The evaluation of the anti-HIV-1 activity of synthetic lignanolides and their intermediates is reported. The antiviral activity was studied through luciferase-based assays targeting the HIV-1 promoter activation induced by either, the HIV-1 Tat protein or the cellular transcription factor NF-kappaB, both known as crucial factors in HIV-1 replication. Among the compounds tested, three of them 2, 4 and 13 were further analysed for their anti-HIV-1 activity by recombinant virus assays, showing a suitable profile for development of novel anti-HIV-1 drugs.