Neuroprotective Indole Alkaloids from the Soil-Derived Fungus Trichocladium sp. XZ8

A chemical investigation of the soil-derived fungus Trichocladium sp. XZ8 led to the isolation of five new indole alkaloids, trichindoles A–E (1–5), with diverse architectures, along with seven known analogues (6–12). Their structures were elucidated by extensive spectroscopic data analysis, and their absolute configurations were determined by single-crystal X-ray diffraction and modified Mosher's method. Compound 1 is a polyketide-alkaloid hybrid incorporating a rare succinimide motif, and compound 2 represents the first example of a dimeric isopentenyl indole-containing alkaloid bridged by a propane-1,2-diol moiety. Compounds 1, 4, 8, 11, and 12 showed significant neuroprotective effects against RSL3-induced ferroptosis in PC12 cells at 10 μM. Moreover, 1 and 4 might ameliorate RSL3-induced ferroptosis through the regulation of the SLC7A11 pathway and ferritinophagy, suggesting their potential as promising lead compounds for the treatment of neurodegenerative diseases.