NEW ALKENYLDIARYLMETHANES WITH ENHANCED POTENCIES AS ANTI-HIV AGENTS WHICH ACT AS NONNUCLEOSIDE REVERSE-TRANSCRIPTASE INHIBITORS

Twenty-two new alkenyldiarylmethanes (ADAMs) were synthesized and eval uated for inhibition of HIV-1 replication. The most potent compound pr oved to be methyl 3',3 ''-dichloro-4',4 ''-dimethoxy-5', 5 ''-bis(meth oxycarbonyl)-6, (ADAM II), which displayed an EC50 of 13 nM for inhibi tion of the cytopathic effect of HIV-1(RF) in CEM-SS cells. ADAM II in hibited HIV-1 reverse transcriptase with an IC50 of 0.3 mu M but was i nactive as an inhibitor of HIV-1 attachment/fusion to cells, protease, integrase, and the nucleocapsid protein. Molecular target-based and c ell-based assays revealed that ADAM II acted biologically as a nonnucl eoside reverse transcriptase inhibitor (NNRTI). ADAM II inhibited repl ication of a wide variety of laboratory, clinical, and clade-represent ative isolates of HIV-1 in T cell lines and cultures of peripheral blo od mononuclear cells or monocyte/macrophages. Mutations that conferred resistance to ADAM II clustered at residues 101, 103, 108, 139, 179, 181, and 188, which line the nonnucleoside binding pocket of HIV-1 rev erse transcriptase. However, HIV-1 NL4-3 strain expressing a mutation at residue 100 of reverse transcriptase, and an AZT-resistant virus, d isplayed increased sensitivity to ADAM II. Thus, ADAM II could serve a s an adjunct therapy to AZT and NNRTIs that select for L100I resistanc e mutations.