The fluoroquinolone antibacterials represented generically by 1 (Table I) have generated much excitement after the discovery that a fluorine atom at C-6 enhances antibacterial activity. Norfloxacin is generally considered to be the first derivative noted for a significant increase in activity. However, flumequine was the first to demonstrate the advantage of a C-6 fluorine atom. The next entries into this class of antibacterials were ofloxacin, ciprofloxacin, and more recently tosufloxacin, all of which contain a piperazinyl or aminopyrrolidinyl moiety for R, and diverse groups for R1. Structure-activity studies have demonstrated that the optimum substituent at the C-6 position was a fluorine atom in both the quinolone and naphthyridone series. As part of our continuing efforts in structure-activity studies in the quinolone and naphthyridone series, we have discovered that derivatives without fluorine atom at the C-6 position could retain overall antimicrobial activity comparable to that of ciprofloxacin. In this communication we describe the synthesis and biological activity of a series of 7-(aminopyrrolidinyl)-1-cyclopropyl-1,4-dihydro-4-oxo-3-quinolinecarboxylic acids in which the fluorine atom is appended at C-5 or C-8 and then compare of these compounds to known references and C-6 fluoro analogues. Although several compounds showed acceptable efficacy in vivo in both PCP and TOKA assays, only the phosphate prodrug 8i (L-693,989) showed high activity in both assays and additionally possessed superior solution stability. The observation that 8i was hydrolytically stable and yet had in vivo activity comparable to the parent 4 suggested that the phosphate ester underwent rapid enzymatic hydrolysis. Preliminary pharmacokinetic data in primates (rhesus and chimpanzee) showed that prodrug 8i was efficiently converted to parent drug 4 and produced a more sustained therapeutic level of 4 than direct iv administration of 4 itself. Because of the favorable overall profile, the phosphate ester was chosen for further evaluation as a potential clinical agent for the treatment of PCP and candidiasis.