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J Med Chem. 2014 Jun 12;57(11):4640-60. doi: 10.1021/jm500109z. Epub 2014 May 14.

Investigation of a novel series of 2-hydroxyisoquinoline-1,3(2H,4H)-diones as human immunodeficiency virus type 1 integrase inhibitors.

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Université Lille Nord de France , F-59000 Lille, France.


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.

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