Natural product inspired scaffold hopping strategy: Identification of potent anticancer 2-arylpyridopyrimidinones...

Harnessing the structural complexity and bioactivity of natural products is a proven strategy for discovering novel therapeutics. Here, we report a natural product-inspired structural elaboration of 2-aryl pyridopyrimidinones with C3 installation of drug-privileged motifs. Molecularly diverse analogues were synthesized by an approach of construction of pyridopyrimidinone skeleton, a Pd-catalyzed heterocyclic ring imine-ether CO bond activation-arylation reaction followed by Ullmann-type or Buchwald-Hartwig coupling reactions of CN, CP, CO, and CS bond formations, which enabled an efficient access to flavonoid-inspired molecules with various substitution/functional motifs. These analogs exhibited potent anticancer activity against multiple carcinoma cell lines. The representative most potent compound 3 s showed significant cytotoxicity against highly aggressive triple-negative breast adenocarcinoma (MDA-MB-231, IC₅₀ = 1.16 ± 0.36 μM), minimal toxicity toward normal kidney epithelial cells (HEK 293) and remarkable selectivity (SI = 72). Wound closure and transwell assays indicated that compound 3s was found to suppress cell migration in a concentration-dependent fashion. Functional mechanistic studies with various biophysical experiments revealed the compound's pronounced effect in apoptosis induction and biological function interference, such as Bax upregulation, caspase-3/PARP cleavage, and AKT suppression, mitochondrial membrane potential disruption, accumulation of cytoplasmic and mitochondrial ROS, which led to sub-G₀ accumulation and G₂/M phase cell cycle arrest. Structure-activity and cheminformatics analyses provides identification of potential key pharmacophoric features and favorable natural product- and drug-likeness profiles.