Design and Optimization of Tricyclic Phtalimide Analogues as Novel Inhibitors of HIV-1 Integrase
- 16 November 2004
- journal article
- research article
- Published by American Chemical Society (ACS) in Journal of Medicinal Chemistry
- Vol. 48 (6) , 1930-1940
- https://doi.org/10.1021/jm049559q
Abstract
Human immunodeficiency virus type-1 integrase is an essential enzyme for effective viral replication and hence a valid target for the design of inhibitors. We report here on the design and synthesis of a novel series of phthalimide analogues as integrase inhibitors. The short synthetic pathway enabled us to synthesize a series of analogues with a defined structure diversity. The presence of a single carbonyl−hydroxy−aromatic nitrogen motif was shown to be essential for the enzymatic activity and this was confirmed by molecular docking studies. The enzymatically most active compound from this series is 7-(3,4-dichlorobenzyl)-5,9-dihydroxypyrrolo[3,4-g]quinoxaline-6,8-dione (15l) with an IC50 value of 112 nM on the HIV-1 integrase enzyme, while ((7-(4-chlorobenzyl)-5,9-dihydroxy-pyrrolo[3,4-g]quinoxaline-6,8-dione (15k)) showed an EC50 of 270 nM against HIV-1 in a cell-based assay.Keywords
This publication has 15 references indexed in Scilit:
- HIV-1 integrase: a target for new AIDS chemotherapeutics.Current Topics in Medicinal Chemistry, 2004
- Development of Resistance against Diketo Derivatives of Human Immunodeficiency Virus Type 1 by Progressive Accumulation of Integrase MutationsJournal of Virology, 2003
- Metal-Dependent Inhibition of HIV-1 Integrase by β-Diketo Acids and Resistance of the Soluble Double-Mutant (F185K/C280S)Molecular Pharmacology, 2003
- Diketo acid inhibitor mechanism and HIV-1 integrase: Implications for metal binding in the active site of phosphotransferase enzymesProceedings of the National Academy of Sciences, 2002
- Patented small molecule inhibitors of HIV-1 integrase: a 10-year sagaExpert Opinion on Therapeutic Patents, 2002
- Active Site Binding Modes of HIV-1 Integrase InhibitorsJournal of Medicinal Chemistry, 2000
- HIV-1 Integrase Inhibitor Interactions at the Active Site: Prediction of Binding Modes Unaffected by Crystal PackingJournal of the American Chemical Society, 2000
- The Mobility of an HIV-1 Integrase Active Site Loop Is Correlated with Catalytic Activity,Biochemistry, 1999
- Crystal structures of the catalytic domain of HIV-1 integrase free and complexed with its metal cofactor: high level of similarity of the active site with other viral integrases 1 1Edited by R. HuberJournal of Molecular Biology, 1998
- Crystal Structure of the Catalytic Domain of HIV-1 Integrase: Similarity to Other Polynucleotidyl TransferasesScience, 1994