Discovery of New Antimicrobial Benzopyran Meroterpenoids from <i>Acremonium sclerotigenum</i> LW14 Using HSQC-Based DeepSAT

Guided by HSQC-based DeepSAT strategy, 17 new benzopyran-type ascochlorin meroterpenoids, acremopyrans A-Q (<b>1</b>-<b>17</b>), were obtained from the deep-sea derived fungus <i>Acremonium sclerotigenum</i> LW14. Extensive spectroscopic data analysis, quantum chemical calculations, and X-ray diffraction analysis allowed the determination of their structures and absolute configurations. Compounds <b>1</b>-<b>15</b> represent the first reported examples of ascochlorins bearing a 3-hydroxy-2-methylchroman-2-yl group from nature. Among them, acremopyrans A-D (<b>1</b>-<b>4</b>) are four diastereomers that encompass all possible stereoisomeric configurations at C-10 and C-11. Compounds <b>12</b>-<b>15</b> are rare benzopyran-type ascochlorins characterized by cyclization via the C-2 hydroxyl group. Furthermore, compounds <b>16</b> and <b>17</b> 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 <b>3</b>, <b>4</b>, <b>11</b>, <b>16</b>, and <b>17</b> exhibited significant activity against <i>Cryptococcus gattii</i> 3271G1 (MIC = 2-8 μg/mL), with efficacy comparable to or better than that of fluconazole (MIC = 8 μg/mL). Compound <b>11</b> showed potent antifungal efficacy against <i>C</i>. <i>gattii</i> 3271G1 with a MIC value of 2 μg/mL. Structure-activity relationship (SAR) analysis of compounds <b>1</b>-<b>17</b> 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 <b>11</b>, <b>16</b>, and <b>17</b> also displayed antibacterial activities against <i>Bacillus subtilis</i>, with the same MIC value of 16 μg/mL. Scanning electron microscopy (SEM) observations revealed that these compounds inhibit <i>B. subtilis</i> growth by destroying its structure.