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

摘要

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.