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

Seventeen novel polyhydroquinoline <b>(1)</b> based Schiff bases <b>(4-20)</b> were synthesized in excellent yields through Hantzsch reaction, characterized by means of spectroscopic techniques and finally screened for their <i>in vitro</i> tyrosinase inhibitory potential. Among the series, five compounds <b>12</b> (IC₅₀ = 8.93 ± 0.27 µM), <b>8</b> (IC₅₀ = 16.64 ± 0.32 µM), <b>5</b> (IC₅₀ = 17.74 ± 0.34 µM), <b>4</b> (IC₅₀ = 18.46 ± 0.37 µM) and <b>18</b> (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 <b>7, 15, 9, 6, 10, 13, 14</b> and <b>11</b> 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 <b>19, 20, 17</b> and <b>16</b> 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 <b>12</b> with the active site residues of tyrosinase. The molecular dynamic simulation indicates that the most potent inhibitors <b>12</b> and <b>8</b> 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.