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  • Title: Design and optimization of tricyclic phtalimide analogues as novel inhibitors of HIV-1 integrase.
    Author: Verschueren WG, Dierynck I, Amssoms KI, Hu L, Boonants PM, Pille GM, Daeyaert FF, Hertogs K, Surleraux DL, Wigerinck PB.
    Journal: J Med Chem; 2005 Mar 24; 48(6):1930-40. PubMed ID: 15771437.
    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 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.
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