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.