Journal
ACS MEDICINAL CHEMISTRY LETTERS
Volume 4, Issue 7, Pages 41-46Publisher
AMER CHEMICAL SOC
DOI: 10.1021/ml400009t
Keywords
HIV; antiretroviral; integrase; 3 ' processing; 2-hydroxy-1,3-dioxoisoquinoline-4-carboxamide
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Funding
- le Ministere de l'Enseignement Superieur et de la Recherche Francaise
- le Centre National de la Recherche Scientifique (CNRS)
- l'Agence Nationale de la Recherche contre le Sida (ANRS)
- FP7 project CHAARM
- IWT
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A series of 2-hydroxy-1,3-dioxoisoquinoline-4-carboxamides featuring an N-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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