|
Abstract
|
In this study, benzyl-1,2,3-triazole-linked 5-benzylidene (thio)barbiturate derivatives 7a–d and 8a–h were designed as potential tyrosinase inhibitors and free-radical scavengers. The twelve derivatives were synthesized via the [3+2] cycloaddition reaction of the corresponding benzyl azide as a dipole and the corresponding alkyne as a dipolarophile in the presence of copper(I) species, generated in situ from copper(II)/ascorbate. The thiobarbiturate derivative 8h and the barbiturate derivative 8b bearing 4-fluoro and 4-bromo groups on the benzyl–triazole moiety were found to be the most potent tyrosinase inhibitors with IC50 values of 24.6 ± 0.9 and 26.8 ± 0.8 μM, respectively. Almost all the compounds showed a good radical scavenging activity with EC50 values in the range of 29.9–324.9 μM. Derivatives 7a, 8f, and 8h were the most potent free-radical scavengers with EC50 values of 29.9 ± 0.8, 36.8 ± 0.9, and 39.2 ± 1.1 μM, respectively. The kinetic analysis revealed that compound 8h was a mixed-type tyrosinase inhibitor. The molecular docking analysis indicated that 8b and 8h were well accommodated in the active site of the tyrosinase enzyme and possessed the most negative binding energy values of −8.55 and −8.81 kcal/mol, respectively. Moreover, it was found that the two residues, Asn81 and Glu322, played a significant role in forming stable enzyme–inhibitor complexes.
|