Three new alkaloids from Haplophyllum tuberculatum as competitive type of in-vitro α-glucosidase inhibitors

In a search for new drug-like molecules, we investigated Haplophyllum tuberculatum as a potential source of α-glucosidase inhibitors. Three new natural products (2, 6, and 7), and one previously synthesized compound (4), isolated here as a natural product for the first time, were isolated from an ethyl acetate extract. Additionally, six known compounds (1, 3, 5, and 8–10) were also characterized. The structures of all compounds were elucidated by 1D- and 2D-NMR techniques and HR-ESI-MS. All phytochemicals were evaluated for inhibitory activity against α-glucosidase and eight natural products (1 and 4-10) exhibited appreciable activities with IC₅₀ values ranging from 2.28 ± 0.64–71.10 ± 2.47 μM, whilst 2 and 3 exhibited weak activities with IC₅₀ values of 146.73 ± 2.73 and 260.53 ± 3.18 μM, respectively. Compounds 10 (IC₅₀ = 2.28 ± 0.64 μM), 8 (IC₅₀ = 7.16 ± 0.23 μM) and 7 (IC₅₀ = 8.95 ± 0.37 μM) displayed significant inhibition compared to the positive control acarbose (IC₅₀, 875.75 ± 1.24 μM). The α-glucosidase inhibitory activities of all compounds are reported here for the first time. Furthermore, kinetic study of the most potent compounds 8 and 10 exhibited concentration dependent type of inhibition. In addition, molecular docking analysis displayed excellent binding of these molecules in the active site of the α-glucosidase enzyme and the in-silico results and in vitro analysis were well correlated.