Design, synthesis, in silico ADME, DFT, molecular dynamics simulation, anti-tyrosinase, and antioxidant activity of some of the 3-hydroxypyridin-4-one hybrids in combination with acylhydrazone derivatives

Tyrosinase is the rate-limiting enzyme in synthesizing melanin. Melanin is responsible for changing the color of fruits and vegetables and protecting against skin photo-carcinogenesis. Herein, some of the hybrids of 3-hydroxypyridine-4-one and acylhydrazones were designed and synthesized to study the anti-tyrosinase and antioxidant activities. The diphenolase activity of mushroom tyrosinase using LDOPA assayed the inhibitory effects, and the antioxidant activity was assessed using DPPH free radical. The synthesized derivatives were confirmed using 1H-NMR, C-13-NMR, IR, and Mass spectroscopy. Among analogs, compound 5h bearing furan ring with IC50 = 8.94 lM was more potent than kojic acid (IC50 = 16.68 lM). The pharmacokinetic profile of the compounds showed that the tested compounds had suitable oral bioavailability and drug-likeness properties. The molecular docking studies showed that compound 5h was located in the tyrosinase-binding site. Also, the molecular dynamics simulation was performed on compound 5h, proving the obtained molecular docking results. At the B3LYP/6-31+G**.. level of theory, the reactivity descriptors for 5 g and 5h were investigated using DFT calculations. Also, IR frequency was calculated to verify DFT results with experimental data. The electrostatic potential energy of the surface and the HOMO and LUMO molecular orbitals were also studied. It agrees with experimental results that the 5h is a soft molecule and ready for chemical reaction with other interacting molecules.

Automated summary

In this study, hybrids of 3-hydroxypyridine-4-one and acylhydrazones were synthesized and evaluated for their anti-tyrosinase and antioxidant activities. The results showed that compound 5h exhibited potent inhibitory effects on tyrosinase and strong antioxidant activity. Molecular docking and dynamics simulation confirmed the binding site of compound 5h with tyrosinase. Furthermore, reactivity descriptors and molecular orbitals of 5g and 5h were investigated using DFT calculations and compared with experimental data.