Impact of the Central Hydroxyl Groups on the Activity of Symmetrical HIV-1 Protease Inhibitors Derived From l-Mannaric Acid

The influence of the central hydroxyl groups on the anti-viral activity of symmetrical HIV-1 protease inhibitors derived from l-mannaric acid has been examined. l-Iditol was synthesized and used as a chiral precursor for the synthesis of the corresponding inhibitor with inverted configuration at C-3 and C-4. Key intermediates were 3,4-O-isopropylidene-l-iditol and the activated l-idaric acid succinimidyl ester. The configurations of the central hydroxyl groups required for optimal inhibition of the HIV-1 protease were determined to be the C-3R and C-4R, i.e. the l-manno-configuration. Three C2-symmetric inhibitors were converted to their thiocarbonates and reduced to provide the corresponding hydroxyethyl transition-state mimics. Deletion of the C-4 hydroxyl group in these inhibitors gave no further improvement in the anti-viral activity.