Journal of medicinal chemistry vol:56 issue:6 pages:2311-2322
We describe a fragment-based approach for the discovery of a novel class of inhibitors of the HIV-1 integrase (IN) interaction with the cellular cofactor lens epithelium-derived growth factor (LEDGF/p75). On the basis of an initial molecular modeling study suggesting the favorable binding of the "privileged" fragment 8-hydroxyquinoline with IN at the IN-LEDGF/p75 interface, a set of modified 8-hydroxyquinoline fragments was evaluated for potency with an established AlphaScreen assay. Micromolar IC50 values for inhibition of IN-LEDGF/p75 were observed, 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. An approximately 7-fold increase in potency and reduction in cytotoxicity was achieved from the initial 8-hydroxyquinoline fragments to our most potent lead compound. This is the first study providing evidence for 8-hydroxyquinolines as novel inhibitors of the IN-LEDGF/p75 interaction. Our lead compounds are drug-like, have low molecular weights, and are amenable to various substitutions suitable for enhancing their potency and selectivity.