Discovery of <i>neo</i>-Clerodane Diterpenoids\nfrom <i>Ajuga campylantha</i> as Neuroprotective Agents\nagainst Ferroptosis and Neuroinflammation

Abstract

Twelve new <i>neo</i>-clerodane diterpenoids,\neight undescribed\nmethoxy/ethoxy acetal analogues, and one new <i>nor</i>-iridane\nmonoterpenoid were isolated from <i>Ajuga campylantha</i>. Their structures were elucidated using a combination of spectroscopic\ndata, quantum chemical calculations, and X-ray crystallography. This\nresearch reveals the distinctive structural features of <i>A.\ncampylantha</i> diterpenes, including distinct C rings and 4,18-double\nbonds, distinguishing them from diterpenes of other plants in the <i>Ajuga</i> genus. Compound <b>2</b> represents the first\nexample of a 19(5→6)-<i>abeo</i>-clerodane formed\nthrough a Wagner–Meerwein rearrangement. The isolated compounds\nwere assessed for their neuroprotective effects against RSL3-induced\nferroptosis in HT22 cells and LPS-induced neuroinflammation in BV-2\ncells. Notably, compound <b>7</b> inhibits ferroptosis (EC₅₀ = 10 μM) with a potentially new mechanism of action.\nThe preliminary structure–activity relationship studies revealed\nthat the furan-clerodane diterpenoids possess potential ferroptosis\ninhibitory activity, while the lactone-clerodanes do not. This study\nrepresents the first report of furan-containing clerodanes within\nthe <i>Ajuga</i> genus, providing fresh insights into the\nphytochemistry and pharmacological potential of <i>A. campylantha</i>.