jm070284z_si_001.pdf (69.23 kB)
Design and Synthesis of HIV-1 Protease Inhibitors Incorporating Oxazolidinones as P2/P2‘ Ligands in Pseudosymmetric Dipeptide Isosteres
journal contribution
posted on 2007-09-06, 00:00 authored by G. S. Kiran Kumar Reddy, Akbar Ali, Madhavi N. L. Nalam, Saima Ghafoor Anjum, Hong Cao, Robin S. Nathans, Celia A. Schiffer, Tariq M. RanaA series of novel HIV-1 protease inhibitors based on two pseudosymmetric dipeptide isosteres have been
synthesized and evaluated. The inhibitors were designed by incorporating N-phenyloxazolidinone-5-carboxamides into the hydroxyethylene and (hydroxyethyl)hydrazine dipeptide isosteres as P2 and P2‘ ligands.
Compounds with (S)-phenyloxazolidinones attached at a position proximal to the central hydroxyl group
showed low nM inhibitory activities against wild-type HIV-1 protease. Selected compounds were further
evaluated for their inhibitory activities against a panel of multidrug-resistant 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 have been determined. A
comparison of the inhibitor−protease structures with the LPV−protease structure provides valuable insight
into the binding mode of the new inhibitors to the protease enzyme. Based on the crystal structures and
knowledge of structure−activity relationships, new inhibitors can be designed with enhanced enzyme
inhibitory and antiviral potencies.