Synthetic Strategies towards Imidazopyridinones and 7‐Azaoxindoles and their Evaluation as Antibacterial Agents

• Published in: European journal of organic chemistry 2021-05, Vol.2021 (18), p.2701-2712
• Main Authors: Blindheim, Fredrik Heen, Olsen, Cecilie Elisabeth, Krogh Søgaard, Caroline, Otterlei, Marit, Sundby, Eirik, Hoff, Bård Helge
• Format: Article
• Language: English
• Subjects: 7-Azaoxindole; Antiinfectives and antibacterials; Aqueous solutions; Carbocyclization; Cross coupling; E coli; Heterocyclic compounds; Imidazopyridinone; Kinases; Suzuki cross-coupling; Thymidylate monophosphate kinase
• ISSN: 1434-193X; 1099-0690
• DOI: 10.1002/ejoc.202100172

Imidazopyridinones and 7‐azaoxindoles are two classes of heterocyclic compounds with only limited previous use in organic and medicinal chemistry. Various synthetic methods and routes have been evaluated to identify safe and robust chemistry to advanced imidazopyridinone building blocks and inhibitor structures. Preparation of the 7‐azaoxindoles was challenged by instability of the core scaffold. Key to the successful isolation of the target structure was development of a mild Suzuki cross‐coupling in non‐aqueous media. The imidazopyridinones were potent inhibitors of the E. coli thymidylate monophosphate kinase, while the 7‐azaoxindole showed low activity. The compounds were inactive in cell‐based studies, indicating poor cell wall penetration. Various synthetic methods and routes have been evaluated to prepare advanced imidazopyridinones and 7‐azaoxindoles. The target molecules were investigated as E. coli thymidylate monophosphate kinase inhibitors. Enzymatic assays showed the imidazopyridinones to be active inhibitors of E. coli thymidylate monophosphate kinase. In contrast the target 7‐azaoxindole demonstrated low activity.