In vitro and in silico PTP-1B inhibition and in vivo antidiabetic activity of semisynthetic moronic acid derivatives.

Six derivatives (1-6) of moronic acid were semi-synthesized and their in vitro protein tyrosine phosphatase 1B (PTP-1B) inhibition activity assessed. Derivatives 2 (IC50=10.8 ± 0.5 µM) and 6 (IC50=7.5 ± 0.1 µM) displayed the most potent inhibitory activity. Therefore, they (50mg/Kg) were tested for their antidiabetic effect in vivo using a non-insulin dependent diabetes mellitus rat model. The results indicated that they decrease plasma glucose levels during all the experiment (p <0.05). Docking analysis of 2 and 6 with PTP-1B orthosteric site A and allosteric site B, showed that 2 had polar and Van der Waals interactions in both sites with Val49, Gln262, Met258, Phe182, Ala217, Ile219 and Gly259, displaying more affinity for site A. Compound 6 showed polar interaction with Gln262 and Van der Waals with Val49, Ile219, Gly259, Arg254, Ala27, Phe52, Met258, Asp48 and Phe182, suggesting that the potential binding site is localized in site B, close to the catalytic site A. Therefore, derivatives 2 and 6 have potential for the development of antidiabetic agents.

Discovery of thiazolidine-2,4-dione/biphenylcarbonitrile hybrid as dual PPAR α/γ modulator with antidiabetic effect: in vitro, in silico and in vivo approaches.

A small series of thiazolidine-2,4-dione and barbituric acid derivatives 1-4 was prepared using a short synthetic route, and all compounds were characterized by elemental analysis, mass spectrometry, and NMR ((1)H, (13)C) spectroscopy. Their in vitro relative expression of peroxisome proliferator-activated receptor α and peroxisome proliferator-activated receptor γ was evaluated. Compound 1 showed an increase in the mRNA expression of both peroxisome proliferator-activated receptor isoforms, as well as the GLUT-4 levels. The antidiabetic activity of compound 1 was determined at 50 mg/kg single dose using a non-insulin-dependent diabetes mellitus rat model. The results indicated a significant decrease in plasma glucose levels. Additionally, we performed a molecular docking of compound 1 into the ligand binding pocket of peroxisome proliferator-activated receptor α and peroxisome proliferator-activated receptor γ. In these binding models, compound 1 may bind into the active site of both isoforms showing important short contacts with the peroxisome proliferator-activated receptor γ residues: Tyr 473, His 449, Ser 289, His 323; and peroxisome proliferator-activated receptor α residues: Tyr 464, His 440, Ser 280 and Tyr 314.