New phenolic bisabolane sesquiterpenoids discovered from the marine-derived fungus Aspergillus sydowii assisted by molecular networking and SMART strategies

Three previously undescribed phenolic bisabolane sesquiterpenoids (PBS) including a pair of new enantiomers (±)-aspersydonol A (1a/1b) and aspersydonol B (2), along with 12 known analogs (3–14) were isolated from the marine-associated fungus Aspergillus sydowii LF51 guided by a combined application of molecular networking and Small Molecule Accurate Recognition Technology (SMART) approaches. Their structures were elucidated by spectroscopic analyses and electronic circular dichroism (ECD) calculations. Compound 2 represents the first example of natural PBS with a hexahydrodibenzo[b,d]furan skeleton. Antifungal assays revealed that compounds 3, 6, 9, and 11 exhibited moderate activities against Cryptococcus spp. (MICs = 32–64 μg/mL), with additive effects against Cryptococcus gattii R265 combined with Amphotericin B (AmB), reducing MICs to 4–32 μg/mL. Compound 9 showed an additive effect with fluconazole (FLC) against C. gattii R265, lowering its MIC to 2 μg/mL. Mechanistic studies revealed that compound 9 inhibited C. gattii R265 by suppressing urease activity, disrupting membrane integrity, and inducing oxidative damage via ROS accumulation. Furthermore, compound 3 displayed moderate antibacterial efficacy against Mycobacterium smegmatis.