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

Abstract

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.

Natural and Bioinspired Phenolic Compounds as Tyrosinase Inhibitors for the Treatment of Skin Hyperpigmentation: Recent Advances

“…Rather low IC50 values have been determined also for resveratrol derivatives such as (E)-2,3-bis(4-hydroxyphenyl)acrylonitrile (IC50 = 5.06 μM) [169] and dihydrooxyresveratrol glucosides [170] (Figure 19). As to other natural phenol-inspired synthetic compounds [157][158][159][160][161], the best results have been reported for a carvacrol derivative containing a 3,5-dihydroxyphenyl moiety (IC 50 = 0.0167 µM) [159] ( Figure 19). Good inhibition properties have been exhibited also by some rhododendrol glycosides (IC 50 = 0.56-9.15 µM) [160] and eugenol derivatives (IC 50 ca.…”

“…Interactions with specific amino acids in the tyrosinase binding pocket has been predicted also for synthetic inhibitors, such as hydroxylated chalcone derivatives [151,155], 2-(3, 4-dihydroxybenzylidene) malononitrile [215], or carvacrol derivatives featuring a 2,4-dihydroxyphenyl moiety, able to interact with amino acid HIS85 through the 2-hydroxy group [159]. Other important structural requirements have been also underlined: for example, a three carbons tether with a diamide-link in dimeric cynnamoyl analogues is required to efficiently inhibit melanin production on α-MSH stimulated B16F1 cells [139].…”

Tyrosinase Inhibitors from Natural and Synthetic Sources as Skin-lightening Agents

“…Carvacrol is a naturally occurring monoterpene phenol, having odoriferous and antimicrobial activities, used as meat preservatives or flavoring agents in the food industry. Ashraf et al (2017) synthesized carvacrol derivatives 1-6 (benzoic acid substituted) and 7-10 (cinnamic acid substituted), with the aim to possess potent tyrosinase inhibitory activity (Figure 8). Among the deriva- tivecompounds, 9(2-[2-methyl-5-(propan-2-yl)phenoxy]-2-oxoethyl(2E)-3-(2,4dihydroxyphenyl)prop-2-enoate) found to possess https://dx.doi.org/10.7831/ras.7.41 48 ©2019 Reviews in Agricultural Science strongest anti-tyrosinase activity (IC 50 0.0167μM) compare with standard kojic acid (IC 50 16.69μM).…”

Isotope effects in mechanistic studies of l-tyrosine halogen derivatives hydroxylation catalyzed by tyrosinase

“…3′-Iodo- l -Tyr may bond, not only with free enzyme, but also with enzyme–substrate complex. That type of inhibition of tyrosinase is known in literature for some carvacrol derivatives and terephthalic acid [ 22 , 23 ].…”