Design and Synthesis of HIV-1 Protease Inhibitors Incorporating Oxazolidinones as P2/P2' Ligands in Pseudosymmetric Dipeptide Isosteres

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• 作者：G. S. Kiran Kumar Reddy ; Akbar Ali ; Madhavi N. L. Nalam ; Saima Ghafoor Anjum ; Hong Cao ; Robin S. Nathans ; Celia A. Schiffer ; Tariq M. Rana
• 刊名：Journal of Medicinal Chemistry
• 出版年：2007
• 出版时间：September 6, 2007
• 年：2007
• 卷：50
• 期：18
• 页码：4316 - 4328
• 全文大小：458K
• 年卷期：v.50,no.18(September 6, 2007)
• ISSN：1520-4804

文摘

A series of novel HIV-1 protease inhibitors based on two pseudosymmetric dipeptide isosteres have beensynthesized 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 groupshowed low nM inhibitory activities against wild-type HIV-1 protease. Selected compounds were furtherevaluated for their inhibitory activities against a panel of multidrug-resistant protease variants and for theirantiviral potencies in MT-4 cells. The crystal structures of lopinavir (LPV) and two new inhibitors containingphenyloxazolidinone-based ligands in complex with wild-type HIV-1 protease have been determined. Acomparison of the inhibitor-protease structures with the LPV-protease structure provides valuable insightinto the binding mode of the new inhibitors to the protease enzyme. Based on the crystal structures andknowledge of structure-activity relationships, new inhibitors can be designed with enhanced enzymeinhibitory and antiviral potencies.