title: Fragment-based discovery of 8-hydroxyquinoline inhibitors of the HIV-1 integrase-lens epithelium-derived growth factor/p75 (IN-LEDGF/p75) interaction.
abstract: 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.
authors: Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California , 1985 Zonal Avenue, Los Angeles, California 90089, USA.
authors: Erik
authors: E
authors: Serrao
authors: Bikash
authors: B
authors: Debnath
authors: Hiroyuki
authors: H
authors: Otake
authors: Yuting
authors: Y
authors: Kuang
authors: Frauke
authors: F
authors: Christ
authors: Zeger
authors: Z
authors: Debyser
authors: Nouri
authors: N
authors: Neamati
mesh_terms: D019380:Anti-HIV Agents / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D002460:Cell Line; D055808:Drug Discovery; D019427:HIV Integrase / Q000737:chemistry / Q000378:metabolism*; D015497:HIV-1 / Q000187:drug effects / Q000201:enzymology*; D006801:Humans; D020128:Inhibitory Concentration 50; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D008958:Models, Molecular; D015125:Oxyquinoline / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D000077489:Piperazine; D010879:Piperazines / Q000737:chemistry; D010880:Piperidines / Q000737:chemistry; D011485:Protein Binding / Q000187:drug effects; D011487:Protein Conformation; D013329:Structure-Activity Relationship
chemical_list: D019380:Anti-HIV Agents; D036341:Intercellular Signaling Peptides and Proteins; D010879:Piperazines; D010880:Piperidines; C119380:lens epithelium-derived growth factor; D000077489:Piperazine; D015125:Oxyquinoline; C032727:piperidine; D019427:HIV Integrase; C514801:p31 integrase protein, Human immunodeficiency virus 1