Aminodiol HIV protease inhibitors. Synthesis and structure-activity relationships of P-1/P-1' compounds: Correlation between lipophilicity and cytotoxicity

A series of novel aminodiol inhibitors of HIV protease based on the lead compound 1 with structural modifications at P-1' were synthesized in order to reduce the cytotoxicity of 1. We have observed a high degree of correlation between the lipophilicity and the cytotoxicity of this series of inhibitors. It was found that appropriate substitution at the para position of the P-1' phenyl group of 1 resulted in the identification of equipotent (both against the enzyme and in cell culture) compounds (101, 10m, 10n, and 15c) which possess significantly decreased cytotoxicity.