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

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 and as antimelanogenic agents. The tyrosinase inhibitory activity of synthesized derivatives and was determined and it was found that derivative possesses excellent activity with IC = 0.0089 µM compared to standard kojic acid (IC = 16.69 µM). The presence of hydroxyl groups at the and the position of cinnamic acid phenyl ring in compound plays a vital role in tyrosinase inhibitory activity. The compound also exhibited good activity (IC = 8.26 µM) compared to standard kojic acid. The enzyme inhibitory kinetics results showed that compound is a competitive inhibitor while is a mixed-type inhibitor. The mode of binding for compounds and 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 formed stable complex with target protein. The cytotoxicity results showed that compound is safe at a dose of 12 µg/mL against murine melanoma (B16F10) cells. The same dose of 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 may serve as a lead structure to design more potent antimelanogenic agents.