Document Detail

Fragment-based discovery of 8-hydroxyquinoline inhibitors of the HIV-1 integrase-lens epithelium-derived growth factor/p75 (IN-LEDGF/p75) interaction.
MedLine Citation:
PMID:  23445471     Owner:  NLM     Status:  MEDLINE    
On the basis of an initial molecular modeling study suggesting the favorable binding of the "privileged" fragment 8-hydroxyquinoline with HIV-1 integrase (IN) at the IN-lens epithelium-derived growth factor/p75 (LEDGF/p75) interface , we developed a set of modified 8-hydroxyquinoline fragments demonstrating micromolar IC50 values for inhibition of the IN-LEDGF/p75 interaction, but significant cytotoxicity was associated with these initial compounds. Diverse modifications at the C5 and C7 carbons of the 8-hydroxyquinoline core improved potency, but reduction of diversity to only modifications at the C5 position ultimately yielded potent inhibitors with low cytotoxicity. Two of these particular compounds, 5-((p-tolylamino)methyl)quinolin-8-ol and 5-(((3,4-dimethylphenyl)amino)methyl)quinolin-8-ol, inhibited viral replication in MT-4 cells with low micromolar EC50. This is the first study providing evidence for 8-hydroxyquinolines as novel inhibitors of the IN-LEDGF/p75 interaction. Our lead compounds are druglike, have low molecular weights, and are amenable to various substitutions suitable for enhancing their potency and selectivity.
Erik Serrao; Bikash Debnath; Hiroyuki Otake; Yuting Kuang; Frauke Christ; Zeger Debyser; Nouri Neamati
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2013-03-18
Journal Detail:
Title:  Journal of medicinal chemistry     Volume:  56     ISSN:  1520-4804     ISO Abbreviation:  J. Med. Chem.     Publication Date:  2013 Mar 
Date Detail:
Created Date:  2013-03-28     Completed Date:  2013-05-23     Revised Date:  2013-09-17    
Medline Journal Info:
Nlm Unique ID:  9716531     Medline TA:  J Med Chem     Country:  United States    
Other Details:
Languages:  eng     Pagination:  2311-22     Citation Subset:  IM    
Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California , 1985 Zonal Avenue, Los Angeles, California 90089, USA.
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MeSH Terms
Anti-HIV Agents / chemistry,  pharmacology*,  toxicity
Cell Line
Drug Discovery*
HIV Integrase / chemistry,  metabolism*
HIV-1 / drug effects,  enzymology*
Inhibitory Concentration 50
Intercellular Signaling Peptides and Proteins / metabolism*
Models, Molecular
Oxyquinoline / chemistry,  pharmacology*,  toxicity
Piperazines / chemistry
Piperidines / chemistry
Protein Binding / drug effects
Protein Conformation
Structure-Activity Relationship
Grant Support
Reg. No./Substance:
0/Anti-HIV Agents; 0/Intercellular Signaling Peptides and Proteins; 0/Piperazines; 0/Piperidines; 0/lens epithelium-derived growth factor; 0/p31 integrase protein, Human immunodeficiency virus 1; 148-24-3/Oxyquinoline; 1RTM4PAL0V/piperazine; 67I85E138Y/piperidine; EC 2.7.7.-/HIV Integrase

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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