Phthalazine PDE IV inhibitors: Conformational study of some 6-methoxy-1,4-disubstituted derivatives

Thomas Haack, Raimondo Fattori, Mauro Napoletano, Franco Pellacini, Giovanni Fronza, Giuseppina Raffaini, Fabio Ganazzoli

Research output: Contribution to journalArticle

Abstract

This report describes the detailed conformational analysis and synthesis of a series of phthalazine phosphodiesterase-type (IV) (PDE IV) inhibitors bearing either mono- or dichloro 4-methylenepyridine at the 'down' position of the phthalazine nucleus or different heterocycles at the 'top' position 4 of the phthalazine moiety. Both the mono- and dichloro 4-methylenepyridine units linked at carbon C1 of the phthalazine nucleus show identical conformational behaviour with the substituent preferentially oriented towards the external part of the molecule and the pyridine plane almost orthogonal to that of phthalazine ring. The heterocyclic five-membered rings linked at carbon C4 of phthalazine show quite different conformational behaviour. The 1,3-thiazole ring exists in a well-defined conformation almost coplanar with respect to the phthalazine nucleus while the 1,2,4-triazole and the 1,3-diazole heterocycles show a great conformational freedom with large torsion angles. Compound 3 bearing the thiazole ring at C4 displays the major biological activity, thus suggesting that a planar and rather rigid conformation of the pentacycle should favour the PDE IV inhibition capacity of this class of compounds.

Original languageEnglish
Pages (from-to)4425-4433
Number of pages9
JournalBioorganic and Medicinal Chemistry
Volume13
Issue number14
DOIs
Publication statusPublished - Jul 15 2005

Keywords

  • Conformational analysis
  • Molecular dynamics
  • NMR
  • PDE IV inhibitors

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Organic Chemistry
  • Drug Discovery
  • Pharmaceutical Science

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    Haack, T., Fattori, R., Napoletano, M., Pellacini, F., Fronza, G., Raffaini, G., & Ganazzoli, F. (2005). Phthalazine PDE IV inhibitors: Conformational study of some 6-methoxy-1,4-disubstituted derivatives. Bioorganic and Medicinal Chemistry, 13(14), 4425-4433. https://doi.org/10.1016/j.bmc.2005.04.057