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Structure-Based Design, Synthesis, Biological Evaluation and Molecular Docking Study of 4-Hydroxy-N'-methylenebenzohydrazide Derivatives Acting as Tyrosinase Inhibitors as Potentiate Anti-Melanogenesis Activities

Author(s):

Aida Iraji, Mahsima Khoshneviszadeh, Pegah Bakhshizadeh, Najmeh Edraki* and Mehdi Khoshneviszadeh  

Abstract:


Background: Melanogenesis is a process of melanin synthesize, which is a primary response for the pigmentation of human skin. Tyrosinase is a key enzyme, which catalyzes a rate-limiting 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 benzyl ring of the molecule and evaluate as tyrosinase inhibitor. In addition, computational analysis and metal chelatory potential have been evaluated.

Method: Design and synthesized compounds were evaluated for activity against mushroom tyrosinase. The metal chelatory capacity of potent compound was examined using mole ratio method. Molecular docking of the synthesized compounds were carried out into the tyrosine active site.

Result: 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 of in vitro results were performed via 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 chelatory assay indicate 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.

Keywords:

Structure-based design, Tyrosinase inhibitor, 4-hydroxy-N`-methylene benzo hydrazide, Molecular docking, Metal chelatation

Affiliation:

Medicinal and Natural Products Chemistry Research Center, Shiraz University of Medical Sciences, Shiraz, Medicinal and Natural Products Chemistry Research Center, Shiraz University of Medical Sciences, Shiraz, Medicinal and Natural Products Chemistry Research Center, Shiraz University of Medical Sciences, Shiraz, Medicinal and Natural Products Chemistry Research Center, Shiraz University of Medical Sciences, Shiraz, Medicinal and Natural Products Chemistry Research Center, Shiraz University of Medical Sciences, Shiraz



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