NONPEPTIDIC POTENT HIV-1 PROTEASE INHIBITORS - (4-HYDROXY-6-PHENYL-2-OXO-2H-PYRAN-3-YL)THIOMETHANES THAT SPAN P-1-P-2' SUBSITES IN A UNIQUE MODE OF ACTIVE-SITE BINDING

Using molecular modeling and the information derived from the X-ray crystal structure of HIV-1 protease (HIV PR) complexed with the pyran-2-one 1, a series of (4-hydroxy-6-phenyl-2-oxo-2H-pyran-3-yl)thiomethanes was designed and analyzed as novel, nonpeptidic inhibitors of HIV PR. Structure-activity studies led to the discovery of inhibitor 19 having (RS)-1-(cyclopentylthio)-3-methylbutyl functionalization at the C-3 position, which exhibited a K-c of 33 nM. A X-ray crystallographic structure of 19 bound to HIV PR showed that structural water-301 (inhibitor-flap-bridging water) was displaced by the inhibitor. Interestingly, the enol moiety of the pyran-2-one formed a hydrogen bond directly with Asp125 and with Asp25 via a bridging water molecule, thus illustrating a unique mode of active site binding by an HIV PR inhibitor. The pendant cyclopentyl and isobutyl groups of 19 occupied the S-1' and S-2' binding sites, respectively, whereas the 6-phenyl group occupied a region in between the S-1 and S-3 pockets of HIV PR. Selected compounds were tested for antiviral activity on H9 cells infected with HIV-1(IIIb). A correlation between enzymatic activity and antiviral activity was not found in this series. The best antiviral compound in this series, 18, contained (RS)-3-[cyclopentyl(cyclopentylthio )methyl] functionalization at the C-3 position of the pyran-2-one ring and exhibited a CIC50 of 14 mu M and TC50 of 70 mu M. These studies demonstrate that potent enzyme inhibition can be achieved by inhibitors that span only three subsites.