Synthesis, Structure-Activity Relationship, and Pharmacophore Modeling Studies of Pyrazole-3-Carbohydrazone Derivatives as Dipeptidyl Peptidase IV Inhibitors

Deyan Wu, Fangfang Jin, Weiqiang Lu, Jin Zhu, Cui Li, Wei Wang, Yun Tang, Hualiang Jiang, Jin Huang, Guixia Liu, Jian Li

Research output: Contribution to journalArticlepeer-review

25 Scopus citations

Abstract

Type 2 diabetes mellitus (T2DM) is a metabolic disease and a major challenge to healthcare systems around the world. Dipeptidyl peptidase IV (DPP-4), a serine protease, has been rapidly emerging as an effective therapeutic target for the treatment for T2DM. In this study, a series of novel DPP-4 inhibitors, featuring the pyrazole-3-carbohydrazone scaffold, have been discovered using an integrated approach of structure-based virtual screening, chemical synthesis, and bioassay. Virtual screening of SPECS Database, followed by enzymatic activity assay, resulted in five micromolar or low-to-mid-micromolar inhibitory level compounds (1-5) with different scaffold. Compound 1 was selected for the further structure modifications in considering inhibitory activity, structural variability, and synthetic accessibility. Seventeen new compounds were synthesized and tested with biological assays. Nine compounds (6e, 6g, 6k-l, and 7a-e) were found to show inhibitory effects against DPP-4. Molecular docking models give rational explanation about structure-activity relationships. Based on eight DPP-4 inhibitors (1-5, 6e, 6k, and 7d), the best pharmacophore model hypo1 was obtained, consisting of one hydrogen bond donor (HBD), one hydrogen bond acceptor (HBA), and two hydrophobic (HY) features. Both docking models and pharmacophore mapping results are in agreement with pharmacological results. The present studies give some guiding information for further structural optimization and are helpful for future DPP-4 inhibitors design.

Original languageEnglish (US)
Pages (from-to)897-906
Number of pages10
JournalChemical Biology and Drug Design
Volume79
Issue number6
DOIs
StatePublished - Jun 2012
Externally publishedYes

Keywords

  • Dipeptidyl peptidase IV
  • Inhibitors
  • Molecular docking
  • Pharmacophore modeling
  • Synthesis

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Pharmacology
  • Drug Discovery
  • Organic Chemistry

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