STYRYLQUINOLINE DERIVATIVES - A NEW CLASS OF POTENT HIV-1 INTEGRASE INHIBITORS THAT BLOCK HIV-1 REPLICATION IN CEM CELLS

On the basis of the fact that several polynucleotidyl transferases, re lated to HIV integrase, contain in their active site two divalent meta l cations, separated by ca. 4 Angstrom, new potential HIV integrase in hibitors were designed, in which a quinoline substructure is linked to an aryl nucleus possessing various hydroxy substitution patterns, by means of an ethylenic spacer. Although the most active compounds conta in the catechol structure, this group is not essential for the activit y, since compound 21 that lacks such a moiety is a potent drug, implic ating the presence of a different pharmacophore. The most promising st yrylquinolines thus synthesized inhibit HIV-1 integrase in vitro at mi cromolar or submicromolar concentrations and block HIV replication in CEM cells, with no significant cellular toxicity in a 5-day period ass ay. These inhibitors are active against integrase core domain-mediated disintegration, suggesting that fragment 50-212 is their actual targe t. These new styrylquinolines may provide lead compounds for the devel opment of novel antiretroviral agents for AIDS therapeutics, based upo n inhibition of HIV integrase. They might also be used in the elucidat ion of the mechanism of inhibition of this enzyme; e.g., they could se rve as candidates for cocrystallization studies with HIV integrase.