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

doi:10.1016/j.ejmech.2016.03.083

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European Journal of Medicinal Chemistry. 2016-07-19, vol. 117, p. 256-68

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Herein, we report further insight into the biological activities displayed by the 2-hydroxyisoquinoline-1,3(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.< Réduire

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Alkylation

Anti-HIV Agents

Cell Line

Drug Resistance

Viral

HIV Integrase Inhibitors

Humans

Isoquinolines

Structure-Activity Relationship

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

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