SUCHAUD, Virginie; BAILLY, Fabrice; LION, Cedric; CALMELS, Christina; ANDRÉOLA, Marie-Line; CHRIST, Frauke; DEBYSER, Zeger; COTELLE, Philippe

doi:10.1021/jm500109z

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Journal of Medicinal Chemistry. 2014-06-12, vol. 57, n° 11, p. 4640-60

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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.< Réduire

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Aryl Hydrocarbon Hydroxylases

Cell Line

Tumor

Cytochrome P-450 CYP2C9

Cytochrome P-450 CYP3A

Cytochrome P-450 CYP3A Inhibitors

Drug Resistance

Viral

HIV Integrase Inhibitors

HIV-1

Humans

Isoquinolines

Molecular Docking Simulation

Mutation

Structure-Activity Relationship

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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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