[Synthesis and antibacterial activity of 7-(7-aminomethyl-5-azaspiro [2,4] hept-5-yl)-1-cyclopropyl-6-fluoro-8-methoxy-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid and its analogues].
OBJECTIVE
To find new antibacterial agents of quinolone with high activity and low toxicity.


METHODS
To design and synthesize 7-(7-aminomethyl-5-azaspiro [2,4] hept-5-yl)-1-cyclopropyl-6-fluoro-8-methoxy-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid and its analogues, and to study their antibacterial activity in vitro and in vivo.


RESULTS
Twenty new compounds (2 - 11, 17 - 26) were obtained including five targeted compounds (22 - 26). The structures of the compounds were confirmed by 1HNMR, MS and HRMS. Compounds 22 - 26 showed broad spectrum of antibacterial activity against Gram-positive and Gram-negative organisms. Especially for compound 24, the relevant MIC values for 13 strains of Gram-positive organisms were < 0.001 - 0.03 mg(-1), including 4 strains of S. pneumoniae, 2 strains of S. pyogenes, 3 strains of S. aureus and 2 strains of Enterococci which exhibited more potent activity than contrast agents (clinafloxacin and gatifloxacin). The MIC values of 24 for 6 strains Gram-positive organisms were 0.01 - 1 mg x L(-1), which exhibited equal or lower activity than contrast agents. They were more effective than ciprofloxacin and gatifloxacin against intraperitoneal infections caused by S. pneumoniae and S. aureus in mice.


CONCLUSIONS
Compounds (23, 24 and 26) showed excellent antibacterial activity in vitro and in vivo and should be worth further investigation.
Qi
Jian-jun
JJ
Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100050, China.
Guo
Hui-yuan
HY
Liu
Ming-liang
ML
Sun
Lan-ying
LY
D000818:Animals; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D002939:Ciprofloxacin / Q000494:pharmacology; D005260:Female; D024841:Fluoroquinolones / Q000494:pharmacology; D000077734:Gatifloxacin; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D008968:Molecular Conformation; D015394:Molecular Structure; D011804:Quinolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D013141:Spiro Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D013211:Staphylococcus aureus / Q000187:drug effects; D013296:Streptococcus pneumoniae / Q000187:drug effects
C488564:7-(7-aminomethyl-5-azaspiro(2,4) hept-5-yl)-1-cyclopropyl-6-fluoro-8-methoxy-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid; D000900:Anti-Bacterial Agents; D024841:Fluoroquinolones; D011804:Quinolines; D013141:Spiro Compounds; D002939:Ciprofloxacin; C057477:clinafloxacin; D000077734:Gatifloxacin