One-pot four-component synthesis of some novel hydrazone-Schiff bases of polyhydroquinoline as potent tyrosinase inhibitors: in vitro, molecular docking and simulations approaches.

Abstract

Seventeen novel polyhydroquinoline (1) based Schiff bases (4-20) were synthesized in excellent yields through Hantzsch reaction, characterized by means of spectroscopic techniques and finally screened for their in vitro tyrosinase inhibitory potential. Among the series, five compounds 12 (IC₅₀ = 8.93 ± 0.27 µM), 8 (IC₅₀ = 16.64 ± 0.32 µM), 5 (IC₅₀ = 17.74 ± 0.34 µM), 4 (IC₅₀ = 18.46 ± 0.37 µM) and 18 (IC₅₀ = 18.64 ± 0.39 µM) were found potent inhibitors of tyrosinase enzyme by comparing with kojic acid (IC₅₀ = 18.30 ± 0.41 µM). Likewise, eight derivatives 7, 15, 9, 6, 10, 13, 14 and 11 ascribed significant activity having IC₅₀ values of 20.72 ± 0.45, 22.53 ± 0.61, 24.17 ± 0.40, 25.72 ± 0.60, 26.43 ± 0.39, 27.90 ± 0.53, 28.37 ± 0.59 and 29.15 ± 0.64 µM respectively, while the remaining four hydrazone-Schiff bases 19, 20, 17 and 16 exhibited good to less inhibitory potential in the range of IC₅₀ values from 31.58 ± 0.67 to 63.69 ± 1.30 µM. Docking studies indicate excellent binding of the hydrazide moiety of the most active compound 12 with the active site residues of tyrosinase. The molecular dynamic simulation indicates that the most potent inhibitors 12 and 8 showed that root mean square deviation profile of the complexes stabilized at low nanoseconds, indicating stable conformations. These compounds did not induce significant structural changes in the protein.