Design, synthesis, docking, molecular dynamics and bioevaluation studies on novel N-methylpicolinamide and thienopyrimidine derivatives with inhibiting NF-κB and TAK1 activities: Cheminformatics tools RDKit applied in drug design

Eur J Med Chem. 2021 Nov 5:223:113576. doi: 10.1016/j.ejmech.2021.113576. Epub 2021 Jun 5.

Abstract

Using cheminformatics tools RDKit and literature investigation, four series of 24 thienopyrimidine/N-methylpicolinamide derivatives substituted with pyrimidine were designed, synthesized and evaluated for activities against three cancer cell lines (MDA-MB-231, HCT116 and A549), TAK1 kinase and NF-κB signaling pathway. Almost all compounds showed selectivity toward the A549 cell lines and the most promising compound 38 could inhibit TAK1 kinase and NF-κB signaling pathway with the IC50 values of 0.58 and 0.84 μM. Moreover, 38 can induce cell cycle arrest of A549 cells at the G2/M checkpoint with 30.57% and induce apoptosis (34.94%) in a concentration-dependent manner. And western blot showed that compound 38 could inhibit TNF-α-induced IκBα phosphorylation, IκBα degradation, p65 phosphorylation and TAK1 phosphorylation, and reduce the expression of p65. What's more, the studies of docking, molecular dynamics, MM/PBSA and frequency analysis theoretically supported the conclusions of the bioevaluation.

Keywords: Cheminformatics; Molecular dynamics; N-methylpicolinamide; NF-κB; TAK1; Thienopyrimidine.

MeSH terms

  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / metabolism
  • Antineoplastic Agents / pharmacology*
  • Apoptosis / drug effects
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Drug Design
  • G2 Phase Cell Cycle Checkpoints / drug effects
  • Humans
  • MAP Kinase Kinase Kinases / antagonists & inhibitors*
  • MAP Kinase Kinase Kinases / metabolism
  • Molecular Docking Simulation
  • Molecular Dynamics Simulation
  • NF-kappa B / antagonists & inhibitors*
  • NF-kappa B / metabolism
  • Picolinic Acids / chemical synthesis
  • Picolinic Acids / metabolism
  • Picolinic Acids / pharmacology*
  • Protein Binding
  • Protein Kinase Inhibitors / chemical synthesis
  • Protein Kinase Inhibitors / metabolism
  • Protein Kinase Inhibitors / pharmacology
  • Pyrimidines / chemical synthesis
  • Pyrimidines / metabolism
  • Pyrimidines / pharmacology*
  • Thiophenes / chemical synthesis
  • Thiophenes / metabolism
  • Thiophenes / pharmacology*

Substances

  • Antineoplastic Agents
  • NF-kappa B
  • Picolinic Acids
  • Protein Kinase Inhibitors
  • Pyrimidines
  • Thiophenes
  • MAP Kinase Kinase Kinases
  • MAP kinase kinase kinase 7
  • picolinamide