1026729-95-2Relevant academic research and scientific papers
Synthesis and antimicrobial activity of 4H-4-oxoquinolizine derivatives: Consequences of structural modification at the C-8 position
Ma, Zhenkun,Chu, Daniel T. W.,Cooper, Curt S.,Li, Qun,Fung, Anthony K. L.,Wang, Sanyi,Shen, Linus L.,Flamm, Robert K.,Nilius, Angela M.,Alder, Jeffery D.,Meulbroek, Jonathan A.,Or, Yat Sun
, p. 4202 - 4213 (2007/10/03)
The antibacterial 4H-4-oxoquinolizines were introduced recently to overcome bacterial resistance to fluoroquinolones. They exhibit potent antibacterial activity against Gram-positive, Gram-negative, and anaerobic organisms and are highly active against some quinolone-resistant bacteria including quinolone-resistant MRSA. Preliminary studies indicated that oxoquinolizines possess distinct activity and toxicity profiles as compared with their parent quinolones. In order to develop a potent antibacterial agent with the desired spectrum of activity, good tolerability, and balanced pharmacokinetic profile, we synthesized and evaluated a series of oxoquinolizines with various substituents at the C-8 position. Most compounds tested in this study demonstrated better activity against Gram-positive bacteria than ciprofloxacin and exhibited good susceptibility against ciprofloxacin- and methicillin-resistant S. aureus. While maintaining potent in vitro activity, several compounds showed improved in vivo efficacy over ABT-719 as indicated by the mouse protection test. As an example, the oral ED50 values for the cis-3-amino-4-methylpiperidine analogue 3ss against S. aureus NCTC 10649M, S. pneumoniae ATCC 6303, and E. coli JUHL were 0.8, 2.0, and 1.4 mg/kg, compared to 3.0, 10.0, and 8.3 mg/kg for ABT-719. The current study revealed that the steric and electronic environment conformation, and absolute stereochemistry of the C-8 group are very important to the antibacterial profiles. Structural modifications of the C-8 group provide a useful means to improve the antibacterial activities, physicochemical properties, and pharmacokinetic profiles. Manipulation of the C-8 group also allows us to generate analogues with the desired spectrum of activity, such as analogues that are selective against respiratory pathogens.
Synthesis and structure-activity relationships of 2-pyridones: A novel series of potent DNA gyrase inhibitors as antibacterial agents
Li, Qun,Chu, Daniel T. W.,Claiborne, Akiyo,Cooper, Curt S.,Lee, Cheuk M.,Raye, Kathleen,Berst, Kristine B.,Donner, Pamela,Wang, Weibo,Hasvold, Lisa,Fung, Anthony,Ma, Zhenkun,Tufano, Michael,Flamm, Robert,Shen, Linus L.,Baranowski, John,Nilius, Angela,Alder, Jeff,Meulbroek, Jonathan,Marsh, Kennan,Crowell, DeAnne,Hui, Yuhua,Seif, Louis,Melcher, Laura M.,Henry, Rodger,Spanton, Steven,Faghih, Ramin,Klein, Larry L.,Tanaka, S. Ken,Plattner, Jacob J.
, p. 3070 - 3088 (2007/10/03)
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-a]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.
