Encleistoids A-M, C-ring aromatized ent-cleistanthane diterpenoids with anti-HIV activity from two Phyllanthaceae species.

Cleistanthane diterpenoids represent an important class of bioactive natural products widely distributed within the Phyllanthaceae family. In this study, a systematic phytochemical investigation of two medicinal plants from this family, Actephila merrilliana Chun and Phyllanthus reticulatus Poir., led to the isolation of thirteen previously undescribed ent-cleistanthane diterpenoids, encleistoids A-M (1-13), along with a known analogue (14). Their structures were established by extensive spectroscopic analysis, quantum chemical calculations, and single-crystal X-ray diffraction. All isolates share an aromatized C-ring. Notably, compounds 1 and 2 are rare rearranged ent-cleistanthane diterpenoids featuring a seven-membered B-ring formed by ring expansion; compounds 3-8 are uncommon tetranor-, trinor-, or nor- derivatives; and compounds 12 and 13 bear an unusual (tetrahydrofuran-2-yl)oxy substituent. Bioactivity evaluation revealed that several isolates exhibited significant anti-HIV-1 activity, with compound 14 being the most potent (IC50 = 0.56 ± 0.25 μM). This study substantially expands the structural repertoire of cleistanthane diterpenoids from the Phyllanthaceae family and highlights their potential for anti-HIV drug discovery.