Discovery of novel non-cyclam polynitrogenated CXCR4 coreceptor inhibitors

Sofia Pettersson, Violeta I. Pérez-Nueno, Laia Ros-Blanco, Raimon Puig De La Bellacasa, María Obdulia Rabal, Xavier Batllori, Bonaventura Clotet, Imma Clotet-Codina, Mercedes Armand-Ugón, José Esté, José I. Borrell, Jordi Teixidó

Research output: Indexed journal article Articlepeer-review

17 Citations (Scopus)


HIV cell fusion and entry have been validated as targets for therapeutic intervention against infection. Bicyclams were the first low-molecular-weight compounds to show specific interaction with CXCR4. The most potent bicyclam was AMD3100, in which the two cyclam moieties are tethered by a 1,4-phenylenebis- (methylene) bridge. It was withdrawn from clinical trials owing to its lack of oral bioavailability and cardiotoxicity. We have designed a combinatorial library of non-cyclam polynitrogenated compounds by preserving the main features of AMD3100. At least two nitrogen atoms on each side of the p-phenylene moiety, one in the benzylic position and the other(s) in the heterocyclic system were maintained, and the distances between them were similar to the nitrogen atom distances in cyclam. A selection of diverse compounds from this library were prepared, and their in vitro activity was tested in cell cultures against HIV strains. This led to the identification of novel potent CXCR4 coreceptor inhibitors without cytotoxicity at the tested concentrations.

Original languageEnglish
Pages (from-to)1549-1557
Number of pages9
Issue number10
Publication statusPublished - 20 Oct 2008


  • Antiviral agents
  • Heterocycles
  • Medicinal chemistry
  • Molecular modeling
  • Reductive amination


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