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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

Abstract : 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.
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https://hal.univ-lille.fr/hal-03174247
Contributeur : Lilloa Université de Lille <>
Soumis le : vendredi 19 mars 2021 - 09:08:11
Dernière modification le : samedi 20 mars 2021 - 03:31:38

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Muriel Billamboz, Virginie Suchaud, Fabrice Bailly, Cedric Lion, Marie-Line Andreola, et al.. 2-hydroxyisoquinoline-1,3(2H,4H)-diones (HIDs) as human immunodeficiency virus type 1 integrase inhibitors: Influence of the alkylcarboxamide substitution of position 4. European Journal of Medicinal Chemistry, Elsevier, 2016, European journal of medicinal chemistry, 117, pp.256-268. ⟨10.1016/j.ejmech.2016.03.083⟩. ⟨hal-03174247⟩

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