Document Report Card

ID: ALA1129258

Journal: J Med Chem

Title: Synthesis and structure-activity relationships of 2-pyridones: a novel series of potent DNA gyrase inhibitors as antibacterial agents.

Authors: Li Q, Chu DT, Claiborne A, Cooper CS, Lee CM, Raye K, Berst KB, Donner P, Wang W, Hasvold L, Fung A, Ma Z, Tufano M, Flamm R, Shen LL, Baranowski J, Nilius A, Alder J, Meulbroek J, Marsh K, Crowell D, Hui Y, Seif L, Melcher LM, Plattner JJ.

Abstract: Two novel series of 2-pyridones were synthesized by transposition of the nitrogen of 4-quinolones to the bridgehead position. This subtle interchange of the nitrogen atom with a carbon atom yielded two novel heterocyclic nuclei, pyrido[1,2-alpha]pyrimidine and quinolizine, which had not previously been evaluated as antibacterial agents and were found to be potent inhibitors of DNA gyrase. Quinolizines with a methyl group at the 9-position such as (S)-45a (ABT-719) demonstrate exceptional broad spectrum antibacterial activity. Most notably, they are active against resistant bacteria such as methicillin-resistant Staphylococcus aureus, vancomycin-resistant strains of enterococci, and ciprofloxacin-resistant organisms. In addition, 2-pyridones also possess favorable physiochemical and pharmacokinetic properties. These 2-pyridones were synthesized from the commercially available starting materials by 10-17 linear transformations. The structure of an adduct yielded by this sequence, (S)-45a (ABT-719), was determined by X-ray crystallographic analysis.

CiteXplore: 8759628

DOI: 10.1021/jm960207w