In the present work, novel 5‐((1‐benzyl‐1,2,3‐triazol‐4‐yl)methoxybenzylidene)‐2‐(arylamino)thiazol‐4‐one thiazolone incorporated triazole derivatives have been designed as tyrosinase inhibitors. The compounds were synthesized through click reaction in good yield. Moreover, the antityrosinas activity of the synthesized derivatives was evaluated. In the search for establishing a click copper‐catalyzed azide/alkyne cycloaddition (CuAAC) reaction under strict conditions, in terms of a novel air‐stable, a recyclable and efficient magnetic catalyst was planned for new triazole derivatives as a well‐organized copper iodide supported on the functionalized Fe3O4@SiO2 core‐shell (CuI/Fe3O4@SiO2(TMS‐EDTA) nanoparticles). The engineered nanocatalyst synthesized for the first time and characterized by different methods, including FT‐IR spectroscopy, XRD, FESEM, EDX, TEM, TGA, and BET analysis. The excellent catalytic performance in ethanol with high surface area (351.7 m2g−1) and short reaction time for diverse functional groups (120–200 min), no use of toxic solvents, reusability of the catalyst, and using eco‐friendly conditions are the advantageous of this work. Moreover,the nanocatalyst can be used at least five times without any significant decrease in the yield of the reaction. The thiazolidine‐triazole derivatives 9a, 9c, 9e, and 9 g showed promising tyrosinase inhibitory activity with IC50 values in the range of 5.90–9.81 μM. The compounds were found to be considerably more potent tyrosinase inhibitors than the reference inhibitor kojic acid (IC50 = 18.36 μM).
In this work, the synthesis of novel triazole derivatives with barbituric motifs in good yields is described. The alkyne was prepared through the Knoevenagel reaction of barbituric derivatives with ortho and para O-propargylated hydroxybenzaldehyde. The mechanism and regioselectivity of this [3+2] cycloaddition reaction were investigated using the density functional theory at the B3LYP/6-31+G(d) level of theory. The computational studies revealed that a di-copper catalyzed stepwise mechanism, involving six-membered ring intermediate, is the preferred pathway. The regioselectivity was explained in terms of frontier molecular orbital (FMO) interactions, local and global electrophilicity and nucleophilicity indices. Accordingly, the favored interactions for di-copper acetylide are in good agreement with the observed regioselectivity, while completely opposite results were obtained for a possible uncatalysed reaction.
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 IC 50 values of 24.6 ± 0.9 and 26.8 ± 0.8 μM, respectively. Almost all the compounds showed a good radical scavenging activity with EC 50 values in the range of 29.9-324.9 μM. Derivatives 7a, 8f, and 8h were the most potent free-radical scavengers with EC 50 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.
Evaluation of B3LYP/6-31G(d,p), wB97xD/6-31G(d,p) and M06-2X/6-31G(d,p) methods revealed the importance of π/π interactions in regio- and stereoselectivity of cycloaddition reactions.
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