| Abstract: | | Hit, Lead & Candidate Discovery | Protein tyrosine phosphatase 1B (PTP‐1B) has attracted interest as a novel target for the treatment of type 2 diabetes, this because its role in the insulin‐signaling pathway as a negative regulator. Thus, the aim of current work was to obtain seven ursolic acid derivatives as potential antidiabetic agents with PTP‐1B inhibition as main mechanism of action. Furthermore, derivatives 1 – 7 were submitted in vitro to enzymatic PTP‐1B inhibition being 3, 5, and 7 the most active compounds (IC50 = 5.6, 4.7, and 4.6 μM, respectively). In addition, results were corroborated with in silico docking studies with PTP‐1B orthosteric site A and extended binding site B, showed that 3 had polar and Van der Waals interactions in both sites with Lys120, Tyr46, Ser216, Ala217, Ile219, Asp181, Phe182, Gln262, Val49, Met258, and Gly259, showing a docking score value of −7.48 Kcal/mol, being more specific for site A. Moreover, compound 7 showed polar interaction with Gln262 and Van der Waals interactions with Ala217, Phe182, Ile219, Arg45, Tyr46, Arg47, Asp48, and Val49 with a predictive docking score of −6.43 kcal/mol, suggesting that the potential binding site could be localized in the site B adjacent to the catalytic site A. Finally, derivatives 2 and 7 (50 mg/kg) were selected to establish their in vivo antidiabetic effect using a noninsulin‐dependent diabetes mice model, showing significant blood glucose lowering compared with control group (p < .05). |
