New Polyketides and a Ferroptosis Inhibitor from the Marine-Derived Fungus Diaporthe searlei CS-HF-1

As a driver of neurodegenerative disorders, ischemic injuries, and acute organ dysfunction, ferroptosis represents a therapeutic target, and its inhibition may provide novel therapies. In our ongoing efforts to discover ferroptosis inhibitors from fungal strains, chemical investigation of the strain <i>Diaporthe searlei</i> CS-HF-1 led to the isolation of four polyketide-derived alkaloids (<b>1</b>-<b>3</b> and <b>17</b>) and fourteen polyketides (<b>4</b>-<b>16</b> and <b>18</b>), including three new isoindolone derivatives (<b>1</b>-<b>3</b>), a new phthalide (<b>4</b>), a new butyrolactone derivative (<b>10</b>), and three new nonenolides (<b>11</b>-<b>13</b>). The structures were determined by comprehensive spectroscopic analysis. The structures of <b>1</b>, <b>2</b>, and <b>10</b> were confirmed by comparison of experimental and calculated ¹³C NMR chemical shifts. The absolute configurations of compounds <b>10</b>, <b>11</b>, and <b>14</b> were assigned by ECD calculations, while those of <b>12</b> and <b>13</b> were assigned based on their biogenetic relationship with <b>14</b>. Notably, compound <b>1</b> represents the first isoindolone featuring a primary amide group attached to the lactam nitrogen, while compound <b>2</b> is the first naturally occurring isoindolone dimer. These compounds were assessed for the anti-ferroptotic activity. As a result, asperlactone A (<b>15</b>) exhibited inhibition on RSL3-induced ferroptosis in HT22 cells with an EC₅₀ of 11.3 ± 0.4 μM. Preliminary mechanistic study revealed that <b>15</b> attenuated lipid peroxidation, as evidenced by reduced MDA levels, elevated GSH content, and suppression of lipid radical generation. This study offers a new chemotype for the development of novel ferroptosis inhibitors.