Construction and biological evaluation of novel carbazole-5-phenyl-1,3,4-oxadiazole derivatives as multi-target...

To achieve new multi-target inhibitors simultaneously acting on α-glucosidase, α-amylase, and protein tyrosine phosphatase 1B (PTP1B), twenty-one novel carbazole-5-phenyl-1,3,4-oxadiazole derivatives (5a-5u) were synthesized and screened for in vitro enzyme inhibitory activity. All synthesized derivatives 5a-5u showed noticeable anti-α-glucosidase and anti-α-amylase activities (IC₅₀: 9.79 ± 0.21-132.65 ± 1.52 μM, 6.15 ± 0.11-25.16 ± 0.75 μM, respectively) in comparison with the standard acarbose (IC₅₀: 210.57 ± 0.91 μM, 26.17 ± 1.12 μM, respectively). The compound 5l that possessed the best inhibition activity on both α-glucosidase and α-amylase (IC₅₀ = 9.79 ± 0.21, 6.36 ± 0.16 μM, respectively) also exhibited a fine inhibitory effect on PTP1B with an IC₅₀ value of 19.08 ± 4.52 μM, as the reference drug ursolic acid of 4.43 ± 0.40 μM. Kinetic measurement, multispectral techniques, and molecular docking study were used to reveal the interaction mechanism of preferred compound 5l with α-glucosidase, α-amylase, and PTP1B. The derivative 5l could inhibit the activity of these enzyme proteins via binding to the enzyme or its substrate complex, quenching their intrinsic fluorescence, or affecting the conformation of enzyme proteins, and forming hydrophobic interactions and hydrogen bonds with them. In conjunction with the potential properties of compound 5l in inhibiting the postprandial blood glucose rise and low cytotoxicity, the title derivatives are expected to become lead molecules in developing new multi-target antidiabetes drugs.