Podocarpane diterpenoids with various subtypes from Strophioblachia glandulosa Pax var. cordifolia combined with fluconazole activation of the Hog1 pathway demonstrating antifungal activity.

A 5/6/6-fused diterpenoid cordifolia A (1), a 3,4:12,13-diseco- podocarpane diterpenoid cordifolia B (2), three new 5/6/5 tricyclic diterpenoids with a spiro furan lactone core cordifolias C-E (3-5), two cleistantane diterpenoids cordifolias F-G (6-7), and a known podocarpane analogue 12-hydroxy-13-methylpodocarpa-9,11,13-trien-3-one (8) were obtained from the aerial parts of Strophioblachia glandulosa Pax var. cordifolia. Their structures were identified by spectral analysis including 1D, 2D NMR, HRESIMS data, and single-crystal X-ray diffraction, as well as quantum chemistry calculations. Compounds 1-5, 7 and 8 were assessed for their antifungal activity in combination with fluconazole (FLC) against FLC-resistant Candida albicans strains. Compounds 1-5 showed no synergistic antifungal effect, while compounds 7 and 8 exhibited significant synergistic activity. Compound 8 was therefore selected for further mechanistic investigation. Further mechanistic studies revealed that compound 8 combined with FLC exerts synergistic antifungal activity by activating the Hog1 signaling pathway to suppress hyphal formation and morphological transformation of resistant C. albicans.