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.