Design, synthesis, in silico pharmacokinetics prediction and biological evaluation of 1,4-dihydroindeno[1,2-c]pyrazole chalcone as EGFR /Akt pathway inhibitors

Eur J Med Chem. 2019 Feb 1:163:636-648. doi: 10.1016/j.ejmech.2018.12.011. Epub 2018 Dec 8.

Abstract

In an attempt to develop potent and selective anticancer agents, a series of 15 conjugates of 1,4-dihydroindeno[1,2-c]pyrazole chalcone (12a-o) were designed, synthesized and evaluated for their antiproliferative activity against MCF7, A549, MDA-MB-231, HCT116 and SKBR3 human cancer cell lines. Among them, 12h, 12l and 12m showed IC50 values: 3.82, 5.33 and 4.21 μM, respectively, on A549 cell with respect to the positive control, Erlotinib (IC50 value: 10.26 μM). Detailed biological assays showed accumulation of mitotic cells in G2/M phase. In addition, Western blot analysis and immunofluorescence study revealed inhibition of EGFR and Akt pathways. In silico computational studies were also carried out to predict the binding modes and pharmacokinetic parameters of these conjugates.

MeSH terms

  • A549 Cells
  • Cell Cycle Checkpoints / drug effects
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Chalcones / pharmacokinetics*
  • Computer Simulation
  • Drug Design*
  • ErbB Receptors / antagonists & inhibitors
  • ErbB Receptors / metabolism
  • Humans
  • Inhibitory Concentration 50
  • Oncogene Protein v-akt / antagonists & inhibitors*
  • Oncogene Protein v-akt / metabolism
  • Pyrazoles / pharmacokinetics

Substances

  • Chalcones
  • Pyrazoles
  • EGFR protein, human
  • ErbB Receptors
  • Oncogene Protein v-akt