Synthesis, computational studies, tyrosinase inhibitory kinetics and antimelanogenic activity of hydroxy substituted 2-[(4-acetylphenyl)amino]-2-oxoethyl derivatives

Abstract

The over expression of melanogenic enzymes like tyrosinase caused many hyperpigmentaion disorders. The present work describes the synthesis of hydroxy substituted 2-[(4-acetylphenyl)amino]-2-oxoethyl derivatives 3a-e and 5a-e as antimelanogenic agents. The tyrosinase inhibitory activity of synthesized derivatives 3a-e and 5a-e was determined and it was found that derivative 5c possesses excellent activity with IC 50 ¼ 0.0089 mM compared to standard kojic acid (IC 50 ¼ 16.69 mM). The presence of hydroxyl groups at the ortho and the para position of cinnamic acid phenyl ring in compound 5c plays a vital role in tyrosinase inhibitory activity. The compound 5d also exhibited good activity (IC 50 ¼ 8.26 mM) compared to standard kojic acid. The enzyme inhibitory kinetics results showed that compound 5c is a competitive inhibitor while 5d is a mixed-type inhibitor. The mode of binding for compounds 5c and 5d with tyrosinase enzyme was also assessed and it was found that both derivatives irreversibly bind with target enzyme. The molecular docking and molecular dynamic simulation studies were also performed to find the position of attachment of synthesized compounds at tyrosinase enzyme (PDB ID 2Y9X). The results showed that all of the synthesized compounds bind well with the active binding sites and most potent derivative 5c formed stable complex with target protein. The cytotoxicity results showed that compound 5c is safe at a dose of 12 mg/mL against murine melanoma (B16F10) cells. The same dose of 5c was selected to determine antimelanogenic activity; the results showed that it produced antimelenogenic effects in murine melanoma (B16F10) cells. Based on our investigations, it was proposed that compound 5c may serve as a lead structure to design more potent antimelanogenic agents.

The Role of Anthocyanins, Deoxyanthocyanins and Pyranoanthocyanins on the Modulation of Tyrosinase Activity: An In Vitro and In Silico Approach

“…There were small energy discrepancies in the binding affinities predicted by docking and the IC50 values of all compounds. However similar differences were also observed in comparable docking studies [38,40,41]. The ac tive sites of mTYR and hTYRP1 enzymes are characterized by a binuclear metal center (Cu and Zn ions, respectively) coordinated by six histidine residues.…”

“…The interaction mode of the various pigments into the binding pockets of mTYR and hTYRP1 was also assessed by a molecular docking study. This computational technique has been successfully used to predict the binding of potential inhibitors to tyrosinase en zymes [38][39][40][41][42]. To validate the docking protocol, the crystallographic inhibitor tropolone was re-docked.…”

Assessment of the Pharmacological Properties and Phytochemical Profile of Bruguiera gymnorhiza (L.) Lam Using In Vitro Studies, In Silico Docking, and Multivariate Analysis

“…Melanin has multifaceted roles; apart from giving colour to the skin, it also acts as a skin photo-protector and convert harmful UV light into harmless heat. Despite its good side, an overproduction of melanin leads to numerous undesirable skin problems including melanoma, lentigo, and post-inflammatory hyperpigmentation frequently caused by eczema, acne, and psoriasis [49,50]. Melanin also has a questioning side.…”

Molecular Docking, Synthesis, and Tyrosinase Inhibition Activity of Acetophenone Amide: Potential Inhibitor of Melanogenesis

“…The tyrosinase inhibitory activity of acetophenone moiety has only been rarely reported [23]. Nazir et al and Rafiq et al reported that hydroxyl-substituted benzoic/cinnamic acid analogues exhibited potent tyrosinase inhibition [24,25].…”