TETRAHYDRONAPHTHALENE LIGNAN COMPOUNDS AS POTENT ANTI-HIV TYPE-1 AGENTS

Anti-HIV-1 activity of tetrahydronaphthalene (THN) derivatives of lign an compounds was studied, THN derivatives prevented cell death caused by HIV-1 infection in MT-4 cells, They also inhibited giant cell forma tion by HIV-1 in Sup-T1 cells, and p24 production in HIV-1-infected H9 cells, The 50% effective concentration (ED50) of the most active comp ound, )-1,3,3a,4,9,9a-hexahydronaphtho[2,3-c]thiophene], for inhibitio n of the cytopathic effects of HIV-1 infection ranged from 0.15 to 0.8 mu M. The 50% cytotoxic concentration (CC50) of compound 1737 measure d by the viability of MT-4 cells was 58 mu M, indicating a selective i ndex (CC50/ED50) of 70-400, Substitution of the phenyl ring with other structures markedly decreased cytotoxicity but did not affect the ant iviral activity of the compounds, This resulted in compounds with a hi gh selective index, One such compound was )-1,3,3a,4,9,9a-hexahydronap htho[2,3-c]thiophene], with a selective index higher than 770, The tim e-of-addition experiment indicated that these compounds acted at or ne ar the reverse transcription step of the HIV-1 life cycle, THN derivat ives inhibited HIV-1 reverse transcriptase (RT) in vitro at a concentr ation of 1 mu M. Resistant viruses selected in the presence of THN der ivatives showed some degree of cross-resistance to other nonnucleoside RT inhibitors, but not to the nucleo-side RT inhibitor, AZT, THN deri vatives failed to inhibit replication of pyridinone- and nevirapine-re sistant EW strains, However, compound 1737 inhibited replication of a TIBO-resistant strain more effectively than the wild-type HIV-1, Consi stent with this result, compound 1737 also inhibited TIBO-resistant RT more effectively than the wild-type RT in vitro, These results sugges ted that THN derivatives interact with RT in a manner similar to but s lightly different from that of other nonnucleoside HIV-1 RT inhibitors .