Design and synthesis of HIV-1 protease inhibitors incorporating oxazolidinones as P2/P2' ligands in pseudosymmetric dipeptide isosteres

MEDI 90

G. S. Kiran Kumar Reddy1, Akbar Ali1, Madhavi N. L. Nalam2, Saima Ghafoor Anjum1, Hong Cao1, Robin S. Nathan1, 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 based on hydroxyethylene and (hydroxyethyl)hydrazine dipeptide isosteres incorporating N-phenyloxazolidinone-5-carboxamides as P2 and P2' ligands are described. In addition to their inhibitory activities against wild-type protease, selected compounds were further evaluated for their activities against a panel of multidrug-resistant (MDR) protease variants and for their antiviral potencies in MT-4 cells. The crystal structures of lopinavir (LPV) and two new inhibitors containing phenyloxazolidinone-based ligands in complex with wild-type HIV-1 protease are also presented.
 

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