Discovery of New Antimicrobial Benzopyran Meroterpenoids from Acremonium sclerotigenum LW14 Using HSQC-Based DeepSAT

Guided by HSQC-based DeepSAT strategy, 17 new benzopyran-type ascochlorin meroterpenoids, acremopyrans A–Q ( 1 – 17 ), were obtained from the deep-sea derived fungus Acremonium sclerotigenum LW14. Extensive spectroscopic data analysis, quantum chemical calculations, and X-ray diffraction analysis allowed the determination of their structures and absolute configurations. Compounds 1 – 15 represent the first reported examples of ascochlorins bearing a 3-hydroxy-2-methylchroman-2-yl group from nature. Among them, acremopyrans A–D ( 1 – 4 ) are four diastereomers that encompass all possible stereoisomeric configurations at C-10 and C-11. Compounds 12 – 15 are rare benzopyran-type ascochlorins characterized by cyclization via the C-2 hydroxyl group. Furthermore, compounds 16 and 17 are the first examples of benzopyran-type ascochlorins possessing a novel 6/6/6/6-fused tetracyclic scaffold. The relationship between the structural features and spectroscopic characteristics including ECD and optical rotation data is discussed. Biological evaluation showed that compounds 3, 4, 11, 16, and 17 exhibited significant activity against Cryptococcus gattii 3271G1 (MIC = 2–8 μg/mL), with efficacy comparable to or better than that of fluconazole (MIC = 8 μg/mL). Compound 11 showed potent antifungal efficacy against C . gattii 3271G1 with a MIC value of 2 μg/mL. Structure–activity relationship (SAR) analysis of compounds 1 – 17 indicated that the introduction of C-2 and C-12 hydroxyl groups, C-5 chlorine atom, and the presence of the C-9/C-10 double bond, as well as the configuration of C-10 and C-11 are crucial for antifungal activity. In addition, compounds 11, 16, and 17 also displayed antibacterial activities against Bacillus subtilis, with the same MIC value of 16 μg/mL. Scanning electron microscopy (SEM) observations revealed that these compounds inhibit B. subtilis growth by destroying its structure.