Phainanones A-D, Four Aromatic Diterpenoids with Anti-HIV Activity from Phyllanthus hainanensis

A comprehensive chemical investigation of the extract from Phyllanthus hainanensis led to the isolation and identification of four new aromatic diterpenoids, phainanones A-D (1-4), along with one known analogue (5). Phainanones A (1) and B (2) are novel ent-cleistanthane-type diterpenoids, with 1 characterized as a 17-nor derivative and 2 as a 3-nor derivative, both sharing a rearranged 5/6/6 tricyclic ring system. Their structures with absolute configurations were established by comprehensive spectroscopic analysis, ECD calculations, and X-ray crystallography. Putative biosynthetic pathways for compounds 1 and 2 were also proposed. In biological assays, compounds 2-4 potently inhibited the HIV-1 Bal pseudovirus while showing low cytotoxicity (IC₅₀ 0.54-3.3 μM; CC₅₀ > 30). The most active compound 2 also exhibited strong activity against HIV-1_IIIB (IC₅₀ = 1.0 ± 0.11 μM, SI > 98). Furthermore, its time-dependent inhibition profile indicates that it may act at a postentry step, interfering with early viral replication events such as reverse transcription. This study highlights compound 2 as a promising lead for anti-HIV drug development.