Design, synthesis, and biological evaluation of HIV-1 protease inhibitors incorporating phenyloxazolidines as novel P2 ligands

MEDI 94

Akbar Ali1, G. S. Kiran Kumar Reddy1, Hong Cao1, Saima Ghafoor Anjum1, Madhavi N. L. Nalam2, Celia A. Schiffer2, and Tariq M. Rana1. (1) Chemical Biology Program, Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, 364 Plantation Street, Worcester, MA 01605, (2) Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, MA
The design, synthesis and biological evaluation of novel HIV-1 protease inhibitors incorporating N-phenyloxazolidines into the (hydroxyethylamino)sulfonamide scaffold as P2 ligands is described. Series of inhibitors with variations at P2, P2', and P1' were synthesized. Compounds with (S)-enantiomer of substituted phenyloxazolidines at P2 show highly potent inhibitory activities against wild-type HIV-1 protease. Selected inhibitors were evaluated against a panel of multi-drug resistant (MDR) mutant proteases as well as for their anti-viral potencies in cellular assays. Crystal structure analysis of the two most potent inhibitors in complex with wild-type HIV-1 protease provided valuable information on the interactions between the inhibitor and the protease enzyme.
 

Poster Session
7:00 PM-9:00 PM, Sunday, August 19, 2007 BCEC -- Exhibit Hall - B2, Poster

Division of Medicinal Chemistry

The 234th ACS National Meeting, Boston, MA, August 19-23, 2007