The preparation and antibacterial activity of a series of the title compounds (21-73) are described. These compounds were prepared from the 2-methylthio derivatives 2 and 3 via the 2-methylthio-8-substituted compounds 4-20; compounds 4-20 easily underwent displacement reactions with a variety of piperazines to afford 2-(4-substituted or unsubstituted 1-piperazinyl) derivatives 21-56, of which 21, 22, 27 and 51 with unsubstituted piperazinyl group at position 2 are converted subsequently into 57-73 by alkylation, acylation, sulfonylation, or addition of isocyanates to the piperazine nitrogen. The hexahydro-1H-1,4-diazepinyl analog 74 was also prepared. The most active members in this series of compounds were found to be 8-ethyl- and 8-vinyl-5,8-dihydro-5-oxo-2-(1-piperazinyl)pyrido(2,3-d)pyrimidine-6-carboxylic acids (22 and 51), both of which are more active in vitro and in vivo against gram-negative bacteria, including Pseudomonas aeruginosa, than piromidic acid (1). Structure-activity relationships are discussed.