Table 9. Derivatives of SB-400868 and their Activity against L. infantum and Associated ADME Dataa.
| ID | R | L.inf pEC50 | PMM pCC50 | SI | aq. sol.b | HLM clintc | RH clintd | logD7.4 | LLEe |
|---|---|---|---|---|---|---|---|---|---|
| 16a | 5.7 | 5.1 | 4 | 180 | 64 | 26 | 2.2 | 3.5 | |
| 16b | 2-Me | 6.0 | 5.7 | 2 | nt | nt | nt | nt | NA |
| 16c | 3,4-Cl | 6.2 | 5.1 | 13 | 3 | 100 | 38 | 3.4 | 2.8 |
| 16d | 3,4-OMe | 5.7 | 4.5 | 16 | nt | nt | nt | nt | NA |
| 16e | 3,5-OMe | 5.9 | 5.1 | 6 | 97 | 53 | >300 | 2.4 | 3.5 |
| 16f | 3-Me | 6.2 | 5.1 | 13 | 560 | 76 | 63 | 2.8 | 2.4 |
| 16g | 3-Cl | 6.1 | 4.6 | 32 | 51 | 140 | 51 | 3.0 | 3.1 |
| 16h | 3-[N] | 4.2 | 4.2 | 1 | >1000 | 24 | 2.4 | 1.1 | 3.1 |
| 16i | 3-[N], 4-CN | 4.2 | 4.2 | 1 | nt | nt | nt | nt | NA |
| 16j | 3-CN | 5.0 | 4.2 | 6 | 37 | 44 | 23 | 2.0 | 3.0 |
| 16k | 4-[N] | 4.2 | 4.2 | 1 | >1000 | 26 | 4.8 | 1.2 | 3.0 |
| 16l | 3-F, 4[N] | 4.6 | 4.5 | 1 | nt | nt | nt | nt | NA |
| 16m | 4-CN | 4.5 | 4.2 | 2 | 38 | 99 | 8.0 | 1.9 | 2.6 |
| 16n | 3-OMe, 4-CN | 4.6 | 4.2 | 3 | nt | nt | nt | nt | NA |
| 16o | 3-CF3, 4-CN | 4.6 | 4.2 | 3 | nt | nt | nt | nt | NA |
| 16p | 4-Cl | 5.8 | 5.1 | 5 | 4 | 170 | 22 | 3.0 | 2.8 |
| 16q | 4-F | 5.5 | 4.5 | 10 | nt | nt | nt | nt | NA |
| 16r | 4-Me | 6.3 | 5.7 | 4 | 32 | 82 | 49 | 2.7 | 3.6 |
| 16s | 4-CF3 | 5.7 | 4.5 | 16 | nt | nt | nt | nt | NA |
| 16t | 4-OCF3 | 6.2 | 5.1 | 13 | 38 | 62 | 54 | 2.9 | 3.3 |
| 16u | 4-SOMe | 4.7 | 4.2 | 3 | 760 | <3 | <1 | 0.9 | 3.8 |
| 16v | 4-SO2Me | 4.2 | 4.2 | 1 | 320 | <3 | <1 | 1.2 | 3.0 |
| 16w | 4-CON(Me)2 | 4.4 | 4.2 | 2 | 780 | <3 | <1 | 1.1 | 3.3 |
| 16x | 4-COMe | 5.2 | 4.5 | 5 | nt | nt | nt | nt | NA |
| 16y | 4-NH2 | 5.6 | 5.1 | 3 | nt | nt | nt | nt | NA |
| 16z | 5.5 | 4.3 | 16 | 10 | 34 | 49 | 2.6 | 2.9 | |
| 16aa | 5.4 | 4.5 | 8 | nt | nt | nt | nt | NA | |
| 16ab | 6.5 | 5.7 | 6 | 3 | 43 | 150 | 4.1 | 2.4 | |
| 16ac | 6.5 | 5.7 | 6 | 3 | 62 | >300 | 2.9 | 3.6 | |
| 16ad | 5.9 | 5.1 | 6 | nt | nt | nt | nt | NA |
a
NA, not applicable; nt, not tested.
b
Thermodynamic aqueous solubility μM.
c
μL/min/mg protein.
d
μL/min/106 cells.
e
LLE = pEC50 – LogD7.4.