Casuattimines A-N, fourteen new Lycopodium alkaloids from Lycopodiastrum casuarinoides with Ca3.1 channel inhibitory activity.

Two new dimeric Lycopodium alkaloids, casuattimines A and B (1 and 2), along with twelve previously undescribed Lycopodium alkaloids, casuattimines C-N (3-14), and eight known Lycopodium alkaloids, were isolated from Lycopodiastrum casuarinoides. Casuattimines A and B (1 and 2) are the first two ether-linked Lycopodium alkaloid dimers. Casuattimines C and D (3 and 4) are unique Lycopodium alkaloids characterized by a long fatty acid chain. Structural elucidation was achieved through HRESIMS, NMR, and electronic circular dichroism (ECD) calculations. In addition, the absolute configurations of compounds 7, 13, and 14 were determined by single crystal X-ray diffraction. Compounds 1, 2, and 4 demonstrated notable Ca3.1 channel inhibitory activities presenting IC values of 10.75 ± 1.02 μM, 9.33 ± 0.79 μM, and 7.14 ± 0.86 μM, respectively. The dynamics of compound 4 against the Ca3.1 channel and preliminary structure-activity relationships of these active Lycopodium alkaloids were also discussed.