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

4‑Substituted 2‑Hydroxyisoquinoline-1,3(2<i>H</i>,4<i>H</i>)‑diones as a Novel Class of HIV‑1 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 IC₅₀ 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 3′ processing (3′-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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