Structure-activity relationships and binding mode of styrylquinolines as potent inhibitors of HIV-1 integrase and replication of HIV-1 in cell culture

Our prior studies showed that polyhydroxylated styrylquinolines are potent HIV-1 integrase (IN) inhibitors that block the replication of HIV-1 in cell culture at nontoxic concentrations. To explore the mechanism of action of these inhibitors, various novel styrylquinoline derivatives were synthesize d and tested against HIV-1 IN and in cell-based assays. Regarding the in vi tro experiments, the structural requirements for biological activity are a carboxyl group at C-7, a hydroxyl group at C-8 in the quinoline subunit, an d an ancillary phenyl ring. However the in vitro inhibitory profile tolerat es deep alterations of this ring, e.g. by the introduction of various subst ituents or its replacement by heteroatomic nuclei. Regarding the ex vivo as says, the structural requirements for activity are more stringent than for in vitro inhibition. Thus, in addition to an o-hydroxy acid group in the qu inoline, the presence of one ortho pair of substituents at C-3' and C-4', p articularly two hydroxyl groups, in the ancillary phenyl ring is imperative ly required for inhibitory potency. Starting from literature data and the S ARs developed in this work, a putative binding mode of styrylquinoline inhi bitors to HIV-1 IN was derived.