Expedient solid-phase synthesis of both symmetric and asymmetric diol libraries targeting aspartic proteases

C2-symmetric diols have been shown to be highly potent against HIV-1 protease (PR). However, gaining access to these compounds has been hampered by the need of multistep solution-phase reactions which are often tedious and inefficient. In this Letter, we have disclosed a solid-phase strategy for rapid preparation of small molecule-based, symmetric and asymmetric diols as potential HIV-1 protease inhibitors. Upon biological screening, we found one of them, SYM-5, to be a potent and selective inhibitor (Ki = 400 nM) against HIV-1 protease.

A solid-phase strategy for rapid preparation of small molecule-based, symmetric and asymmetric diols is described, and of the 75 diols synthesized, one was found to be a potent and selective inhibitor (Ki = 400 nM) against HIV-1 protease.Figure optionsDownload as PowerPoint slide