title: Design and synthesis of HIV-1 protease inhibitors incorporating oxazolidinones as P2/P2' ligands in pseudosymmetric dipeptide isosteres.
abstract: A 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.
authors: Chemical Biology Program and Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, Massachusetts 01605, USA.
authors: G S Kiran Kumar
authors: GS
authors: Reddy
authors: Akbar
authors: A
authors: Ali
authors: Madhavi N L
authors: MN
authors: Nalam
authors: Saima Ghafoor
authors: SG
authors: Anjum
authors: Hong
authors: H
authors: Cao
authors: Robin S
authors: RS
authors: Nathans
authors: Celia A
authors: CA
authors: Schiffer
authors: Tariq M
authors: TM
authors: Rana
mesh_terms: D002460:Cell Line; D004151:Dipeptides / Q000737:chemistry*; D015195:Drug Design; D024921:Drug Resistance, Multiple, Viral; D016333:HIV Protease / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D017320:HIV Protease Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D015497:HIV-1 / Q000187:drug effects* / Q000201:enzymology; D006801:Humans; D008024:Ligands; D061466:Lopinavir; D008958:Models, Molecular; D015394:Molecular Structure; D023303:Oxazolidinones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011744:Pyrimidinones / Q000737:chemistry; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D004151:Dipeptides; D017320:HIV Protease Inhibitors; D008024:Ligands; D023303:Oxazolidinones; D011744:Pyrimidinones; D061466:Lopinavir; D016333:HIV Protease
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