Table 1.
In Vitro Properties and Neonatal Mouse Efficacy of Bumped-Kinase Inhibitors
| Compound | R1 | R2 | IC50, µM | C. parvum EC50, µM, Mean ± SD | CC50, µM | Percentage of Protein Bound in Plasma, by Species | Percentage Reduction in Parasite Burden in Neonatal Mice, Mean ± SD | |||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| CpCDPK1 | c-SrC | hERG | HepG2 | CRL- 8155 | HCT-8 | Human | Mouse | |||||
| RM-1–22 |
|
|
0.059 | 0.121 | ND | 5.3 ± 0.3 | 30.9 | 10.4 | >20 | ND | ND | ND |
| RM-1–89 |
|
|
0.012 | 0.549 | >10 | 0.7 ± 0.2 | ND | 30 | >20 | ND | ND | ND |
| 1243 |
|
|
>5 | >10 | ND | >20 | ND | ND | >20 | ND | ND | ND |
| 1266 |
|
|
0.58 | >10 | ND | >80 | >40 | >40 | >20 | ND | ND | ND |
| 1294 |
|
|
0.001 | >10 | 0.76 | 2.7 ± 1 | >40 | >40 | >20 | 85 | 84 | 56 ± 14 |
| 1318 |
|
|
0.001 | >10 | 10 | 3.2 ± 0.5 | >40 | >40 | >20 | 77 | 55 | 69 ± 11 |
| 1369 |
|
|
0.001 | >10 | 10 | 2.4 ± 0.7 | >40 | >40 | >20 | 77 | 37 | 74 ± 10 |
| 1412 |
|
|
0.008 | >10 | >10 | 2.2 ± 0.6 | >40 | >40 | >20 | 94 | 85 | 14 ± 15 |
| 1416 |
|
|
0.289 | >10 | ND | 20 ± 2.8 | ND | ND | >20 | ND | ND | ND |
| 1534 |
|
|
0.005 | >10 | 25 | 2.2 ± 0.3 | >40 | 39.9 | >20 | 99.9 | 99.9 | 61 ± 13 |
| 1546 |
|
|
0.001 | >10 | >30 | 1.3 ± 0.3 | >40 | >40 | >20 | 92 | 81 | 33 ± 8 |
| 1550 |
|
|
0.001 | 7.4 | >30 | 5.5 ± 2.4 | >40 | >40 | >20 | 83 | 84 | 50 ± 14 |
| 1553 |
|
|
0.002 | >10 | >30 | 1.6 ± 0.3 | >40 | 39.5 | >20 | 91 | 90 | 36 ± 12 |
| 1556 |
|
|
0.003 | >10 | 25 | 3.2 ± 0.6 | >40 | 22.7 | >20 | 99.9 | 86 | 61 ± 11 |
| 1557 |
|
|
0.007 | >10 | 14 | 5.5 ± 0.3 | >40 | 31.1 | >20 | 91 | 84 | 33 ± 11 |
| 1610 |
|
|
0.462 | ND | ND | 37.7 ± 5.4 | >40 | >40 | >20 | ND | ND | ND |
| 1624 |
|
|
0.426 | ND | ND | >80 | >40 | >40 | >20 | ND | ND | ND |
| 1649a |
|
|
0.002 | >10 | >30 | 2.3 ± 1.3 | >40 | >40 | >20 | 56 | 90 | 56 ± 10 |
| 1663 |
|
|
0.021 | >10 | 7.6 | 6.7 ± 0.5 | >40 | >40 | >20 | 96 | 86 | 76 ± 13 |
| Paromomycinb | … | … | … | … | … | … | … | … | … | … | … | 18 ± 14 |
The central scaffold of each compounds is , unless otherwise indicated.
Abbreviations: CC50, 50% cytotoxicity concentration; C. parvum, Cryptosporidium parvum; EC50, 50% effective concentration; IC50, 50% inhibitory concentration; ND, not determined.
aThe central scaffold is .
bParomomycin was selected as the standard comparator because it consistently yielded better activity than nitazoxanide in experimental mouse models.