Synthesis and Antimicrobial Activity of 4H-4-Oxoquinolizine Derivatives:  Consequences of Structural Modification at the C-8 Position

• Published in: Journal of medicinal chemistry 1999-10, Vol.42 (20), p.4202-4213
• Main Authors: 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
• Format: Article
• Language: English
• Subjects: 3-Amino-4-methylpiperidine; 4-Oxoquinolizines; Animals; Anti-Bacterial Agents - chemical synthesis; Anti-Bacterial Agents - chemistry; Anti-Bacterial Agents - pharmacology; Antibacterial agents; Antibiotics. Antiinfectious agents. Antiparasitic agents; Biological and medical sciences; Gram-Negative Bacteria - drug effects; Gram-Positive Bacteria - drug effects; Medical sciences; Mice; Pharmacology. Drug treatments; Quinolizines - chemical synthesis; Quinolizines - chemistry; Quinolizines - pharmacology; Staphylococcus aureus; Stereoisomerism; Structure-Activity Relationship
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm990191k

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.