Kinetic and in silico studies of novel hydroxy-based thymol analogues as inhibitors of mushroom tyrosinase

Ashraf, Zaman; Rafiq, Muhammad; Seo, Sung‐Yum; Kwon, Kang Sung; Babar, Mustafeez Mujtaba; Zaidi, Najam‐us‐Sahar Sadaf

doi:10.1016/j.ejmech.2015.05.031

Cited by 65 publications

(45 citation statements)

References 35 publications

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“…The carvacrol derivatives 4c, 6b and 6c were selected to determine their kinetic mechanism of enzyme inhibition.A series of experiments were performed to determine the inhibition kinetics by following the already reported method [42–43]. Inhibitor 6b with concentrations 0.0, 7.0, 28 μM, in case of Lineweaver-Burk plot and with concentrations0.0, 1.75, 7.0, 14.0, 28 μM in case of Dixon plot was used respectively.…”

Section: Methodsmentioning

confidence: 99%

Carvacrol derivatives as mushroom tyrosinase inhibitors; synthesis, kinetics mechanism and molecular docking studies

et al. 2017

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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 0.0167μM) than standard kojic acid (IC50 16.69μM). The derivatives 4c and 6b also showed good tyrosinase inhibitory activity with (IC50 16.69μM) and (IC50 16.69μM) 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 μM, 10 μM, and 0.05 μMrespectively. 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.

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Section: Methodsmentioning

confidence: 99%

Carvacrol derivatives as mushroom tyrosinase inhibitors; synthesis, kinetics mechanism and molecular docking studies

et al. 2017

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“…Dexibuprofen–antioxidants mutual prodrugs have been synthesized by following the previously reported method with slight modification [20]. For the first time natural antioxidants menthol, sesamol and umbelliferon were used for the preparation of mutual prodrugs of dexibuprofen.…”

Section: Resultsmentioning

confidence: 99%

Synthesis, Bioevaluation and Molecular Dynamic Simulation Studies of Dexibuprofen–Antioxidant Mutual Prodrugs

Ashraf

Alamgeer

Rasool

et al. 2016

IJMS

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Dexibuprofen–antioxidant conjugates were synthesized with the aim to reduce its gastrointestinal effects. The esters analogs of dexibuprofen 5a–c were obtained by reacting its –COOH group with chloroacetyl derivatives 3a–c. The in vitro hydrolysis data confirmed that synthesized prodrugs 5a–c were stable in stomach while undergo significant hydrolysis in 80% human plasma and thus release free dexibuprofen. The minimum reversion was observed at pH 1.2 suggesting that prodrugs are less irritating to stomach than dexibuprofen. The anti-inflammatory activity of 5c (p < 0.001) is more significant than the parent dexibuprofen. The prodrug 5c produced maximum inhibition (42.06%) of paw-edema against egg-albumin induced inflammation in mice. Anti-pyretic effects in mice indicated that prodrugs 5a and 5b showed significant inhibition of pyrexia (p < 0.001). The analgesic activity of 5a is more pronounced compared to other synthesized prodrugs. The mean percent inhibition indicated that the prodrug 5a was more active in decreasing the number of writhes induced by acetic acid than standard dexibuprofen. The ulcerogenic activity results assured that synthesized prodrugs produce less gastrointestinal adverse effects than dexibuprofen. The ex vivo antiplatelet aggregation activity results also confirmed that synthesized prodrugs are less irritant to gastrointestinal mucosa than the parent dexibuprofen. Molecular docking analysis showed that the prodrugs 5a–c interacts with the residues present in active binding sites of target protein. The stability of drug–target complexes is verified by molecular dynamic simulation study. It exhibited that synthesized prodrugs formed stable complexes with the COX-2 protein thus support our wet lab results. It is therefore concluded that the synthesized prodrugs have promising pharmacological activities with reduced gastrointestinal adverse effects than the parent drug.

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“…A series of experiments was performed to calculate the inhibitory kinetics of compounds 4c , 6a , 6b and 6d following the previously reported method 30. The compounds’ concentrations were as follows: 0, 3.125, 6.25 and 12.5 µM for 4c ; 0, 0.3915 and 0.783 µM for 6a ; 0, 0.453, 0.965, 1.813 and 3.626 µM for 6b ; and 0, 0.08, 0.16 and 0.32 µM for 6d .…”

Section: Methodsmentioning

confidence: 99%

Development of highly potent melanogenesis inhibitor by in vitro, in vivo and computational studies

Abbas

Ashraf

Hassan

et al. 2017

DDDT

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The present work describes the synthesis of few hydroxylated amide derivatives as melanogenesis inhibitors. In vitro, in vivo and computational studies proved that compound 6d is a highly potent melanogenesis inhibitor compared to standard kojic acid. The title amides 4a–e and 6a–e were synthesized following simple reaction routes with excellent yields. Most of the synthesized compounds exhibited good mushroom tyrosinase inhibitory activity, but compound 6d showed excellent activity (IC50 0.15 µM) compared to standard kojic acid (IC50 16.69 µM). Lineweaver–Burk plots were used for the determination of kinetic mechanism, and it was found that compounds 4c and 6d showed non-competitive inhibition while 6a and 6b showed mixed-type inhibition. The kinetic mechanism further revealed that compound 6d formed irreversible complex with the target enzyme tyrosinase. The Ki values determined for compounds 4c, 6a, 6b and 6d are 0.188, 0.84, 2.20 and 0.217 µM respectively. Results of human tyrosinase inhibitory activity in A375 human melanoma cells showed that compound 6d exhibited 91.9% inhibi-tory activity at a concentration of 50 µg/mL. In vivo cytotoxicity evaluation of compound 6d in zebrafish embryos showed that it is non-toxic to zebrafish. Melanin depigmentation assay performed in zebrafish indicated that compound 6d possessed greater potential in decreasing melanin contents compared to kojic acid at the same concentration. Computational studies also supported the wet lab findings as compound 6d showed a highest binding affinity with the target protein (PDBID: 2Y9X) with a binding energy value of −7.90 kcal/mol. Molecular dynamic simulation studies also proved that amide 6d formed the most stable complex with tyrosinase. Based upon our in vitro, in vivo and computational studies, we propose that compound 6d is a promising candidate for the development of safe cosmetic agent.

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Kinetic and in silico studies of novel hydroxy-based thymol analogues as inhibitors of mushroom tyrosinase

Cited by 65 publications

References 35 publications

Carvacrol derivatives as mushroom tyrosinase inhibitors; synthesis, kinetics mechanism and molecular docking studies

Carvacrol derivatives as mushroom tyrosinase inhibitors; synthesis, kinetics mechanism and molecular docking studies

Synthesis, Bioevaluation and Molecular Dynamic Simulation Studies of Dexibuprofen–Antioxidant Mutual Prodrugs

Development of highly potent melanogenesis inhibitor by in vitro, in vivo and computational studies

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