SYNTHESIS AND BIOLOGICAL EVALUATION OF CERTAIN ALKENYLDIARYLMETHANES AS ANTI-HIV-1 AGENTS WHICH ACT AS NONNUCLEOSIDE REVERSE-TRANSCRIPTASE INHIBITORS

Several novel alkenyldiarylmethane (ADAM) non-nucleoside HIV-1 reverse transcriptase inhibitors were synthesized. The most potent of these p roved to be 3',3''-dibromo-4',4 ''-dimethoxy-5',5 ''-bis(methoxycarbon yl)-1,1-diphenyl-1-heptene (8). ADAM 8 inhibited the cytopathic effect of HIV-1 in CEM cell culture with an EC(50) value of 7.1 mu M and was active against an array of laboratory strains of HIV-1 in CEM-SS and MT-4 cells, but was inactive as an inhibitor of HIV-2. In common with the other known non-nucleoside reverse transcriptase inhibitors, ADAM 8 was an effective inhibitor of HIV-1 reverse transcriptase (IC50 1 mu M) with poly(rC). oligo(dG), but not with poly(rA). oligo(dT), as the template/primer. ADAM 8 was inactive against HIV-1 reverse transcript ases containing non-nucleoside reverse transcriptase inhibitor resista nce mutations at residues 101, 106, 108, 139, 181, 188, and 236, while it remained active against enzymes with mutations at residues 74, 98, 100, 103, and at 103/181. An AZT-resistant virus having four mutation s in reverse transcriptase was more sensitive to inhibition by ADAM 8 than the wild-type HIV-1. In addition, ADAM 8 displayed synergistic ac tivity with AZT, but lacked synergy with ddI. ADAM 8 or a structurally related analog may therefore be useful as an antiviral agent in combi nation with AZT or with other NNRTIs that are made ineffective by muta tions at residues which do not confer resistance to ADAM 8.