Styrylquinoline Derivatives: A New Class of Potent HIV-1 Integrase Inhibitors That Block HIV-1 Replication in CEM Cells
- 25 June 1998
- journal article
- research article
- Published by American Chemical Society (ACS) in Journal of Medicinal Chemistry
- Vol. 41 (15), 2846-2857
- https://doi.org/10.1021/jm980043e
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 Å, 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.This publication has 38 references indexed in Scilit:
- Hiv integrase: a target for aids therapeuticsTrends in Biotechnology, 1997
- The catalytic domain of human immunodeficiency virus integrase: ordered active site in the F185H mutantFEBS Letters, 1996
- Inhibition of the Human Immunodeficiency Virus Type 1 Integrase by Guanosine Quartet StructuresBiochemistry, 1996
- Different enzymes with similar structures involved in Mg2+-mediated polynucleotidyl transferNature Structural & Molecular Biology, 1995
- Effect of Topoisomerase Inhibitors on the in Vitro HIV DNA Integration ReactionBiochemical and Biophysical Research Communications, 1993
- Inhibition of HIV-1 integration protein by aurintricarboxylic acid monomers, monomer analogs, and polymer fractionsBiochemical and Biophysical Research Communications, 1992
- Potentially Amyloidogenic, Carboxyl-Terminal Derivatives of the Amyloid Protein PrecursorScience, 1992
- Structural details of ribonuclease H from Escherichia coli as refined to an atomic resolutionJournal of Molecular Biology, 1992
- Syntheses of Some Medium Sized Cyclic Triamines and Their Cobalt(III) ComplexesBulletin of the Chemical Society of Japan, 1972
- 7‐formyl‐8‐quinolinolsJournal of Heterocyclic Chemistry, 1967