literature
Project description:Background: It is estimated that one in five people worldwide faces a diagnosis of a malignant neoplasm during their lifetime. Carvacrol and its isomer, thymol, are natural compounds that act against several diseases, including cancer. Thus, this systematic review aimed to examine and synthesize the knowledge on the antitumor effects of carvacrol and thymol. Methods: A systematic literature search was carried out in the PubMed, Web of Science, Scopus and Lilacs databases in April 2020 (updated in March 2021) based on the PRISMA 2020 guidelines. The following combination of health descriptors, MeSH terms and their synonyms were used: carvacrol, thymol, antitumor, antineoplastic, anticancer, cytotoxicity, apoptosis, cell proliferation, in vitro and in vivo. To assess the risk of bias in in vivo studies, the SYRCLE Risk of Bias tool was used, and for in vitro studies, a modified version was used. Results: A total of 1,170 records were identified, with 77 meeting the established criteria. The studies were published between 2003 and 2021, with 69 being in vitro and 10 in vivo. Forty-three used carvacrol, 19 thymol, and 15 studies tested both monoterpenes. It was attested that carvacrol and thymol induced apoptosis, cytotoxicity, cell cycle arrest, antimetastatic activity, and also displayed different antiproliferative effects and inhibition of signaling pathways (MAPKs and PI3K/AKT/mTOR). Conclusions: Carvacrol and thymol exhibited antitumor and antiproliferative activity through several signaling pathways. In vitro, carvacrol appears to be more potent than thymol. However, further in vivo studies with robust methodology are required to define a standard and safe dose, determine their toxic or side effects, and clarify its exact mechanisms of action. This systematic review was registered in the PROSPERO database (CRD42020176736) and the protocol is available at https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=176736.
| S-EPMC8293693 | biostudies-literature
Project description:The impaired activity of tyrosinase and laccase can provoke serious concerns in the life cycles of mammals, insects and microorganisms. Investigation of inhibitors of these two enzymes may lead to the discovery of whitening agents, medicinal products, anti-browning substances and compounds for controlling harmful insects and bacteria. A small collection of novel reversible tyrosinase and laccase inhibitors with a phenylpropanoid and hydroxylated biphenyl core was prepared using naturally occurring compounds and their activity was measured by spectrophotometric and electrochemical assays. Biosensors based on tyrosinase and laccase enzymes were constructed and used to detect the type of protein-ligand interaction and half maximal inhibitory concentration (IC50). Most of the inhibitors showed an IC50 in a range of 20-423 nM for tyrosinase and 23-2619 nM for laccase. Due to the safety concerns of conventional tyrosinase and laccase inhibitors, the viability of the new compounds was assayed on PC12 cells, four of which showed a viability of roughly 80% at 40 µM. In silico studies on the crystal structure of laccase enzyme identified a hydroxylated biphenyl bearing a prenylated chain as the lead structure, which activated strong and effective interactions at the active site of the enzyme. These data were confirmed by in vivo experiments performed on the insect model Tenebrio molitur.
| S-EPMC7321210 | biostudies-literature
Project description:Boswellia carterii have been used in traditional medicine for many years for management different gastrointestinal disorders. In this study, we wish to report urease inhibitory activity of four isolated compound of boswellic acid derivative.4 pentacyclic triterpenoid acids were isolated from Boswellia carterii and identified by NMR and Mass spectroscopic analysis (compounds 1, 3-O-acetyl-9,11-dehydro-?-boswellic acid; 2, 3-O-acetyl-11-hydroxy-?-boswellic acid; 3. 3-O- acetyl-11-keto-?-boswellic acid and 4, 11-keto-?-boswellic acid. Their inhibitory activity on Jack bean urease were evaluated. Docking and pharmacophore analysis using AutoDock 4.2 and Ligandscout 3.03 programs were also performed to explain possible mechanism of interaction between isolated compounds and urease enzyme.It was found that compound 1 has the strongest inhibitory activity against Jack bean urease (IC50?=?6.27?±?0.03 ?M), compared with thiourea as a standard inhibitor (IC50?=?21.1?±?0.3 ?M).The inhibition potency is probably due to the formation of appropriate hydrogen bonds and hydrophobic interactions between the investigated compounds and urease enzyme active site and confirms its traditional usage.
| S-EPMC3575251 | biostudies-literature
Project description:The remarkable biological activities of oregano essential oils (EOs) have recently prompted a host of studies aimed at exploring their potential innovative applications in the food and pharmaceutical industries. The chemical composition and biological activities of EOs from two Origanum vulgare genotypes, widely cultivated in Sicily and not previously studied for their biological properties, were characterized. Plants of the two genotypes, belonging to the carvacrol (CAR) and thymol (THY) chemotypes and grown in different cultivation environments, were considered for this study. The chemical profiles, including the determination of enantiomeric distribution, of the EOs, obtained by hydrodistillation from dried leaves and flowers, were investigated by GC-MS. Biological activity was evaluated as antimicrobial properties against different pathogen indicator strains, while intestinal barrier integrity, reduction in pathogen adhesion and anti-inflammatory actions were assayed in the intestinal Caco-2 cell line. The chemical profile of the CAR genotype was less complex and characterized by higher levels of the most active compound, i.e., carvacrol, when compared to the THY genotype. The enantiomeric distribution of chiral constituents did not vary across genotypes, while being markedly different from that observed in Origanum vulgare genotypes from other geographical origins. In general, all EOs showed high antimicrobial activity, both in vitro and in a food matrix challenge test. Representative EOs from the two genotypes resulted not altering epithelial monolayer sealing only for concentrations lower than 0.02%, were able to reduce the adhesion of selected pathogens, but did not exert relevant anti-inflammatory effects. These results suggest their potential use as control agents against a wide spectrum of foodborne pathogens.
| S-EPMC10059975 | biostudies-literature
Project description:Some Salmonella enterica serovars are frequently associated with disease outbreaks in low-moisture foods (LMF) due to their ability to adapt efficiently to desiccation stress. These serovars are often persistent during food processing. Disruption of these resistance responses was accomplished previously using the membrane-active lipopeptide, paenibacterin. This study was initiated to determine how desiccation resistance mechanisms are overcome when Salmonella Tennessee, a known resistant serovar, is treated with the membrane-active food additives carvacrol and thymol. Knowing that the minimum inhibitory concentrations (MICs) of carvacrol and thymol against Salmonella Tennessee are 200 and 100 µg/mL, the concentrations tested were 100-400 and 50-200 µg/mL, respectively. Results show that desiccation-adapted Salmonella Tennessee, prepared by air drying at 40% relative humidity and 22-25 °C for 24 h, was not inactivated when exposed for 4.0 h to less than 2xMIC of the two additives. Additionally, treatment of desiccation-adapted Salmonella Tennessee for 120 min with carvacrol and thymol at the MIC-level sensitized the cells (1.4-1.5 log CFU/mL reduction) to further desiccation stress. Treating desiccation-adapted Salmonella Tennessee with carvacrol and thymol induced leakage of intracellular potassium ions, reduced the biosynthesis of the osmoprotectant trehalose, reduced respiratory activity, decreased ATP production, and caused leakage of intracellular proteins and nucleic acids. Carvacrol, at 200-400 µg/mL, significantly downregulated the transcription of desiccation-related genes (proV, STM1494, and kdpA) as determined by the reverse-transcription quantitative PCR. The current study revealed some of the mechanisms by which carvacrol and thymol combat desiccation-resistant Salmonella Tennessee, raising the feasibility of using these additives to control desiccation-adapted S. enterica in LMF.
| S-EPMC8779931 | biostudies-literature