Reddy, G. S. Kiran KumarAli, AkbarNalam, Madhavi N. L.Anjum, Saima G.Cao, HongNathans, Robin S.Schiffer, Celia A.Rana, Tariq M.2022-08-232022-08-232007-08-192010-02-05J Med Chem. 2007 Sep 6;50(18):4316-28. Epub 2007 Aug 16. <a href="http://dx.doi.org/10.1021/jm070284z">Link to article on publisher's site</a>0022-2623 (Print)10.1021/jm070284z17696512https://hdl.handle.net/20.500.14038/26133A 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.en-USCell LineDipeptidesDrug DesignDrug Resistance, Multiple, ViralHIV ProteaseHIV Protease InhibitorsHIV-1HumansLigandsModels, MolecularMolecular StructureOxazolidinonesPyrimidinonesStereoisomerismStructure-Activity RelationshipBiochemistry, Biophysics, and Structural BiologyPharmacology, Toxicology and Environmental HealthJournal Articlehttps://escholarship.umassmed.edu/bmp_pp/711134044bmp_pp/71