Synthesis, biological evaluation, molecular docking, MD simulation and DFT analysis of new 3-hydroxypyridine-4-one...

In the present study, ten new substituted 3-hydroxypyridine-4-one derivatives were synthesized in a four-step method, and their chemical structures were confirmed using various spectroscopic techniques. Subsequently, the inhibitory activities of these derivatives against tyrosinase enzyme and their antioxidant activities were evaluated. Amongest the synthesized compounds, 6b bearing a 4-OH-3-OCH₃ substitution was found to be a promising tyrosinase inhibitor with an IC₅₀ value of 25.82 μM, which is comparable to the activity of kojic acid as control drug. Kinetic study indicated that compound 6b is a competitive inhibitor of tyrosinase enzyme, which was confirmed by molecular docking results. The molecular docking study and MD simulation showed that compound 6b was properly placed within the tyrosinase binding pocket and interacted with key residues, which is consistent with its biological activity. The DFT analysis demonstrated that compound 6b is kinetically more stable than the other compounds. In addition, compounds 6a and 6b exhibited the best antioxidant activities. The findings indicate that compound 6b could be a promising lead for further studies.