title: Synthesis and antibacterial activity of thiazolopyrazine-incorporated tetracyclic quinolone antibacterial agents. 2.
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.
authors.affiliation: New Drug Research Laboratories, Kanebo Ltd., Osaka, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Jinbo
authors.forename: H
authors.initials: H
authors.lastname: Kondo
authors.forename: M
authors.initials: M
authors.lastname: Taguchi
authors.forename: Y
authors.initials: Y
authors.lastname: Inoue
authors.forename: F
authors.initials: F
authors.lastname: Sakamoto
authors.forename: G
authors.initials: G
authors.lastname: Tsukamoto
mesh_terms: D042462:4-Quinolones; D000818:Animals; D000890:Anti-Infective Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000633:toxicity*; D006090:Gram-Negative Bacteria / Q000187:drug effects; D006094:Gram-Positive Bacteria / Q000187:drug effects; D007202:Indicators and Reagents; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D009904:Optical Rotation; D011719:Pyrazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000633:toxicity*; D013203:Staphylococcal Infections / Q000188:drug therapy*; D013211:Staphylococcus aureus; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000633:toxicity*
chemical_list: D042462:4-Quinolones; D000890:Anti-Infective Agents; D007202:Indicators and Reagents; D011719:Pyrazines; D013844:Thiazoles