SYNTHESIS AND STRUCTURE-ACTIVITY-RELATIONSHIPS OF 2-PYRIDONES - A NOVEL SERIES OF POTENT DNA GYRASE INHIBITORS AS ANTIBACTERIAL AGENTS

Two novel series of 2-pyridones were synthesized by transposition of t he nitrogen of 4-quinolones to the bridgehead position. This subtle in terchange of the nitrogen atom with a carbon atom yielded two novel he terocyclic nuclei, pyrido[1,2-a]pyrimidine and quinolizine, which had not previously been evaluated as antibacterial agents and were found t o be potent inhibitors of DNA gyrase. Quinolizines with a methyl group at the 9-position such as (S)-45a (ABT-719) demonstrate exceptional b road spectrum antibacterial activity. Most notably, they are active ag ainst resistant bacteria such as methicillin-resistant Staphylococcus aureus, vancomycin-resistant strains of enterococci, and ciprofloxacin -resistant organisms. In addition, a-pyridones also possess favorable physiochemical and pharmacokinetic properties. These 2-pyridones were synthesized from the commercially available starting materials by 10-1 7 linear transformations. The structure of an adduct yielded by this s equence, (S)-45a (ABT-719), was determined by X-ray crystallographic a nalysis.