A series of 11 fluoroqulnolone antibacterial agents, including 8 newly synthesized molecules and 3 reference compounds (pefloxacin, ciprofloxacin, and sparfioxacin), were forE. coi, which were 0.60, 0.64, and 0.74 (n = 11) for E. coil, P. aerugunosa, and S. awwus, respectively, rose to 0.85, 0.74, and 0.74 (n = 11) for the same microorganisms, respectively, when the accumulatin of the drug by the cell was taken into account. It WAs concluded that the inhibitory activity against DNA gyrase remains the most important parameter for quinolone potency, but that intracellular accumulation must be tahken into account, since, for a given organism, both parameters are under the control of the physicochemical properties of the qulnolones.The MIC of a quinolone against a particular organism is determined by at least two factors: its rate of penetration across the bacterial cell envelope (31, 34) and its inhibitory activity against the supercoiling reaction catalyzed by its target, the enzyme DNA gyrase (15). Although both of these activities should be at their optimum to ensure the maxmal antibacterial potency of a compound, it is evident that the second of these properties is the more important, since a qumolone devoid of activity against DNA gyrase is not active against a bacterium, despite sufficient drug accumulation. Moreover, it has been documented that most highlevel quinolone resistance arises from gyrase modifications (13,30,35,38,44). Conversely, poor penetration into bacteria may impair the effectiveness of a quinolone that is highly active against gyrase. This could explain the lack of a clear correlation between antibacterial activity and inhibition of isolated DNA gyrase observed for some quinolones (2, 15). Several studies dealing with the structure-activity relationships of fluoroquinolones have been published (3, 10-12, 15, 16, 18, 24, 36), and the investigators sometimes attempted to identify separately those factors that are necessary for gyrase inhibition from those that are needed for penetration into the cell. With regard to penetration into the bacterial cell, physical properties such as relative hydrophobicity (23, 28) or charge or molecular weight (7,8,31) are important. As a general rule, bulky size, negative charge, and increasing hydrophobicity retard the penetration of antibacterial agents into gram-negative organisms through porn channels (9,20,21), although hydrophobic molecules appear to use an alternative route, through lipopolysaccha-* Corresponding author. ride (8). For gram-positive organisms, the molecular weight of the antimicrobial agent has little influence on the agent's potency, and positively charged hydrophobic molecules have been shown to have a better rate of penetration (17,19).The structural features necessary for enzyme inhibition appear to be different from those required for penetration, and analysis of these features is more complex (10,24).We have at our disposal a series of fluoroquinolones with a wide range of hydrophobicities (logarithm of the coefficient of distri...

A series of 5-substituted-6-fluoro-7-(cycloalkylamino)-1,4-dihydro-4-oxo-1,8- naphthyridine-3-carboxylic acids have been prepared and tested for their in vitro and in vivo antibacterial activities. The 5-methyl group gave better in vitro activity with the 1-cyclopropyl appendage, but poorer activity with the 1-tert-butyl moiety. With the 1-(2,4-difluorophenyl) substitution, the influence of the 7-cycloalkylamino group was determinant: a (3S)-3-amino-pyrrolidine was shown to enhance greatly the in vitro and in vivo activity of the 5-methyl derivative. Compound 33 (BMY 43748) was selected as a promising candidate for an improved therapeutic agent.

No abstract

A series of novel 7-substituted-1-tert-butyl-6-fluoronaphthyridone-3- carboxylic acids has been prepared. These derivatives are characterized by chiral aminopyrrolidine substituents at the 7 position. In this paper we report the full details of the asymmetric synthesis of this series of compounds. Structure-activity relationship studies indicate that the absolute stereochemistry at the asymmetric centers of the pyrrolidine ring is critical for maintaining good activity. Compounds 60 and 61 (3-amino-4-methylpyrrolidine enantiomers) were selected for preclinical evaluation.