Synthesis and Antibacterial Activity of Thiazolopyrazine-Incorporated Tetracyclic Quinolone Antibacterials

A novel series of 8-substituted-9,1-[(N-methylimino)methano]- 7-fluoro-5-oxo-5H-thiazolo[3,2-alpha]-quinoline-4-carboxylic acids 5a-q having a unique thiazolopyrazine-incorporated tetracyclic structure were synthesized, and the in vitro and in vivo activities were determined against Gram-positive and Gram-negative bacteria. All compounds 5a-q had more potent activity than ofloxacin (6), which is one of the most popular quinolones, against Gram-positive and Gram-negative bacteria. The 8-pyrrolidinyl, 5a-e, and 8-morpholino, 5p, derivatives showed the most potent activity against Gram-positive bacteria. It is also significant that these compounds, 5a-q, showed more potent antibacterial activity against methicillin-resistant Staphylococcus aureus isolates (MRSA) than ofloxacin (6). The combination of the morpholino group and this unique tetracyclic thiazolopyrazine skeleton contributes to the enhancement of the antibacterial activity against MRSA isolates. The in vivo antibacterial activities of these compounds, 5a-q, were limited and depended on the structure of the 8-substituent. The 8-(4-alkyl-1-piperazinyl) derivatives 5g, 5h, 5j, and 5n provided good oral efficacy and exhibited more potent activity than ofloxacin (6) against the systematic infection with S. aureus IID 803 in mice.