Synthesis and Antibacterial Activity of Thiazolopyrazine-Incorporated Tetracyclic Quinolone Antibacterial Agents. 2

Yoshikazu Jinbo, Hirosato Kondo, Masahiro Taguchi, Yoshimasa Inoue, Fumio Sakamoto, Goro Tsukamoto

Research output: Contribution to journalArticle

15 Citations (Scopus)

Abstract

A novel series of 8-(2-substituted morpholino)-9,1-[(N-methylimino)methano]-7-fluoro-5-oxo-5H-thiazolo[3,2-a]quinoline-4-carboxylic acids, designated 8a-j, with a unique tetracyclic structure were synthesized, and the in vitro and in vivo antibacterial activities against Gram-positive strains, including methicillin-resistant Staphylococcus aureus isolates (MRSA), and Gram-negative strains were evaluated. These morpholino derivatives, 8a-j, showed excellent in vitro antibacterial activities against Gram-positive bacteria. The substitutions at the C-2 position of the 8-morpholino moiety of compound 8 play an important role in the enhancement of in vivo antibacterial activity. The unsubstituted morpholino derivative 8a, the 2,6-dimethyl derivative 8c, and the 2-ethylmorpholino derivative 8d showed poor in vivo antibacterial activity, while 8b, 8f-h, and 8j exhibited good activities. The 2-(methoxymethyl)morpholino derivative, 8h, showed the most potent activity in vivo. The therapeutic effects of 8h on systemic infection against S. aureus IID 803 were over 10-fold more potent than that of ofloxacin. Compound 8h, which showed superior oral bioavailability, has a chiral center. The enantiomers of 8h were synthesized, and the in vitro and in vivo antibacterial activities were evaluated. Both enantiomers, (S)-8h and (R)-8h, and the racemic compound 8 exhibited similar activities in vitro and in vivo. Compounds 8b and 8f-h also showed good levels of antibacterial activity against MRSA strains. The morpholino derivatives with unique tetracyclic structures are characterized by strong antibacterial activities against MRSA strains.

Original languageEnglish
Pages (from-to)2791-2796
Number of pages6
JournalJournal of Medicinal Chemistry
Volume37
Issue number17
DOIs
Publication statusPublished - Aug 1 1994
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Drug Discovery

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