Coumarin and chalcone, two important kinds of natural product skeletons, both exhibit α-glucosidase inhibitory activity. In this work, coumarin-chalcone derivatives 3 (a∼v) were synthesized, and their α-glucosidase inhibitory activity was screened. The results showed that all synthetic derivatives (IC50: 24.09 ± 2.36 to 125.26 ± 1.18 μM) presented better α-glucosidase inhibitory activity than the parent compounds 3-acetylcoumarin (IC50: 1.5 × 105 μM) and the positive control acarbose (IC50: 259.90 ± 1.06 μM). Among them, compound 3t displayed the highest α-glucosidase inhibitory activity (IC50: 24.09 ± 2.36 μM), which was approximately 10 times stronger than that of acarbose. The kinetic assay of 3t (KI = 18.82 μM, KIS = 59.99 μM) revealed that these compounds inhibited α-glucosidase in a mixed-type manner. Molecular docking was used to simulate the interaction between α-glucosidase and compound 3t.

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To find potential α-glucosidase inhibitors, indolo[1,2-b]isoquinoline derivatives (1–20) were screened for their α-glucosidase inhibitory effects. All derivatives presented potential α-glucosidase inhibitory effects with IC50 values of 3.44 ± 0.36~41.24 ± 0.26 μM compared to the positive control acarbose (IC50 value: 640.57 ± 5.13 μM). In particular, compound 11 displayed the strongest anti-α-glucosidase activity, being ~186 times stronger than acarbose. Kinetic studies found that compounds 9, 11, 13, 18, and 19 were all reversible mix-type inhibitors. The 3D fluorescence spectra and CD spectra results revealed that the interaction between compounds 9, 11, 13, 18, and 19 and α-glucosidase changed the conformational changes of α-glucosidase. Molecular docking and molecular dynamics simulation results indicated the interaction between compounds and α-glucosidase. In addition, cell cytotoxicity and drug-like properties of compound 11 were also investigated.