Identification of 1,3,4-Thiadiazolyl-Containing Thiazolidine-2,4-dione Derivatives as Novel PTP1B Inhibitors with Antidiabetic Activity.

Forty-one 1,3,4-thiadiazolyl-containing thiazolidine-2,4-dione derivatives (MY1-41) were designed and synthesized as protein tyrosine phosphatase 1B (PTP1B) inhibitors with activity against diabetes mellitus (DM). All synthesized compounds (MY1-41) presented potential PTP1B inhibitory activities, with half-maximal inhibitory concentration (IC50) values ranging from 0.41 ± 0.05 to 4.68 ± 0.61 µM, compared with that of the positive control lithocholic acid (IC50 = 9.62 ± 0.14 µM). The most potent compound, MY17 (IC50 = 0.41 ± 0.05 µM), was a reversible, noncompetitive inhibitor of PTP1B. Circular dichroism spectroscopy and molecular docking were employed to analyze the binding interaction between MY17 and PTP1B. In HepG2 cells, MY17 treatment could alleviate palmitic acid (PA)-induced insulin resistance by upregulating the expression of phosphorylated insulin receptor substrate and protein kinase B. In vivo, oral administration of MY17 could reduce the fasting blood glucose level and improve glucose tolerance and dyslipidemia in mice suffering from DM.

Thiazolidine-2,4-dione derivatives as potential α-glucosidase inhibitors: Synthesis, inhibitory activity, binding interaction and hypoglycemic activity.

In order to find effective α-glucosidase inhibitors, a series of thiazolidine-2,4-dione derivatives (C1 âˆ¼ 36) were synthesized and evaluated for α-glucosidase inhibitory activity. Compared to positive control acarbose (IC50 = 654.35 ± 65.81 µM), all compounds (C1 âˆ¼ 36) showed stronger α-glucosidase inhibitory activity with IC50 values of 0.52 ± 0.06 âˆ¼ 9.31 ± 0.96 µM. Among them, C23 with the best anti-α-glucosidase activity was a reversible mixed-type inhibitor. Fluorescence quenching suggested the binding process of C23 with α-glucosidase in a static process. Fluorescence quenching, CD spectra, and 3D fluorescence spectra results also implied that the binding of C23 with α-glucosidase caused the conformational change of α-glucosidase to inhibit the activity. Molecular docking displayed the binding interaction of C23 with α-glucosidase. Compound C23 (8 âˆ¼ 64 µM) showed no cytotoxicity against LO2 and 293 cells. Moreover, oral administration of C23 (50 mg/kg) could reduce blood glucose and improve glucose tolerance in mice.

In Vitro and In Vivo Biological Evaluation of Indole-thiazolidine-2,4-dione Derivatives as Tyrosinase Inhibitors.

Tyrosinase is an important rate-limiting enzyme in melanin biosynthesis. To find potential tyrosinase inhibitors with anti-melanogenic activity, a series of indole-thiazolidine-2,4-dione derivatives 5a~5z were synthesized by incorporating indole with thiazolidine-2,4-dione into one compound and assayed for their biological activities. All compounds displayed tyrosinase inhibitory activities and 5w had the highest anti-tyrosinase inhibitory activity with an IC50 value of 11.2 µM. Inhibition kinetics revealed 5w as a mixed-type tyrosinase inhibitor. Fluorescence quenching results indicated that 5w quenched tyrosinase fluorescence in a static process. CD spectra and 3D fluorescence spectra results suggested that the binding of 5w with tyrosinase could change the conformation and microenvironment of tyrosinase. Molecular docking also represented the binding between 5w and tyrosinase. Moreover, 5w could inhibit tyrosinase activity and melanogenesis both in B16F10 cells and the zebrafish model. Therefore, compound 5w could serve as a tyrosinase inhibitor with anti-melanogenic activity.

Investigation on the inhibition mechanism and binding behavior of paeonol to tyrosinase and its anti-browning property by multi-spectroscopic and molecular docking methods.

Paeonol, as one effective tyrosinase inhibitor, had been used as food preservative and clinical medication for skin disorders. In this study, the inhibition mechanism and binding behavior of paeonol to tyrosinase and its anti-browning property were investigated using multi-spectroscopic and molecular docking methods. Activity assay and kinetic results confirmed paeonol as a reversible mixed-type tyrosinase inhibitor. Results of the mechanistic studies were clarified using fluorescence quenching, synchronous fluorescence, CD spectra and 3D fluorescence, and showed that the binding of paeonol to tyrosinase might change the chromophore microenvironment and conformation of tyrosinase to inhibit enzyme catalytic activity. Molecular docking results revealed the detailed binding between paeonol and tyrosinase. Moreover, paeonol could prevent the browning of fresh-cut apples, as well as inhibiting PPO and POD activities and increasing APX activity. All above findings established a reliable basis for the inhibitory mechanism of paeonol against tyrosinase and therefore contributed to its application in anti-browning.

Synthesis, Anti-Tyrosinase Activity, and Spectroscopic Inhibition Mechanism of Cinnamic Acid-Eugenol Esters.

Tyrosinase plays crucial roles in mediating the production of melanin pigment; thus, its inhibitors could be useful in preventing melanin-related diseases. To find potential tyrosinase inhibitors, a series of cinnamic acid-eugenol esters (c1~c29) was synthesized and their chemical structures were confirmed by 1H NMR, 13C NMR, HRMS, and FT-IR, respectively. The biological evaluation results showed that all compounds c1~c29 exhibited definite tyrosinase inhibitory activity; especially, compound c27 was the strongest tyrosinase inhibitor (IC50: 3.07 ± 0.26 µM), being ~4.6-fold stronger than the positive control, kojic acid (IC50: 14.15 ± 0.46 µM). Inhibition kinetic studies validated compound c27 as a reversible mixed-type inhibitor against tyrosinase. Three-dimensional fluorescence and circular dichroism (CD) spectra results indicated that compound c27 could change the conformation and secondary structure of tyrosinase. Fluorescence-quenching results showed that compound c27 quenched tyrosinase fluorescence in the static manner with one binding site. Molecular docking results also revealed the binding interactions between compound c27 and tyrosinase. Therefore, cinnamic acid-eugenol esters, especially c27, could be used as lead compounds to find potential tyrosinase inhibitors.