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.
Highlights
Tyrosinase a copper containing metalloenzymemediating the o-hydroxylation of monophenols to catechols and the subsequent two-electron oxidation to quinines [1]
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 abnormal accumulation of melaninin keratinocytes caused melasma and post-inflammatory disorders for which patients pursue treatment [15].A number of other melanocytedisorders like senile lentigo, freckles and pigmented acne scars occur in human of all races worldwide[16].Hyperpigmetationdisorders adversely affect person’s psychological and social well-beingwhich results in lower output, overall performance, and self-confidence [17].Tyrosinasecan be linked to neurodegenerative diseases owing to excessive production ofdopaquinonesbyoxidation of dopamine results in neuronal damage and cell death [18,19,20].It has been reported that tyrosinase is responsible for quicker degradation and lesser shelf life of fruits and vegetables during postharvest handling and processing [21,22,23].The therapeutics used currently to treat hyperpigmentation disorders generally associated with side effects
Summary
Tyrosinase a copper containing metalloenzymemediating the o-hydroxylation of monophenols to catechols and the subsequent two-electron oxidation to quinines [1]. The derivatives 4c and 6b 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.
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