Table 5. Pfizer prokaryotic and eukaryotic biochemical SAR for quinolone C-5 and C-7 substitutions in an N-1-cyclopropyl, 6,8-difluoro quinolone scaffold. Etoposide 14 was used as control.
| Compound | R5 | R7 |
E. coli
gyrase cleavage endpoint (μg/ml)a,b |
Topo II DNA cleavage
IC50 (μg/ml)a,c |
|---|---|---|---|---|
|
47 sparfloxacin |
-NH2 | 0.18 | >780 | |
| 48 | -F | 0.19 | >800 | |
| 49 | -H | 0.39 | >760 | |
| 50 | -NH2 | 0.19 | 257 | |
| 51 | -NH2 | * | 62 | |
| 52 | -H | 0.19 | 55 | |
| 53 | -NH2 | 0.19 | 29 | |
| 54 | -NH2 | 0.19 | 30 | |
|
14 etoposide |
- | - | * | 8.3 |
aValues originally reported as μM were converted to μg/ml for this table; blowest drug concentration that stimulates cleavage above that for the drug-free control; cCC50 is the concentration of drug that produces half-maximal stimulation of cleavage; *no data reported.