Aspulvins A-H, Aspulvinone Analogues with SARS-CoV-2 M<sup>pro</sup> Inhibitory and Anti-inflammatory Activities from an Endophytic <i>Cladosporium</i> sp.
Liang XX, Zhang XJ, Zhao YX, Feng J, Zeng JC, Shi QQ, Kaunda JS, Li XL, Wang WG, Xiao WL.
Eight new aspulvinone analogues, aspulvins A-H (<b>1</b>-<b>8</b>) and aspulvinones D, M, O, and R (<b>9</b>-<b>12</b>), were isolated from cultures of the endophytic fungus <i>Cladosporium</i> sp. 7951. Detailed spectroscopic analyses were conducted to determine the structures of the new compounds. All isolates displayed different degrees of inhibitory activity against the severe acute respiratory syndrome coronavirus 2 main protease (SARS-CoV-2 M<sup>pro</sup>) at 10 μM. Notably, compounds <b>9</b>, <b>10</b>, and <b>12</b> showed potential SARS-CoV-2 M<sup>pro</sup> inhibition with IC<sub>50</sub> values of 10.3 ± 0.6, 9.4 ± 0.6, and 7.7 ± 0.6 μM, respectively. For all compounds except <b>3</b> and <b>4</b>, the anti-inflammatory activity occurred by inhibiting the release of lactate dehydrogenase (LDH) with IC<sub>50</sub> values ranging from 0.7 to 7.4 μM. Compound <b>10</b> showed the most potent anti-inflammatory activity by inhibiting Casp-1 cleavage, IL-1β maturation, NLRP3 inflammasome activation, and pyroptosis. The findings reveal that the aspulvinone analogues <b>9</b>, <b>10</b>, and <b>12</b> could be promising candidates for coronavirus disease 2019 (COVID-19) treatment as they inhibit SARS-CoV-2 infection and reduce inflammatory reactions caused by SARS-CoV-2.