title: Design and optimization of tricyclic phtalimide analogues as novel inhibitors of HIV-1 integrase.
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.
authors.affiliation: Tibotec BVBA, Generaal de Wittelaan L 11B 3, B-2800 Mechelen, Belgium. wversch1@tibbe.jnj.com
authors.forename: Wim G
authors.initials: WG
authors.lastname: Verschueren
authors.forename: Inge
authors.initials: I
authors.lastname: Dierynck
authors.forename: Katie I E
authors.initials: KI
authors.lastname: Amssoms
authors.forename: Lili
authors.initials: L
authors.lastname: Hu
authors.forename: Paul M J G
authors.initials: PM
authors.lastname: Boonants
authors.forename: Geert M E
authors.initials: GM
authors.lastname: Pille
authors.forename: Frits F D
authors.initials: FF
authors.lastname: Daeyaert
authors.forename: Kurt
authors.initials: K
authors.lastname: Hertogs
authors.forename: Dominique L N G
authors.initials: DL
authors.lastname: Surleraux
authors.forename: Piet B T P
authors.initials: PB
authors.lastname: Wigerinck
mesh_terms: D019380:Anti-HIV Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001665:Binding Sites; D002460:Cell Line; D019427:HIV Integrase / Q000737:chemistry / Q000378:metabolism*; D019428:HIV Integrase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D015497:HIV-1 / Q000187:drug effects; D006575:Heterocyclic Compounds, 3-Ring / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D008958:Models, Molecular; D010797:Phthalimides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011485:Protein Binding; D011758:Pyrroles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011810:Quinoxalines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: C500069:7-(3,4-dichlorobenzyl)-5,9-dihydroxypyrrolo(3,4-g)quinoxaline-6,8-dione; C500070:7-(4-chlorobenzyl)-5,9-dihydroxypyrrolo(3,4-g)quinoxaline-6,8-dione; D019380:Anti-HIV Agents; D019428:HIV Integrase Inhibitors; D006575:Heterocyclic Compounds, 3-Ring; D010797:Phthalimides; D011758:Pyrroles; D011810:Quinoxalines; D019427:HIV Integrase