Synthesis and Structure−Activity Relationships of 2-Pyridones:  A Novel Series of Potent DNA Gyrase Inhibitors as Antibacterial Agents

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.

The 2-pyridone antibacterial agents: bacterial topoisomerase inhibitors

“…While all the agents named to this point have retained a nitrogen at ring position 1, early work in which that atom had been exchanged for a carbon (4), 46 oxygen (5), 47 or sulfur (6) 48 gave bioisosteres with poor biological properties. Particular and surprising success was achieved, however, when the nitrogen atom at position 1 was exchanged for an unsaturated quaternary carbon atom at position 4a to produce benzo-2-pyridone (quinolizinone) analogs 49,50 (Fig. 2).…”

“…After a number of disappointing routes were explored, ultimately convenient and high-yielding routes were developed. 49,50 Excitingly, the early 2-pyridones that resulted had enhanced potency and usefully altered antimicrobial spectra as compared to analogous 4-Scheme 1. Synthesis of the 9-difluorophenyl-pyridopyrimidone core (7) (ref.…”

“…Synthesis of the 9-difluorophenyl-pyridopyrimidone core (7) (ref. 49) Scheme 2. Synthesis of the 9-cyclopropyl-pyridopyrimidone core (8) (ref.…”

In Vitro Evaluation of CBR-2092, a Novel Rifamycin-Quinolone Hybrid Antibiotic: Studies of the Mode of Action in Staphylococcus aureus

“…Structure-activity relationships derived from the data generated in a range of assays described here revealed that the potency of the quinolone entity was a critical parameter in terms of the retention of antimicrobial activity of rifamycinquinolone hybrid agents against strains exhibiting rifampin resistance. Of the quinolone pharmacophores tested, members of the experimental 4H-4-oxoquinolizine subfamily (25) proved one of the most promising. In CBR-2092 ( Fig.…”

“…In CBR-2092 ( Fig. 1), the rifamycin SV pharmacophore is combined via a chiral linking group with a quinolone entity from the 4H-4-oxoquinolizine subfamily (25); for comparison, Fig. 1 also shows the structures of rifampin, ciprofloxacin, and a representative 4H-4-oxoquinolizine (ABT-719) that were employed in this study as comparator agents.…”