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Biological and Cheminformatics Studies of Newly Designed Triazole Based Derivatives as Potent Inhibitors against Mushroom Tyrosinase

Summary

Researchers developed new chemical compounds based on triazole structures to inhibit tyrosinase, an enzyme that produces melanin in skin. One compound (9h) proved particularly effective at blocking this enzyme, working 170 times better than the standard drug kojic acid. Computer modeling showed how this compound fits into the enzyme’s active site. These findings could lead to safer and more effective treatments for skin discoloration disorders like melasma and age spots.

Background

Melanogenesis is controlled by the enzyme tyrosinase, which catalyzes melanin production. Excess melanin causes various skin disorders including hyperpigmentation, melasma, and melanoma. Existing tyrosinase inhibitors like hydroquinone and kojic acid have significant safety concerns and side effects.

Objective

To synthesize and evaluate a series of nine novel 1,2,4-triazole based compounds for their inhibitory activity against mushroom tyrosinase. To identify the most potent compounds and characterize their binding mechanisms through kinetic and molecular docking studies.

Results

Among nine compounds screened, compound 9h (N-(4-fluorophenyl)-2-(5-(2-fluorophenyl)-4-(4-fluorophenyl)-4H-1,2,4-triazol-3-ylthio) acetamide) showed the most prominent tyrosinase inhibitory activity with IC50 of 0.098 ± 0.009 µM, significantly superior to kojic acid (IC50 = 16.832 ± 1.161 µM). Kinetic analysis showed 9h competitively inhibits tyrosinase with Ki of 0.018 µM. Molecular docking revealed 9h forms hydrogen bonds with His263 in the active site.

Conclusion

The synthesized triazole derivatives demonstrated potent tyrosinase inhibitory activity with 9h as the most promising candidate. Structure-activity relationship analysis revealed that fluorine substitution at specific positions enhanced inhibitory activity. These compounds represent novel scaffolds for developing depigmentation agents and warrant further clinical investigation for melanogenesis-related disorders.
  • Published in:Molecules,
  • Study Type:Chemical Synthesis and Enzyme Inhibition Study,
  • Source: PMID: 35268831, DOI: 10.3390/molecules27051731
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