title: Synthesis and antimicrobial activity of 4H-4-oxoquinolizine derivatives: consequences of structural modification at the C-8 position.
abstract: 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 ED(50) 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.
authors.affiliation: Infectious Disease Research, Abbott Laboratories, 200 Abbott Park Road, Abbott Park, Illinois 60064-3537, USA.
authors.forename: Z
authors.initials: Z
authors.lastname: Ma
authors.forename: D T
authors.initials: DT
authors.lastname: Chu
authors.forename: C S
authors.initials: CS
authors.lastname: Cooper
authors.forename: Q
authors.initials: Q
authors.lastname: Li
authors.forename: A K
authors.initials: AK
authors.lastname: Fung
authors.forename: S
authors.initials: S
authors.lastname: Wang
authors.forename: L L
authors.initials: LL
authors.lastname: Shen
authors.forename: R K
authors.initials: RK
authors.lastname: Flamm
authors.forename: A M
authors.initials: AM
authors.lastname: Nilius
authors.forename: J D
authors.initials: JD
authors.lastname: Alder
authors.forename: J A
authors.initials: JA
authors.lastname: Meulbroek
authors.forename: Y S
authors.initials: YS
authors.lastname: Or
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006090:Gram-Negative Bacteria / Q000187:drug effects; D006094:Gram-Positive Bacteria / Q000187:drug effects; D051379:Mice; D011807:Quinolizines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D000900:Anti-Bacterial Agents; D011807:Quinolizines