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-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 IC 50 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. This paper reports a logical drug design story about a novel TAK1 and NF-κB inhibitor 38 from three aspects: rational drug design, bioactivity verification, and theoretical verification. • Using RDKit in drug design, 24 thienopyrimidine/N-methylpicolinamide derivatives were designed and synthesized. • Nearly all the compound show selectivity to A549 cell line. • The most promising compound 38 show potential activity against TAK1 and NF-κB in nano level. • The cell cycle, cell apoptosis and western blot are also performed. • The studies of molecular simulation theoretically supported the conclusions of the bioevaluation.