Organocatalyzed umpolung addition for synthesis of heterocyclic-fused arylidene-imidazolones as anticancer agents.

[Display omitted] • "Nature-to-new" as a medicinal chemistry strategy. • Iterative Scaffold-hopping to identify new chemotype. • Organocatalysed Umpolung Chemistry to construct Arylidene heterocyclic-fused imidazolone scaffold. • Polyphosphoric acid-mediated ester-lactam exchange. • In silico study reveals good drug-like properties. A strategy of "Nature-to-new" with iterative scaffold-hopping was considered for investigation of privileged ring/functional motif-elaborated analogs of natural aurones. An organocatalyzed umpolung chemistry based method was established for molecular-diversity feasible synthesis of title class of chemotypes i.e. (Z)-2-Arylideneimidazo[1,2– a ]pyridinones and (Z)-2-Arylidenebenzo[ d ]imidazo[2,1–b]thiazol-3-ones. Various biophysical experiments indicated their important biological properties. The analogs showed characteristic anticancer activities with efficiency more than an anticancer drug. The compounds induced apoptosis with arrest in the S phase of the cell cycle regulation. The compounds' significant effect in up/down-regulation of various apoptotic proteins, an apoptosis cascade, and the inhibition of topoisomerases-mediated DNA relaxation process was identified. The analysis of the structure-activity relationship, interference with biological events and the drug-likeness physicochemical properties of the compounds in the acceptable window indicated distinctive medicinal molecule-to-properties of the investigated chemotypes. [ABSTRACT FROM AUTHOR]