As part of a general investigation of new antibacterial agents,1 we have prepared a series of 1-alkyl-1,8-naphthyridin-4-one-3-carboxylic acid derivatives. Several members of the series, listed in Table I, were found to be highly effective antibacterial agents both in vitro and in vivo.These 1-alkyl-1,8-naphthyridines are prepared as outlined. The appropriate 6-substituted-2-aminopyridine (I) is condensed with diethyl ethoxymethylenemalonate and the resulting diethyl N-(6substituted-2-pyridyl)-aminomethylenemalonate (II) is cyclized in refluxing Dowtherm A or diethyl phthalate to give the ethyl 4-hydroxy-1,8-naphthyridine-3-carboxylate derivative (III).2 Hydrolysis of the ester (III) to the corresponding acid and alkylation in alcoholwater with potassium hydroxide gives the desired 1-alkyl-1,8-naphthyridin-4-one-3-carboxylic acid (IV). Alternatively, the same
1-Cyclopropyl-6,8-difluoro-1,4-dihydro-7-(2,6-dimethyl-4-pyridinyl)-4-ox o-3-quinolinecarboxylic acid (1), a previously reported potent inhibitor of bacterial DNA gyrase, was found to be interactive with mammalian topoisomerase II (topo II). In a DNA-cleavage assay using topo II isolated from HeLa cells, 1 exhibited an EC50 value of 7.6 microM (VP-16; EC50 = 0.81 microM). A series of analogues modified at the 1-, 2-, 3-, 5-, and 7-positions of 1 were subsequently made and assessed for topo II inhibition. Compound 1 was considerably more potent than derivatives where the 1-substituent was alkyl, aryl, or H, or when N-c-C3H5 was replaced with S. The descarboxyl (i.e., 3-H) analogue had potency comparable to that of 1; when both these compounds were substituted at the 2-position with methyl or phenyl, an interesting relationship between activity and the conformation of the carboxyl group emerged. Upon replacement of the 5-H of 1 with NH2 or F, sustained potency was seen. No enhancement of activity was evident upon replacing the 7-substituent of 1 with other pyridinyl groups, 4-methyl-1-piperazinyl, or pyrrolidinyl groups; however, the 7-(4-hydroxyphenyl) analogue (CP-115,953) was 6-fold more potent than 1. The topo II inhibitory properties of 1 translated to modest in vitro cytotoxicity and in vivo activity versus P388.
The palladium-catalyzed coupling of 3- and 4-(trialkylstannyl)pyridines with 7-bromo or 7-chloro 1-substituted 1,4-dihydro-4-oxo-3-quinolinecarboxylates has provided access to the corresponding 1-substituted 1,4-dihydro-4-oxo-7-pyridinyl-3-quinolinecarboxylic acids. The antibacterial activity of these derivatives was studied with the finding that the optimal 1- and 7-position substituents for Gram positive activity are cyclopropyl and 4-(2,6-dimethylpyridinyl), respectively. We find that for the fluorine-substituted derivatives studied, the position of the fluorine on the quinolone nucleus or the number of fluorine atoms does not seem to be important for good Gram positive activity. For 1-cyclopropyl 7-(2,6-dimethyl-4-pyridinyl) derivatives, the 6-fluoro 4a, 8-fluoro 10d, 6,8-difluoro 10b, and 5,6,8-trifluoro 8, all provided equal antibacterial activity against Staphylococcus aureus ATCC 29213. There is also a correlation between the substitution on the 7-(4-pyridinyl) group and the Gram positive activity, particularly for S. aureus, clearly indicating that the 2,6-dimethylpyridinyl group is optimal. The MIC50 value for the most potent agents in this study against S. aureus ATCC 29213 is 0.008 microgram/mL. By comparison, ciprofloxacin and aminopyrrolidine 28 gave values of 0.25 and 0.015 microgram/mL, respectively, against this organism.
The preparation of a variety of 1‐ethyl‐1,4‐dihydro‐4‐oxo‐7‐pyridinyl‐3‐quinolinecarboxylic acids with a range of substituents on the pyridine ring is described. Starting with the appropriately substituted aniline and using the first two steps of the Gould‐Jacobs quinoline synthesis the 7‐pyridinyl‐3‐quinolinecarboxylates can be obtained. Ethylation at the 1‐position and hydrolysis of the ester group gives the desired acid products. These compounds have significant antibacterial activity: 1‐ethyl‐1,4‐dihydro‐4‐oxo‐7‐(4‐pyridinyl)‐3‐quinolinecarboxylic acid is now in clinical study and 7‐(2,6‐dimethyl‐4‐pyridinyl)‐1‐ethyl‐1,4‐dihydro‐4‐oxo‐3‐quinolinecarboxylic acid is under advanced evaluation.
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