A Lactone-Enabled Approach to Metronidazole-Based Scaffolds

Key Points

• This research aims to develop stable derivatives of metronidazole using a lactone-based approach.
• Utilized a scaffold-divergent technique to modify metronidazole compounds.
• Synthesis of N1-hydroxyethyl nitroimidazole-2-carboxylic acid was attempted, noting its rapid decarboxylation.
• Applied density functional theory calculations to analyze the instability caused by decarboxylation pathways.
• Identification of a lactone (compound 8) as a stable surrogate for further derivation.
• Successful access to both oxadiazole and amide derivatives from the lactone.
• Detailed theoretical insights into the low-barrier decarboxylation pathway affecting precursor stability.