Medicinal Chemistry Research

, Volume 20, Issue 3, pp 339–345 | Cite as

6-Imino-2-thioxo-pyrimidinones as a new class of dipeptidyl peptidase IV inhibitors

  • Dubravko JelićEmail author
  • Krunoslav Nujić
  • Višnja Stepanić
  • Krunoslav Kovačević
  • Donatella Verbanac
Original Research


Dipeptidyl peptidase IV is a glycoprotein which removes N-terminal dipeptides from physiologically relevant polypeptides. An homologous series of 6-imino-2-thioxo-5-{[3,4,5-tris(methyloxy)phenyl]methyl}-2,5-dihydro-4(3H)-pyrimidinones has been tested for inhibition of DPP IV activity. The inhibitory effects at 0.1 mM were observed. Enzyme kinetic studies revealed that compounds inhibit DPP IV activity competitively. According to the molecular docking analysis, the inhibitors are anchored into the DPP IV hydrolytic site by interactions of the pyrimidinone core with Glu206, Tyr662, and Tyr547, with the alkyl chain entering the S1 pocket. We conclude that pyrimidinone-like compounds are a promising new scaffold for reversible inhibition of DPP IV.


DPP IV inhibitor Pyrimidinone Enzyme kinetics Molecular docking Cytotoxicity 



Dipeptidyl peptidase IV


Glucagon-like peptide-1


Glucose-dependent insulinotropic polypeptide


Structure–activity relationship


Root mean square deviation


Protein Data Bank


Genetic optimisation for ligand docking




European Collection of Cell Cultures


Human monocytic leukemia


Human Caucasian hepatocyte carcinoma



Special thanks to Professor Michael J. Parnham for his help in editing and critical reviewing of this manuscript, as well as to Dr. Andrew Leach for useful remarks. The authors are grateful to Snježana Dragojević for analytical characterization of the tested compounds. We also appreciate the excellent technical assistance provided by Ana Cvetković, Klara Markušić and Željka Tolić.


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Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  • Dubravko Jelić
    • 1
    Email author
  • Krunoslav Nujić
    • 1
  • Višnja Stepanić
    • 1
    • 2
  • Krunoslav Kovačević
    • 1
  • Donatella Verbanac
    • 1
    • 3
  1. 1.GlaxoSmithKline Research Center Zagreb Ltd.ZagrebCroatia
  2. 2.Department for Molecular MedicineRuđer Bošković InstituteZagrebCroatia
  3. 3.University of Zagreb, School of Medicine, Center for Translational and Clinical ResearchZagrebCroatia

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