SYNTHESIS AND ANTIBACTERIAL ACTIVITY OF THIAZOLOPYRAZINE-INCORPORATEDTETRACYCLIC QUINOLONE ANTIBACTERIAL AGENTS .2.

A novel series of 8-(2-substituted oro-5-oxo-5H-thiazolo[3,2-a]quinoli ne-4-carboxylic acids, designated 8a-j, with a unique tetracyclic stru cture were synthesized, and the in vitro and in vivo antibacterial act ivities against Grampositive strains, including methicillin-resistant Staphylococcus aureus isolates (MRSA), and Gram-negative strains were evaluated. These morpholino derivatives, 8a-j, showed excellent in vit ro antibacterial activities against Gram-positive bacteria. The substi tutions at the C-2 position of the 8-morpholino moiety of compound 8 p lay an important role in the enhancement of in vivo antibacterial acti vity. The unsubstituted morpholino derivative 8a, the 2,6-dimethyl der ivative 8c, and the 2-ethylmorpholino derivative 8d showed poor in viv o antibacterial activity while 8b, 8f-h, and 8j exhibited good activit ies. The 2-(methoxymethyl)morpholino derivative, 8h, showed the most p otent activity in vivo. The therapeutic effects of 8h on systemic infe ction against S. aureus IID 803 were over 10-fold more potent than tha t of ofloxacin. Compound 8h, which showed superior oral bioavailabilit y, has a chiral center. The enantiomers of 8h were synthesized, and th e in vitro and in vivo antibacterial activities were evaluated. Both e nantiomers, (S)-8h and (R)-8h, and the racemic compound 8 exhibited si milar activities in vitro and in vivo. Compounds 8b and 8f-h also show ed good levels of antibacterial activity against MRSA strains, The mor pholino derivatives with unique tetracyclic structures are characteriz ed by strong antibacterial activities against MRSA strains.