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2-hydroxyisoquinoline-1,3(2H,4H)-diones as inhibitors of HIV-1 integrase and reverse transcriptase RNase H domain: influence of the alkylation of position 4.

Abstract：

:We report herein the synthesis of a series of fifteen 2-hydroxyisoquinoline-1,3(2H,4H)-dione derivatives. Alkyl and arylalkyl groups were introduced on position 4 of the basis scaffold. All the compounds presented poor inhibitory properties against HIV-1 reverse transcriptase ribonuclease H (RNase H). Four compounds inhibited HIV-1 integrase at a low micromolar level. A docking study using the later crystallographic data available for PFV integrase allowed us to explain the slightly improved integrase inhibitory activities of 4-pentyl and 4-(3-phenylpropyl)-2-hydroxyisoquinoline-1,3(2H,4H)-diones, when compared to the basis scaffold. Physicochemical studies were consistent with 1:1 and 1:2 (metal/ligand) stoichiometries of the magnesium complexes in solution. Unfortunately all tested compounds exhibited high cellular cytotoxicity in cell culture which limited their applications as antiviral agents. However these identified integrase inhibitors provide a very good basis for the development of new hits.

journal_name

Eur J Med Chem

journal_title

European journal of medicinal chemistry

authors

Billamboz M,Bailly F,Lion C,Calmels C,Andréola ML,Witvrouw M,Christ F,Debyser Z,De Luca L,Chimirri A,Cotelle P

doi

10.1016/j.ejmech.2010.11.033

subject

Has Abstract

pub_date

2011-02-01 00:00:00

pages

535-46

issue

2

eissn

0223-5234

issn

1768-3254

pii

S0223-5234(10)00828-7

journal_volume

46

pub_type

杂志文章

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