Nor-halimane and spiro-labdane diterpenoids with anti-inflammatory activity from Leucas ciliata Benth

Eleven previously undescribed diterpenoids, cilileucapenoids A–K (1–10 and 12), comprising two halimane diterpenoids (1 and 12) and nine spiro-labdane diterpenoids (2–10), along with one known analogue (11), were isolated from the whole plant of Leucas ciliata. The structures and absolute configurations were determined through the analysis of their HR-ESI-MS, 1D/2D NMR, electronic circular dichroism (ECD) calculations, Mosher's esterification, and single-crystal X-ray diffraction. Notably, 1 represents the first reported aromatic halimane diterpenoid, while 2 features as a rare dispiro-tetrahydrofuran-labdane skeleton. Compounds 3–10 uniformly incorporate a spiro-tetrahydrofuran moiety. In bioactivity assessments, compounds 1, 3, 4, and 7 demonstrated significant anti-inflammatory effects by inhibiting nitric oxide (NO) production in LPS-stimulated RAW264.7 macrophages, with IC₅₀ values ranging from 9.13 to 25.94 μM. Structure-activity relationship (SAR) analysis further established that the Z-configuration of these diterpenoids confers markedly enhanced anti-inflammatory efficacy relative to the E-configuration.