One-pot synthesis of thioxo-tetrahydropyrimidine derivatives as potent β-glucuronidase inhibitor, biological evaluation, molecular docking and molecular dynamics studies

Bioorg Med Chem. 2020 Apr 1;28(7):115359. doi: 10.1016/j.bmc.2020.115359. Epub 2020 Feb 6.

Abstract

A series of N,N-diethyl phenyl thioxo-tetrahydropyrimidine carboxamide have been synthesized and investigated for their β-glucuronidase inhibitory activities. All molecules exhibited excellent inhibition with IC50 values ranging from 0.35 to 42.05 µM and found to be even more potent than the standard d-saccharic acid. Structure-activity relationship analysis indicated that the meta-aryl-substituted derivatives significantly influenced β-glucuronidase inhibitory activities while the para-substitution counterpart outperforming moderate potency. The most potent compound in this series was 4g bearing thiophene motif with IC50 of 0.35 ± 0.09 µM. To verify the SAR, molecular docking and molecular dynamics studies were also performed.

Keywords: Docking; Molecular dynamics; Synthesis; Thioxo-tetrahydropyrimidine; β-glucuronidase.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Glycoproteins / chemistry
  • Glycoproteins / pharmacology*
  • Humans
  • Models, Molecular
  • Molecular Docking Simulation
  • Molecular Structure
  • Protein Conformation
  • Pyrimidines / chemistry
  • Pyrimidines / pharmacology*
  • Structure-Activity Relationship

Substances

  • Enzyme Inhibitors
  • Glycoproteins
  • Pyrimidines
  • beta-glucuronidase inhibitor