Studies on prodrugs. 11. Synthesis and antimicrobial activity of N-[(4-methyl-5-methylene-2-oxo-1,3-dioxolan-4-yl)oxy]norfloxacin .

The chemical oxidation of N-[(5-methyl-2-oxo-1,3-dioxol-4-yl)methyl] norfloxacin (2) was carried out to afford N-[(4-methyl-5-methylene-2-oxo-1,3-dioxolan-4-yl)oxy]norfloxacin (4). In vitro, 4 exhibited lower activity than that of norfloxacin (NFLX, 1) for both Gram-positive and Gram-negative bacteria. However, in vivo the activity of 4 was higher than that of NFLX. Bioavailability studies in mice showed that 4 liberated a higher concentration of NFLX in plasma than NFLX itself when administered orally. From these data, 4 obtained by the chemical oxidation of 2 functioned as a prodrug of NFLX as well as did 2. The mechanism of the formation of 4 is interpreted in terms of [2,3]-sigmatropic rearrangement.

Synthesis of antimicrobial agents. 1. Syntheses and antibacterial activities of 7-(azole substituted)quinolones.

A series of 6-fluoro- and 6,8-difluoro-7-(azole substituted)-1,4-dihydro-4-oxo-3-quinolinecarboxylic acids were prepared. Structure-activity relationship studies indicated that the antibacterial potency was better when the 6,8-substituents were fluorine atoms and the 7-substituent was either 1-imidazolyl, 20, or 4-methyl-1-imidazolyl, 25. From the results of studies on pharmacokinetic profile and toxicity, 20 and 25 were found to possess excellent antibacterial activities and to show high blood levels after oral administration to mice with low toxicity.

Synthesis and antibacterial activity of new tetracyclic quinolone antibacterials.

A series of 8-substituted-9,1-(epoxymethano)-7-fluoro-5-oxo-5H- thiazolo[3,2-a]quinoline-4-carboxylic acids having a novel tetracyclic structure was synthesized and tested for antibacterial activity. The nature of the heteroatom (N, O, or S) substituted at the 8-position had little influence on the antibacterial activity. Among the six pyrrolidinyl derivatives and the five piperazinyl derivatives, the 8-(3-hydroxy-1-pyrrolidinyl) derivative 6h and the hydrochloride of the 8-(4-methyl-1-piperazinyl) derivative 6l showed the most potent activity against both Gram-positive and Gram-negative bacteria. Against nalidixic acid resistant strains, isolated from Escherichia coli KC-14, compound 6h was less potent than 6l. Replacement of the piperazinyl nitrogen atom by a carbon atom, an oxygen atom, or a sulfur atom (corresponding to the piperidino, morpholino, or thiomorpholino group, respectively) enhanced the activity against Gram-positive bacteria, but reduced the activity against Gram-negative bacteria. Compound 6l also showed potent in vivo antibacterial activity against Gram-positive and Gram-negative bacteria, and did not cause convulsions in mice with the concomitant administration of fenbufen. Replacement of the carboxy group by a sulfonic acid group in 6l resulted in a complete loss of antibacterial activity.

Synthesis of antimicrobial agents. 3. Syntheses and antibacterial activities of 7-(4-hydroxypiperazin-1-yl)quinolones.

A series of novel pyridone carboxylic acids having a 4-hydroxypiperazinyl group at the 7-position of norfloxacin and ciprofloxacin were prepared. The in vivo antibacterial efficacies of these compounds were superior to those of corresponding piperazinyl derivatives. From the results of the studies on the pharmacokinetic profile and toxicity, the 4-hydroxypiperazinyl derivatives were confirmed to be pharmacologically superior to corresponding piperazinyl derivatives. Thus, a 4-hydroxypiperazinyl group was revealed to be a beneficial substituent for potential use in future quinolone antibacterials.

[Bacteriological evaluation of netilmicin].

The following results were obtained from the bacteriological evaluations of netilmicin (NTL), a newly developed antibiotic agent, with gentamicin (GM), dibekacin (DKB) and amikacin (AMK) as the controls. (1) NTL demonstrated broad antibacterial spectra against both Gram-positive and Gram-negative bacteria, but its antibacterial potency against streptococci was not very strong among other Gram-positive bacteria. (2) In terms of distribution of sensitivity of clinically isolated bacterial strains, NTL proved to have antibacterial potency comparable to that of GM and higher potency than that of DKB of AMK against E. coli K. pneumonia, Enterobacter sp., or H. influenzae. However, its efficacy was inferior to GM against Proteus sp., S. marcescens and P. aeruginosa. (3) In conjunction with the influences of pH of culture media or of addition of horse sera upon the antibacterial efficacy, NTL showed an inclination similar to that of GM, DKB and AKM. Its antibacterial efficacy was fortified on the alkaline side or by addition of sera. In connection with the influences of the amounts of inoculated bacteria upon antibacterial efficacy, there were hardly any appreciable influences on it by any of the tested bacterial strains. (4) The interactions of NTL with carbenicillin were evaluated with the chequerboard titration method to find remarkable cooperative actions in any of E. coli, K. pneumoniae, S. marcescens, A. calcoaceticus and P. aeruginosa. (5) The results of evaluation on the patterns of its antibacterial effects revealed that it acted bactericidal in any tested bacterial strains. (6) As to the therapeutic effects against experimental infections in mice, it was found out that NTL = GM greater than DKB and AMK against E. coli, GM greater than NTL = DKB and AMK against K. pneumoniae and GM and DKB greater than NTL greater than or equal to AMK against A. calcoaceticus and P. aeruginosa in the decreasing order of efficacy.