Scaffold hopping in the rational design of novel HIV-1 non-nucleoside reverse transcriptase inhibitors

High-throughput screening hit 1 was identified as a potent, broad-spectrum, non-nucleoside reverse transcriptase inhibitor (NNRTI) of HIV-1 replication. Analysis of the bound conformation of analogs of this inhibitor via molecular modeling and NMR contributed to the design of novel tertiary amide, carbamate, and thiocarbamate based NNRTIs.

Tetrazole thioacetanilides such as 12 were identified as potent NNRTIs via high-throughput screening. Analysis of the binding mode of these inhibitors permitted the successful scaffold hop to tertiary amides (23), carbamates (24), and thiocarbamates (26).Figure optionsDownload as PowerPoint slide