Design, synthesis and biological evaluation of novel coumarin-1, 2, 4-triazole derivatives as dual inhibitors of α-glucosidase and PTP1B

Multi-target inhibitors are one of the important directions in the current research on anti-diabetic drugs. To develop new dual-target inhibitors of protein tyrosine phosphatase 1B (PTP1B) and α-glucosidase, fourteen coumarin-1, 2, 4-triazole derivatives (
10a-10n
) were design and synthesized. All synthetic compounds were screened for their
in vitro
α-glucosidase inhibitory activity by using yeast α-glucosidase enzyme. In comparison with the positive acarbose (IC
50
: 309.83 ± 8.74 μM), these derivatives had moderate to high active inhibitory activity against α-glucosidase with IC
50
values between 9.71 ± 0.28 μM and 160.67 ± 5.10 μM. In addition, the most active compound
10n
also exhibits PTP1B inhibitory activity as compared to the positive ursolic acid (IC
50:
4.55 ± 1.08 μM), with an IC
50
value of 7.31 ± 1.55 μM. SAR analysis demonstrated a significant improvement in α-glucosidase inhibitory activity upon the introduction of substituents with increased steric hindrance. α-Glucosidase inhibition mechanism experiments demonstrate that 10n is a mixed-type inhibitor. Compound
10n
reduced the fluorescence intensity of glucosidase by 47.5% through a static quenching manner. The outcome of synchronous fluorescence indicated the location where 10n bound to the protein was closer to tryptophan residue. The results of CD (α-helix: 36.8% to 26.9%; β-sheets: 15.5% to 21.4%; β-turns: 16.3% to 18.1%; random coils: 29.4% to 37.3%) and 3D fluorescence (reduce the fluorescence intensity of characteristic peak 1 and 2) demonstrated the addition of compound 10n could destroy the original conformation of α-glucosidase. Importantly, molecular docking uncovered 10n could enter active pockets both α-glucosidase (binding energy: -11.7 kcal•mol
-1
) and PTP1B (binding energy: -8.3 kcal•mol
-1
) and interacted with residues through hydrogen bond, hydrophobic contact, π-π stacking interaction. The
in vivo
experiment found
10n
(20 mg/kg, n = 8) could lower postprandial blood sugar levels in Kunming mice (ethical approval has been obtained).