Synthesis and biological properties of substituted 1,4-dihydro-5-methyl-4-oxo-3-quinolinecarboxylic acids.

A series of substituted 1-cyclopropyl-6-fluoro-1, 4-dihydro-5-methyl-4-oxo-3-quinoline carboxylic acids was synthesized and tested for their in vitro and in vivo antibacterial activity. The introduction of a methyl group at the 5-position of quinoline nucleus enhanced characteristically the antibacterial activity against Gram-positive bacteria, including Streptococcus pneumoniae, which is a major pathogen in the respiratory tract infection, while retaining Gram-negative activity. Among them, 1-cyclopropyl-6-fluoro-1, 4-dihydro-5-methyl-7-(3-methyl-1-piperazinyl)-4-oxo-3-quinolinecarboxyli c acid hydrochloride (grepafloxacin) exhibited potent in vitro antibacterial activity against Gram-positive bacteria such as Streptococcus pneumoniae and high in vivo efficacy on the experimental systemic infections caused by the Gram-positive and -negative bacteria tested. It also showed a high distribution to the lung and bronchoalveolar lavage fluid in comparison to reference drugs and is now undergoing clinical evaluation.