Design, synthesis, kinetic mechanism and molecular docking studies of novel 1-pentanoyl-3-arylthioureas as inhibitors of mushroom tyrosinase and free radical scavengers

摘要

Abstract A series of novel 1-pentanoyl-3-arylthioureas was designed as new mushroom tyrosinase inhibitors and free radical scavengers. The title compounds were obtained in excellent yield and characterized by FTIR, 1 H NMR, 13 C NMR and X-ray crystallography in case of compound ( 4a ). The inhibitory effects on mushroom tyrosinase and DPPH were evaluated and it was observed that 1-Pentanoyl-3-(4-methoxyphenyl) thiourea ( 4f ) showed tyrosinase inhibitory activity (IC 50 1.568?±?0.01?mM) comparable to Kojic acid (IC 50 16.051?±?1.27?mM). Interestingly compound 4f exhibited higher antioxidant potential compared to other derivatives. The docking studies of synthesized 1-Pentanoyl-3-arylthioureas analogues were also carried out against tyrosinase protein (PDBID 2ZMX ) to compare the binding affinities with IC 50 values. The predicted binding affinities are in good agreement with the IC 50 values as compound ( 4f ) showed highest binding affinity (?7.50?kcal/mol) compared to others derivatives. The kinetic mechanism analyzed by Line-weavere Burk plots exhibited that compound ( 4f ) inhibit the enzyme inhibits the tyrosinase non-competitively to form an enzyme inhibitor complex. The inhibition constants Ki calculated from Dixon plots for compound ( 4f ) is 1.10?μM. It was also found from kinetic analysis that derivative 4f irreversible enzyme inhibitor complex. It is proposed on the basis of our investigation that title compound ( 4f ) may serve as lead structure for the design of more potent tyrosinase inhibitors. Graphical abstract Display Omitted Highlights ? A small library of novel 1-Pentanoyl-3-arylthioureas ( 4a-4j ) synthesized. ? Mushroom tyrosinase inhibition and free radical scavenging activity were evaluated. ? Most of the compounds show excellent activity, particularly 4f higher than the standard. ? The kinetic mechanism proposed 4f is non-competitive inhibitor of mushroom tyrosinase. ? Molecular docking, druglikeness, Ramachandran graph, Chemo-informatics and Lipinski's rule were studied.