Novel Modifications in the Alkenyldiarylmethane (ADAM) Series of Non-Nucleoside Reverse Transcriptase Inhibitors

In an effort to obtain more insight into the interaction between HIV-1 reverse transcriptase and the alkenyldiarylmethanes (ADAMs), a new series of compounds has been synthesized and evaluated for inhibition of HIV-1 replication. The modifications reported in this new series include primarily changes to the alkenyl chain. The most potent compound proved to be methyl 3‘,3‘ ‘-dibromo-4‘,4‘ ‘-dimethoxy-5‘,5‘ ‘-bis(methoxycarbonyl)-6,6-diphenyl-5-hexenoate (28), which displayed an EC50 of 1.3 nM for inhibition of the cytopathic effect of HIV-1RF in CEM-SS cells. ADAM 28 inhibited HIV-1 reverse transcriptase with an IC50 of 0.3 μM. Mutations that conferred greater than 10-fold resistance to ADAM 28 clustered at residues Val 106, Val 179, Tyr 181, and Tyr 188. Results derived from this series indicate that ADAMs containing chlorines in the aromatic rings might bind to HIV-1 reverse transcriptase in a slightly different mode when compared with those analogues incorporating bromine in the aromatic rings.