Norfloxacin analogues

Pefloxacin (33) is the N-methyl analogue of norfloxacin (58) and is at least partly converted to it by metabolic enzymes in vivo. It has been launched in France for the treatment of a number of infections including those caused by sensitive strains of Pseudomonas aeruginosa. It can be synthesized starting with the Gould-Jacobs reaction of 3-chloro-4-fluoroaniline (28) and diethyl ethoxymethylenemalonate in an addition-elimination sequence leading to 29 which undergoes... 

Norfloxacin (41), the substance which triggered this avalanche of activity, has recently been introduced into clinical practice in the United States. Its synthesis parallels closely that of its N-methyl analogue, pefloxacin, except that the nucleophilic aromatic displacement reaction of 32 is carried out with mono-N-carboethoxypiperazine instead and the final step encompasses deblocking of this carbamoyl ester moiety [8]. 

According to molecular modeling studies, at the ground state the 6-lluoro analogue of 81 overlaps perfectly with the structure of norfloxacin (a well-established quinolone antibacterial agent) and is predicted to exhibit promising antibacterial activity. 

The monofluoro analogues (71) possess very weak oral activity in a mouse protection test against E. coli. On the other hand the difluoro analogues (72b) and (72d) were found to be about 2-fold more active than norfloxacin in this... 

The 3-formyl analogues of norfloxacin, pefloxacin and ciprofloxacin, (82a-c) have also been shown to function as prodrugs of their respective parent... 

It has been established that after oral administration of 3-formyl analogue of norfloxacin in mice the formyl group is metabolized rather fast into the carboxyl one, thus converting 3-formyl derivatives into norfloxacin. Due to a good solubility, a much higher level (at least two times) of the formyl derivative in blood serum can be reached, than on administration of norfloxacin, which at physiological pH values exists in the form of poor soluble zwitter-ionic form. 

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