PD 0305970 and PD 0326448 are new bacterial gyrase and topoisomerase inhibitors (quinazoline-2,4-diones) that possess outstanding in vitro and in vivo activities against a wide spectrum of bacterial species including quinolone-and multidrug-resistant gram-positive and fastidious organism groups. The respective MICs (g/ml) for PD 0305970 capable of inhibiting >90% of bacterial strains tested ranged from 0.125 to 0.5 versus staphylococci, 0.03 to 0.06 versus streptococci, 0.25 to 2 versus enterococci, and 0.25 to 0.5 versus Moraxella catarrhalis, Haemophilus influenzae, Listeria monocytogenes, Legionella pneumophila, and Neisseria spp. PD 0326448 MIC 90 s were generally twofold higher versus these same organism groups. Comparative quinolone MIC 90 values were 4-to 512-fold higher than those of PD 0305970. In testing for frequency of resistance, PD 0305970 and levofloxacin showed low levels of development of spontaneous resistant mutants versus both Staphylococcus aureus and Streptococcus pneumoniae. Unlike quinolones, which target primarily gyrA and parC, analysis of resistant mutants in S. pneumoniae indicates that the likely targets of PD 0305970 are gyrB and parE. PD 0305970 demonstrated rapid bactericidal activity by in vitro time-kill testing versus streptococci. This bactericidal activity carried over to in vivo testing, where PD 0305970 and PD 0326448 displayed outstanding Streptococcus pyogenes 50% protective doses (PD 50 s) (oral dosing) of 0.7 and 3.6 mg/kg, respectively (ciprofloxacin and levofloxacin PD 50 s were >100 and 17.7 mg/kg, respectively). PD 0305970 was also potent in a pneumococcal pneumonia mouse infection model (PD 50 ‫؍‬ 3.2 mg/kg) and was 22-fold more potent than levofloxacin.The continuing emergence and development of bacterial resistance to existing antibacterial agents (fluoroquinolones, macrolides, and vancomycin) in gram-positive organisms have created the need for new compounds that retain activity against these resistant strains (1, 4, 9, 16). PD 0305970 and PD 0326448 are new bacterial gyrase and topoisomerase inhibitors developed as part of a program to introduce an orally active quinazolinedione (QD), displaying highly potent in vitro and in vivo activities versus susceptible and resistant gram-positive and fastidious organism groups. The structure of PD 0305970, 3-amino-7-{(R)-3-[(S)-1-amino-ethyl]-pyrrolidin-1-yl}-1-cyclopropyl-6-fluoro-8-methyl-1H-quinazoline-2,4-dione, is displayed in Fig. 1. PD 0326448 is the des-3-amino version of PD 0305970 (Fig. 2). The data presented here describe the in vitro susceptibilities, in vivo efficacies, and frequencies of resistance for these compounds compared with quinolones in medically significant bacterial species. MATERIALS AND METHODSAntimicrobial agents. The antibacterial compounds used in these studies were obtained from the following sources: PD 0305970, PD 0326448, and gatifloxacin were obtained from the Chemistry Department at Pfizer Global Research and Development, Ann Arbor, MI; garenoxacin was obtained from Bristol Myers, Prin...

The re-emergence of tuberculosis infections which are resistant to conventional drug therapy has demonstrated the need for alternative chemotherapy against Mycobacterium tuberculosis. As part of a study to optimize the quinolone antibacterials against M. tuberculosis, we have prepared a series of N-1- and C-7-substituted quinolones to examine specific structure-activity relationships between modifications of the quinolone at these two positions and activity against mycobacteria. The compounds, synthesized by literature procedures, were evaluated for activity against Mycobacterium fortuitum and Mycobacterium smegmatis as well as Gram-negative and Gram-positive bacteria. The activity of the compounds against M. fortuitum was used as a barometer of M. tuberculosis activity. The results demonstrate that (i) the activity against mycobacteria was related more to antibacterial activity than to changes in the lipophilicity of the compounds, (ii) the antimycobacterial activity imparted by the N-1 substituent was in the order tert-butyl > or = cyclopropyl > 2,4-difluorophenyl > ethyl approximately cyclobutyl > isopropyl, and (iii) substitution with either piperazine or pyrrolidine heterocycles at C-7 afforded similar activity against mycobacteria.

The 3-aminoquinzolinediones represent a new series of antibacterial agents structurally related to the fluoroquinolones. They are inhibitors of bacterial gyrase and topoisomerase IV and demonstrate clinically useful antibacterial activity against fastidious Gram-negative and Gram-positive organisms, including multidrug- and fluoroquinolone-resistant organisms. These agents also demonstrate in vivo efficacy in murine systemic infection models.

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