Styrylquinoline Derivatives:  A New Class of Potent HIV-1 Integrase Inhibitors That Block HIV-1 Replication in CEM Cells

Abstract

On the basis of the fact that several polynucleotidyl transferases, related to HIV integrase, contain in their active site two divalent metal cations, separated by ca. 4 A, new potential HIV integrase inhibitors 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 contain the catechol structure, this group is not essential for the activity, since compound 21 that lacks such a moiety is a potent drug, implicating the presence of a different pharmacophore. The most promising styrylquinolines thus synthesized inhibit HIV-1 integrase in vitro at micromolar or submicromolar concentrations and block HIV replication in CEM cells, with no significant cellular toxicity in a 5-day period assay. These inhibitors are active against integrase core domain-mediated disintegration, suggesting that fragment 50-212 is their actual target. These new styrylquinolines may provide lead compounds for the development of novel antiretroviral agents for AIDS therapeutics, based upon inhibition of HIV integrase. They might also be used in the elucidation of the mechanism of inhibition of this enzyme; e.g., they could serve as candidates for cocrystallization studies with HIV integrase.

HIV-1 Integrase Inhibition of Biscoumarin Analogues

“…The compounds were screened for their inhibitory activity in a 3Ј-processing assay which was performed as described previously. 3,10) Effects against the strand transfer activity were evaluated during the same assay from the homologous integration events and found to be no significant differences from 3Ј-processing inhibition, thus confirming that coumarins affect equally both steps of the integration reaction. Table 1 lists the inhibitory activity of a series of mono-or bis-hydroxylated benzoyl biscoumarins against the recombinant wild-type HIV-1 IN enzyme.…”

Synthesis and HIV-1 Integrase Inhibition of Novel Bis- or Tetra-Coumarin Analogues

“…20,21) Effects against the strand transfer activity were evaluated during the same assay from the homologous integration events and found to be no significantly different from 3Ј-processing inhibition, thus confirming that coumarins affect equally both steps of the integration reaction. Table 1 lists the inhibitory activity of a series of bis-or tetra-coumarin analogues against the recombinant wild-type HIV-1 IN enzyme.…”

Synthesis and Anti-Human Immunodeficiency Virus Type 1 Integrase Activity of Hydroxybenzoic and Hydroxycinnamic Acid Flavon-3-yl Esters

“…Recently, it has also been shown that in case of quinoline derivatives the presence of the catechol structure with free hydroxyl groups is not essential for activity but it may be replaced by a carboxyl or a cyano group (Mekouar et al, 1998). Furthermore, the presence of a carboxyl group has been shown to decrease the cytotoxicity of some derivatives (Mekouar et al, 1998).…”