Design and synthesis of potent C-2-symmetric diol-based HIV-1 protease inhibitors: Effects of fluoro substitution

Implementation of derivatized carbohydrates as C-2-symmetric HIV-1 protease inhibitors has previously been reported. With the objective of improving t he anti-HIV activity of such compounds, we synthesized a series of fluoro s ubstituted P1/P1 ' analogues. These compounds were evaluated for antiviral activity toward both wild type and mutant virus. The potency of the analogu es in blocking HIV-1 protease was moderate, with K-i values ranging from 1 to 7 nM. Nonetheless, compared to the parent nonfluorous inhibitors, a majo rity of the compounds exhibited improved antiviral activity, for example th e 3-fluorobenzyl derivative 9b, which had a K-i value of 7.13 nM and displa yed one of the most powerful antiviral activities in the cellular assay of the series. Our results strongly suggest that fluoro substitution can subst antially improve antiviral activity. The X-ray crystal structures of two of the fluoro substituted inhibitors (9a and 9f) cocrystallized with HIV-1 pr otease are discussed.