Background: Melanogenesis is a process of melanin synthesis, which is a primary response
for the pigmentation of human skin. Tyrosinase is a key enzyme, which catalyzes a ratelimiting
step of the melanin formation. Natural products have shown potent inhibitors, but some of
these possess toxicity. Numerous synthetic inhibitors have been developed in recent years may
lead to the potent anti– tyrosinase agents.
Objective: A number of 4-hydroxy-N'-methylenebenzohydrazide analogues with related structure
to chalcone and tyrosine were constructed with various substituents at the benzyl ring of the molecule
and evaluate as a tyrosinase inhibitor. In addition, computational analysis and metal chelating
potential have been evaluated.
Methods: Design and synthesized compounds were evaluated for activity against mushroom tyrosinase.
The metal chelating capacity of the potent compound was examined using the mole ratio
method. Molecular docking of the synthesized compounds was carried out into the tyrosine active
Results: Novel 4-hydroxy-N'-methylenebenzohydrazide derivatives were synthesized. The two
compounds 4c and 4g showed an IC50 near the positive control, led to a drastic inhibition of tyrosinase.
Confirming in vitro results were performed via the molecular docking analysis demonstrating
hydrogen bound interactions of potent compounds with histatidine-Cu+2 residues with in
the active site. Kinetic study of compound 4g showed competitive inhibition towards tyrosinase.
Metal chelating assay indicates the mole fraction of 1:2 stoichiometry of the 4g-Cu2+ complex.
Conclusion: The findings in the present study demonstrate that 4-Hydroxy-N'-
methylenebenzohydrazide scaffold could be regarded as a bioactive core inhibitor of tyrosinase
and can be used as an inspiration for further studies in this area.