Indole- and Pyrazole-Glycyrrhetinic Acid Derivatives as PTP1B Inhibitors: Synthesis, In Vitro and In Silico Studies

Molecules. 2021 Jul 20;26(14):4375. doi: 10.3390/molecules26144375.

Abstract

Regulating insulin and leptin levels using a protein tyrosine phosphatase 1B (PTP1B) inhibitor is an attractive strategy to treat diabetes and obesity. Glycyrrhetinic acid (GA), a triterpenoid, may weakly inhibit this enzyme. Nonetheless, semisynthetic derivatives of GA have not been developed as PTP1B inhibitors to date. Herein we describe the synthesis and evaluation of two series of indole- and N-phenylpyrazole-GA derivatives (4a-f and 5a-f). We measured their inhibitory activity and enzyme kinetics against PTP1B using p-nitrophenylphosphate (pNPP) assay. GA derivatives bearing substituted indoles or N-phenylpyrazoles fused to their A-ring showed a 50% inhibitory concentration for PTP1B in a range from 2.5 to 10.1 µM. The trifluoromethyl derivative of indole-GA (4f) exhibited non-competitive inhibition of PTP1B as well as higher potency (IC50 = 2.5 µM) than that of positive controls ursolic acid (IC50 = 5.6 µM), claramine (IC50 = 13.7 µM) and suramin (IC50 = 4.1 µM). Finally, docking and molecular dynamics simulations provided the theoretical basis for the favorable activity of the designed compounds.

Keywords: glycyrrhetinic acid; molecular docking; molecular dynamics; p-nitrophenylphosphate assay; protein tyrosine phosphatase 1B.

MeSH terms

  • Enzyme Inhibitors* / chemical synthesis
  • Enzyme Inhibitors* / chemistry
  • Glycyrrhetinic Acid* / analogs & derivatives
  • Glycyrrhetinic Acid* / chemical synthesis
  • Glycyrrhetinic Acid* / chemistry
  • Humans
  • Indoles* / chemical synthesis
  • Indoles* / chemistry
  • Molecular Docking Simulation*
  • Molecular Dynamics Simulation*
  • Protein Tyrosine Phosphatase, Non-Receptor Type 1* / antagonists & inhibitors
  • Protein Tyrosine Phosphatase, Non-Receptor Type 1* / chemistry
  • Pyrazoles* / chemical synthesis
  • Pyrazoles* / chemistry
  • Structure-Activity Relationship

Substances

  • Enzyme Inhibitors
  • Indoles
  • Pyrazoles
  • PTPN1 protein, human
  • Protein Tyrosine Phosphatase, Non-Receptor Type 1
  • Glycyrrhetinic Acid