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
A series of novel 3-quinolinecarboxamides that are structurally similar to the quinolone class of antibacterial agents possess excellent antiherpetic properties. By modifying the quinoline ring at the 1-, 2-, 3-, and 7-positions, analogues were identified that have up to 5-fold increased HSV-2 plaque-reduction potency relative to acyclovir. In a single-dose mouse model of infection, one of the most potent derivatives in vitro, 1-(4-fluorophenyl)-1,4-dihydro-4-oxo-7-(4-pyridinyl)-3-quinolinecarbo xamide (97), displayed comparable oral antiherpetic efficacy to acyclovir at 1/16 the dose; in a multiple-dose regimen, however, 97 was 2-fold less potent. In mice dosed orally with 97, sustained plasma drug levels were evident that may account for the high efficacy observed. The molecular mechanism of action of these agents is not known; however, based on in vitro studies with acyclovir resistant mutants, it is likely that the mechanism differs from that of acyclovir. In vitro plaque-reduction potency was not generally predictive of oral efficacy in mice. An X-ray crystal structure of 97 corroborated the assignment of structure and provided useful insights as to the effect of conformation on plaque-reduction potency.
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