Synthesis and biological evaluation of prodrug-type anti-HIV agents: Esterconjugates of carboxylic acid-containing dipeptide HIV protease inhibitorsand a reverse transcriptase inhibitor

On the basis of substrate transition-state mimic concept of HIV protease, a series of small-sized dipeptide inhibitors containing hydrophilic carboxyl group were designed and synthesized. These dipeptide inhibitors showed goo d HIV protease inhibitory activity, but their anti-HIV activity was poor. T he low antiviral activities of these inhibitors were probably due to their inadequate cell membrane permeability caused by the presence of a free carb oxylic acid in the inhibitors. Based on the prodrug concept as well as the combination of two different classes of anti-HIV agents, conjugates of HIV protease inhibitors with a nucleoside reverse transcriptase inhibitor were synthesized. Some of these conjugates exhibited excellent antiviral activit y compared with that of individual inhibitors. The synergistic enhancement of anti-HIV activities of these conjugates may be due to their ability to p enetrate into the target cell and subsequent regeneration of two different classes of anti-HIV agents in the cytoplasm. (C) 2001 Elsevier Science Ltd. All rights reserved.