Table 6.
In Vitro Liver-Stage Antimalarial Activity and In Vivo Liver-Stage Antimalarial Efficacy of Acridones.
| compd | in vitro vs. P. berghei IC50 (nM)a |
in vivo vs. P. berghei (IVIS) | ||
|---|---|---|---|---|
| dose (mg/kg/d)b | clearance rate at 48 hc | cured mice on day 31d | ||
| T31 | 0.50 | 1 | 76% | 0/5 |
| 4 | 99% | 5/5 | ||
| 10 | 100% | 5/5 | ||
| 40 | 100% | 5/5 | ||
| 18 | 5.9 | - | - | - |
| 19 | 66 | 40 | 55% | 0/5 |
| 20 | 37 | - | - | - |
| 21 | 66 | - | - | - |
| 22 | 1.6 | 1 | 88% | 0/5 |
| 4 | 96% | 0/5 | ||
| 10 | 99% | 1/5 | ||
| 40 | 100% | 3/5 | ||
| 23 | 7.4 | 40 | 60% | 0/5 |
| 24 | 0.46 | - | - | - |
| 25 | 36 | - | - | - |
| 26 | 4.5 | 1 | 97% | 1/5 |
| 4 | 100% | 5/5 | ||
| 10 | 100% | 5/5 | ||
| 40 | 100% | 5/5 | ||
| 27 | 32 | 40 | 64% | 0/5 |
| 28 | 41 | - | - | - |
| 29 | 0.45 | 10 | 15% | 0/5 |
| 40 | 99% | 0/5 | ||
| 30 | 14 | 40 | 63% | 0/5 |
| 31 | 73 | - | - | - |
| 32 | 59 | - | - | - |
| 33 | 824 | - | - | - |
| 34 | 5.6 | - | - | - |
| 35 | 126 | - | - | - |
| 37 | 190 | 40 | 71% | 0/5 |
| 38 | 2.2 | 10 | 40% | 0/5 |
| 40 | 29% | 0/5 | ||
| 39 | 4.4 | 10 | 45% | 0/5 |
| 40 | 86% | 0/5 | ||
| 40 | 0.41 | 40 | 98% | 0/5 |
| 41 | 0.60 | 40 | 0% | 0/5 |
| 42 | 7.4 | - | - | - |
| 43 | 6.8 | 1 | 0% | 0/5 |
| 4 | 12% | 0/5 | ||
| 10 | 0% | 0/5 | ||
| 44 | 2.4 | 1 | 0% | 0/5 |
| 4 | 95% | 0/5 | ||
| 10 | 71% | 0/5 | ||
| 45 | 86 | 40 | 23% | 0/5 |
| 46 | 66 | - | - | - |
| 48 | 4.7 | - | - | - |
| 49 | 86 | - | - | - |
| 50 | 109 | - | - | - |
| 51 | 69 | - | - | - |
| 52 | 48 | - | - | - |
| 53 | 816 | - | - | - |
| 54 | 84 | - | - | - |
| 55 | 1334 | - | - | - |
| 56 | 327 | - | - | - |
| 57 | 52 | - | - | - |
| 58 | 26 | - | - | - |
| 68 | 1.5 | 40 | 100% | 4/5 |
| 69 | 15 | 40 | 99% | 3/5 |
| 70 | 159 | 40 | 0% | 0/5 |
| 72 | 2461 | - | - | - |
| 73 | 1219 | - | - | - |
| 74 | 5.9 | - | - | - |
| 75 | 1429 | - | - | - |
| 76 | 2277 | - | - | - |
| 77 | 164 | - | - | - |
| 78 | 1411 | - | - | - |
| 79 | 98 | - | - | - |
| 80 | 418 | - | - | - |
| 86 | 8.0 | - | - | - |
| 87 | 0.64 | 10 | 95% | 0/5 |
| 40 | 100% | 3/5 | ||
| 88 | 1.7 | 40 | 81% | 0/5 |
| 89 | 7.5 | 40 | 67% | 0/5 |
| 90 | 0.51 | 4 | 99% | 4/5 |
| 10 | 100 | 5/5 | ||
| 40 | 100% | 5/5 | ||
| 91 | 0.12 | 10 | 100% | 1/5 |
| 40 | 100% | 5/5 | ||
| 92 | 0.20 | 40 | 56% | 0/5 |
| 93 | 17 | 40 | 6% | 0/5 |
| 100 | 113 | - | - | - |
| 107 | 0.70 | 10 | 100% | 1/5 |
| 40 | 100% | 5/5 | ||
| 108 | 8.2 | 40 | 10% | 0/5 |
| 109 | 29 | 40 | 50% | 0/5 |
| ATV | 6.5 | - | - | - |
| PQ | 13800 | 5 | 100% | 5/5 |
| CQ | > 31262 | - | - | - |
a
IC50 values are the average of at least three determinations, each carried out in triplicate (±10%).
b
oral doses of drugs were administered on day – 1, day 0, and day 1 with inoculation of sporozoites on day 0.
c
the clearance rate was calculated by the ratio of the mean luminescence signal intensity collected by IVIS in drug treated mice over vehicle-only control mice.
d
the blood parasitemia was measured by flow cytometry up to 31 days after inoculation and the cure was determined with negative parasitemia on day 31.
ATV: atovaquone; PQ: primaquine; CQ: chloroquine.