TABLE 1.
| |||||||||
---|---|---|---|---|---|---|---|---|---|
FabI Inhibitiona | Microsomal Stability | ||||||||
|
|||||||||
Compd | R1 | R2 | R3 | R4 | R5 | cLogP | IC50 (μM) | t1/2 (min) | CLint, app (μl/min/mg) |
1 | H | H | H | H | 3′-H, 4′-H, 5′-H, 6′-H, 7′-H | 3.24 | >100 | 5.8 | 240 |
2 | H | H | H | H | 3′-H, 4′-H, 5′-CH3, 6′-H, 7′-H | 3.70 | 90 | 5.4 | 255 |
3 | H | H | H | H | 3′-H, 4′-H, 5′-OCH3, 6′-H, 7′-H | 3.16 | 38 | 5.6 | 248 |
4 | H | H | H | H | 3′-H, 4′-H, 5′-Br, 6′-H, 7′-H | 4.01 | 27 | 7.4 | 186 |
5 | H | H | H | H | 3′-H, 4′-Cl, 5′-Cl, 6′-H, 7′-H | 4.31 | 4.7 | 4.6 | 304 |
6 | H | H | H | =O | 3′-H, 4′-H, 5′-Cl, 6′-H, 7′-H | 3.57 | >100 | N.A.b | N.A. |
7 | NH2 | H | H | H | 3′-H, 4′-H, 5′-Cl, 6′-H, 7′-H | 3.35 | >100 | 32.5 | 43 |
8 | COCH3 | H | H | H | 3′-H, 4′-H, 5′-Cl, 6′-H, 7′-H | 3.68 | >100 | 3.8 | 365 |
9 | NHCOCH3 | H | H | H | 3′-H, 4′-H, 5′-Cl, 6′-H, 7′-H | 3.50 | >100 | 20.3 | 68 |
10 | CH3 | H | H | H | 3′-H, 4′-Cl, 5′-Cl, 6′-H, 7′-H | 4.83 | 3.2 | 4.3 | 324 |
11 | SCH2CH3 | H | H | H | 3′-H, 4′-H, 5′-Cl, 6′-H, 7′-H | 5.63 | >100 | 3.1 | 452 |
12 | H | CH3 | CH3 | =O | 3′-H, 4′-H, 5′-H, 6′-Cl, 7′-H | 4.53 | >100 | N.A. | N.A. |
13 | H | CH3 | CH3 | CH3 | 3′-H, 4′-H, 5′-Cl, 6′-Cl, 7′-H | 5.57 | 2.75 | 9.2 | 151 |
14 | H | CH3 | CH3 | H | 3′-H, 4′-H, 5′-Cl, 6′-H, 7′-H | 4.76 | 0.3 | 3.8 | 369 |
15 | H | CH3 | CH3 | H | 3′-Cl, 4′-H, 5′-Cl, 6′-H, 7′-H | 5.36 | 0.7 | 4.0 | 345 |
16 | H | CH3 | CH3 | H | 3′-H, 4′-H, 5′-Cl, 6′-Cl, 7′-H | 5.23 | 0.3 | 5.3 | 263 |
17 | H | CH3 | CH3 | H | 3′-H, 4′-OCH3, 5′-Cl, 6′-H, 7′-H | 4.62 | >100 | 2.4 | 573 |
18 | H | CH3 | CH3 | H | 3′-H, 4′-OCH3, 5′-Cl, 6′-H, 7′-Br | 5.60 | >100 | 3.5 | 395 |
19 | H | CH3 | CH3 | H | 3′-H, 4′-H, 5′-OCH3, 6′-H, 7′-H | 4.08 | 0.5c | <2 | >693 |
20 | H | CH3 | CH3 | H | 3′-H, 4′, 5′-OCH2O, 6′-H, 7′-H | 4.02 | 1.0c | 3.7 | 376 |
21 | H | CH3 | CH3 | H | 3′-H, 4′-CH3, 5′-OCH3, 6′-H, 7′-H | 4.54 | 0.25c | <2 | >693 |
22 | H | CH3 | CH3 | H | 3′-H, 4′-CH3, 5′-OH, 6′-H, 7′-H | 3.88 | 1.3 | 3.3 | 426 |
FabI IC50 values determined per published procedures (Hevener et al. 2012);
N.A., not available;
IC50 value determined with reduced FabI concentration of 10 nM.