6 research outputs found
Investigation of a novel series of 2-hydroxyisoquinoline-1,3(2H,4H)-diones as human immunodeficiency virus type 1 integrase inhibitors
We report herein further insight into the biological activities displayed by a series of 2-hydroxyisoquinoline-1,3(2H,4H)-diones (HIDs). Substitution of the N-hydroxyimide two-metal binding pharmacophore at position 4 by carboxamido side chains was previously shown by us to be fruitful for this scaffold, since strong human immunodeficiency virus type 1 integrase (HIV-1 IN) inhibitors in the low nanomolar range associated with low micromolar anti-HIV activities were obtained. We investigated the influence of substitution at position 7 on biological activity. Introduction of electron-withdrawing functional groups such as the nitro moiety at position 7 led to a noticeable improvement of antiviral activity, down to low nanomolar anti-HIV potencies, with advantageous therapeutic indexes going close to those of the clinically used raltegravir and retained potencies against a panel of IN mutants.status: publishe
Investigation of a novel series of 2-hydroxyisoquinoline-1,3(2H,4H)-diones as human immunodeficiency virus type 1 integrase inhibitors.
International audienceWe report herein further insight into the biological activities displayed by a series of 2-hydroxyisoquinoline-1,3(2H,4H)-diones (HIDs). Substitution of the N-hydroxyimide two-metal binding pharmacophore at position 4 by carboxamido side chains was previously shown by us to be fruitful for this scaffold, since strong human immunodeficiency virus type 1 integrase (HIV-1 IN) inhibitors in the low nanomolar range associated with low micromolar anti-HIV activities were obtained. We investigated the influence of substitution at position 7 on biological activity. Introduction of electron-withdrawing functional groups such as the nitro moiety at position 7 led to a noticeable improvement of antiviral activity, down to low nanomolar anti-HIV potencies, with advantageous therapeutic indexes going close to those of the clinically used raltegravir and retained potencies against a panel of IN mutants
4âSubstituted 2âHydroxyisoquinoline-1,3(2<i>H</i>,4<i>H</i>)âdiones as a Novel Class of HIVâ1 Integrase Inhibitors
A series of 2-hydroxy-1,3-dioxoisoquinoline-4-carboxamides
featuring an <i>N</i>-hydroxyimide chelating functionality
was evaluated for their inhibitory properties against human immunodeficiency
virus type 1 integrase (HIV-1 IN). Several derivatives displayed low
nanomolar IC<sub>50</sub> values comparable to that of the clinically
used raltegravir. A marked effect of one compound on both primary
IN-catalyzed reactions, strand transfer (ST), and 3âČ processing
(3âČ-P), emphasizes a novel IN inhibition mechanism establishing
it as a potential new generation IN inhibitor. Substitution of the
2-hydroxyisoquinoline-1,3-dione scaffold at position 4 by carboxamido
chains was beneficial for antiviral activity since reproducible low
micromolar anti-HIV activities were obtained for the first time within
this scaffold
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International audienceLe site de référence du Partenariat européen d'innovation pour un vieillissement actif et en bonne santé MACVIA-LR (contre les maladies chroniques pour un vieillissement en bonne santé en Languedoc-Roussillon