2-hydroxyisoquinoline-1,3(2H,4H)-diones (HIDs) as human immunodeficiency virus type 1 integrase inhibitors: Influence of the alkylcarboxamide substitution of position 4

被引：11
作者：
Billamboz, Muriel [1 ,2 ]
Suchaud, Virginie [1 ,2 ]
Bailly, Fabrice [1 ,2 ]
Lion, Cedric [1 ,3 ]
Andreola, Marie-Line [4 ]
Christ, Frauke [5 ,6 ]
Debyser, Zeger [5 ,6 ]
Cotelle, Philippe [1 ,2 ]
机构：
[1] Univ Lille Nord France, F-59000 Lille, France
[2] Fac Sci Pharmaceut & Biol, Ctr Rech Jean Pierre Aubert, UMR S1172, 3 Rue Prof Laguesse,BP83, F-59006 Lille, France
[3] CNRS, UMR 8576, Unite Glycobiol Struct & Fonct, F-59655 Villeneuve Dascq, France
[4] Univ Bordeaux Segalen, Lab MFP, CNRS, UMR 5234,FR Transbiomed, 146 Rue Leo Saignat, F-33076 Bordeaux, France
[5] Katholieke Univ Leuven, Mol Med, Kapucijnenvoer 33, B-3000 Leuven, Flanders, Belgium
[6] IRC KULAK, Kapucijnenvoer 33, B-3000 Leuven, Flanders, Belgium
来源：
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY | 2016年 / 117卷
关键词：
HIV-1; integrase; Two-metal binding pharmacophore; Antiretroviral; 2-hydroxyisoquinoline-1,3(2H,4H)-diones; STRAND TRANSFER INHIBITORS; HIV-INTEGRASE; DRUG-RESISTANCE; DOUBLE-BLIND; RNASE-H; ELVITEGRAVIR; RALTEGRAVIR; DISCOVERY; SERIES; DOLUTEGRAVIR;
D O I：
10.1016/j.ejmech.2016.03.083
中图分类号：
R914 [药物化学];
学科分类号：
100701 ;
摘要：
Herein, we report further insight into the biological activities displayed by the 2-hydroxyisoquinoline1,3(2H,4H)-dione (HID) scaffold. Previous studies have evidenced the marked fruitful effect of substitution of this two-metal binding pharmacophore at position 4 by phenyl and benzyl carboxamido chains. Strong human immunodeficiency virus type 1 integrase (HIV-1 IN) inhibitors in the low nanomolar range with micromolar (even down to low nanomolar) anti-HIV activities were obtained. Keeping this essential 4-carboxamido function, we investigated the influence of the replacement of phenyl and benzyl groups by various alkyl chains. This study shows that the recurrent halogenobenzyl pharmacophore found in the INSTIs can be efficiently replaced by an n-alkyl group. With an optimal length of six carbons, we observed a biological profile and a high barrier to resistance equivalent to those of a previously reported hit compound bearing a 4-fluorobenzyl group. (C) 2016 Elsevier Masson SAS. All rights reserved.
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收藏
页码：256 / 268
页数：13
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