Fumio Sakamoto

Studies on Prodrugs. VI. Preparation and Characterization of (5-Substituted 2-Oxo-1, 3-dioxol-4-yl) methyl Esters of Mecillinam

Mecillinam is a unique penicillin derivative which exhibits strong antimicrobial activities against Escherichia coli and other gram-negative bacilli.1) As it is not absorbed orally,2) its sodium salt is used parenterally and two of its esters, namely pivmecillinam3) and bacmecillinam4) are clinically used as oral prodrugs mainly for urinary tract infections. We have been developing the (5-substituted 2-oxo-1,3-dioxo1-4-yl)methyl group as a new, useful pro-moiety, and the effectiveness of the prodrugs of ampicillie and norfloxacie has been reported recently. As an extension of this prodrug study we prepared some new mecillinam (5-substituted 2-oxo-1,3-dioxol-4-yl)methyl esters and examined their oral absorbabilities. The *present paper describes the preparation and characterization of these mecillinam esters.

Synthesis and antibacterial activity of a new series of tetracyclic pyridone carboxylic acids.

A series of novel tetracyclic pyridone carboxylic acids replacing the 10-position oxygen atom of 9,1-(epoxymethano)-7-fluoro-8-(4-methyl-1-piperazinyl)-5-oxo-5H-thiazolo [3,2-alpha]quinoline-4-carboxylic acid by imino groups (NR; R = Me, Et, c-Pr, allyl, Ph, benzyl), a sulfur atom, or a carbonyl group was prepared and evaluated for antibacterial activity and inhibitory activity on DNA gyrase isolated from E. coli KL-16. The in vitro antibacterial potency and DNA gyrase inhibitory activity were found to be in the following order: NMe > or = O > S >> C = O. Moreover, a methyl group was the optimal alkyl substituent at the 10-position nitrogen atom for antibacterial activity and for DNA gyrase inhibitory activity. 7-Fluoro-9,1-[(N-methylimino)methano]-8- (4-methyl-1-piperazinyl)-5-oxo-5H-thiazolo[3,2-alpha]quinoline-4-carboxy lic acid (10-NCH3) showed potent in vivo antibacterial activity.