Synthesis and antimicrobial activity of 4H-4-Oxoquinolizine derivatives: Consequences of structural modification at the C-8 position

The antibacterial 4H-4-oxoquinolizines were introduced recently to overcome bacterial resistance to fluoroquinolones. They exhibit potent-antibacteria l activity against Gram-positive, Gramnegative, and anaerobic organisms and are highly active against some quinolone-resistant bacteria including quin olone-resistant MRSA. Preliminary studies indicated that oxoquinolizines po ssess distinct activity and toxicity profiles as compared with their parent quinolones. In order to develop a potent antibacterial agent with the desi red spectrum of activity, good tolerability, and balanced pharmacokinetic p rofile, we synthesized and evaluated a series of oxoquinolizines with vario us substituents at the C-8 position. Most compounds tested in this study de monstrated better activity against Gram-positive bacteria than ciprofloxaci n and exhibited good susceptibility against ciprofloxacin- and methicillin- resistant S. aureus. While maintaining potent in vitro activity, several co mpounds showed improved in vivo efficacy over ABT-719 as indicated by the m ouse protection test. As an example, the oral ED50 values for the cis-3-ami no-4-methylpiperidine analogue 3ss against S, aureus NCTC 10649M, S. pneumo niae 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 s teric and electronic environment, conformation, and absolute stereochemistr y of the C-8 group are very important to the antibacterial profiles. Struct ural modifications of the C-8 group provide a useful means to improve the a ntibacterial activities, physicochemical properties, and pharmacokinetic pr ofiles. 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.