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, 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.
Unité de Chimie Organique, URA du CNRS 1843, Centre d'Etudes Pharmaceutiques, Université Paris-Sud, 5 rue J.-B. Clément, 92296 Châtenay-Malabry, France.
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Mekouar
J F
JF
Mouscadet
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Desmaële
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Subra
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Leh
D
D
Savouré
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Auclair
J
J
d'Angelo
D019380:Anti-HIV Agents / Q000138:chemical synthesis / Q000494:pharmacology / Q000633:toxicity; D002461:Cell Line, Transformed; D019427:HIV Integrase / Q000235:genetics / Q000378:metabolism; D019428:HIV Integrase Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology / Q000633:toxicity; D015497:HIV-1 / Q000187:drug effects* / Q000201:enzymology / Q000502:physiology; D006801:Humans; D009154:Mutation; D011804:Quinolines / Q000138:chemical synthesis / Q000494:pharmacology / Q000633:toxicity; D017384:Sequence Deletion; D013343:Styrenes / Q000138:chemical synthesis / Q000494:pharmacology / Q000633:toxicity; D014407:Tumor Cells, Cultured; D014779:Virus Replication / Q000187:drug effects*
D019380:Anti-HIV Agents; D019428:HIV Integrase Inhibitors; D011804:Quinolines; D013343:Styrenes; D019427:HIV Integrase