Design and optimization of tricyclic phtalimide analogues as novel inhibitors of HIV-1 integrase
| Autor: | Geert M. E. Pille, Kurt Hertogs, Katie I. E. Amssoms, Lili Hu, Inge Dierynck, Paul M. J. G. Boonants, Wim G. Verschueren, Frits Daeyaert, Surleraux Dominique Louis Nest, Piet Wigerinck |
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| Rok vydání: | 2005 |
| Předmět: |
Models
Molecular Anti-HIV Agents viruses Phthalimides HIV Integrase Virus Cell Line Structure-Activity Relationship Quinoxalines Drug Discovery Humans Pyrroles HIV Integrase Inhibitors chemistry.chemical_classification Binding Sites biology biology.organism_classification Nucleotidyltransferase Virology Integrase Enzyme chemistry Viral replication Biochemistry Enzyme inhibitor Lentivirus biology.protein HIV-1 Molecular Medicine Heterocyclic Compounds 3-Ring Tricyclic Protein Binding |
| Zdroj: | Journal of medicinal chemistry. 48(6) |
| ISSN: | 0022-2623 |
| Popis: | 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 IC(50) 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 EC(50) of 270 nM against HIV-1 in a cell-based assay. |
| Databáze: | OpenAIRE |
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