Lindenane Disesquiterpenoids with Anti-HIV-1 Activity from <i>Chloranthus japonicus</i>

Five new lindenane disesquiterpenoids, chlorajaponilides A–E (<b>1</b>–<b>5</b>), together with 11 known analogues were isolated from whole plants of <i>Chloranthus japonicus</i>. The structure and absolute configuration of <b>1</b> was confirmed by X-ray crystallography. Compounds <b>1</b> and <b>2</b> represent the first examples of lindenane disesquiterpenoids with a C-5 hydroxy group and a C-4–C-15 double bond. Compounds <b>8</b>, <b>9</b>, <b>11</b>, and <b>12</b> showed anti-HIV-1 replication activities in both wild-type HIV-1 and two NNRTIs-resistant strains. Shizukaol B (<b>8</b>) exhibited the best activity against HIV_wt, HIV_RT-K103N, and HIV_RT-K103N with EC₅₀ values of 0.22, 0.47, and 0.50 μM, respectively. Compounds <b>8</b>, <b>9</b>, <b>11</b>, and <b>12</b> had significant cytotoxicities against C8166 cells with CC₅₀ values of 0.020, 0.089, 0.047, and 0.022, respectively, and exhibited inhibitory activities against HIV-1 with EC₅₀ values of 0.0014, 0.016, 0.0043, and 0.0033 μM, respectively.