Design, Synthesis, and Cytotoxic Evaluation of Chalcone‐Based Oxazole‐Oxazolo[4,5‐b]Pyridine Compounds

Abstract A series of novel chalcone‐based oxazole‐oxazolo[4,5‐b]pyridine derivatives ( 11a–j ) were designed, synthesized, and evaluated for cytotoxic activity against four human cancer cell lines: cervical (SiHa), lung (A549), breast (MCF‐7), and colon (Colo‐205). The synthesis involved condensing 2‐(2‐formylpyrimidin‐5‐yl)‐N‐(oxazol‐2‐yl)oxazolo[4,5‐b]pyridine‐6‐carboxamide ( 9 ) with aryl ketones ( 10a–j ) using piperidine. Zn nanoparticles facilitated intermediate 5 formation, and SeO₂ was used for oxidation. Structures were confirmed via 1 H NMR, and 13 C NMR, verifying the chalcone moiety and E‐configuration. Cytotoxicity screening revealed six active compounds ( 11a , 11b , 11c , 11d , 11i , 11j ), with 11b (3,4,5‐trimethoxyphenyl) showing the highest potency (IC 50 : 0.03–0.42 µM). SAR analysis indicated electron‐donating groups enhanced activity. Comparisons with known anticancer drugs validated the efficacy of 11b . Preliminary mechanistic studies, including apoptosis induction and cell cycle arrest assays, provided insights into its mode of action. Selectivity assays assessed toxicity against normal cell lines. These findings highlight chalcone‐based oxazole‐oxazolo[4,5‐b]pyridine derivatives as promising anticancer agents. Further computational modeling and docking analyses are needed to optimize lead candidates.