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

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-kappa B signaling pathway. Almost all compounds showed selectivity toward the A549 cell lines and the most promising compound 38 could inhibit TAK1 kinase and NF-kappa B signaling pathway with the IC50 values of 0.58 and 0.84 mu M. 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-alpha-induced IkB alpha phosphorylation, IkB alpha 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. (C) 2021 Elsevier Masson SAS. All rights reserved.

Automated summary

Compound 38 shows potential anticancer activities by inhibiting TAK1 kinase and NF-kappa B signaling pathway to affect the growth cycle and apoptosis of A549 cell lines, which is supported by Western blot and other research methods.