Table 4.
In Vitro Blood-Stage Antiplasmodial Activity and Selectivity of Acridones (86–93, 99–102 and 107–109)
 | |||||||||
|---|---|---|---|---|---|---|---|---|---|
| compd | R1 | R2 | R3 | blood-stage IC50 (nM)a vs. P. falciparum |
cytotoxicity IC50 (nM)a vs. HepG2 Cells |
selectivity index vs. HepG2 IC50/D6 IC50 |
|||
| D6 | Dd2 | 7G8 | Tm90-C2B | ||||||
| 86 | 1-F | 3-F | H | 0.031 | 0.046 | 0.54 | 45 | >29644 | >956258 |
| 87 | 1-F | 3-F | 4’-OCF3 | 0.0040 | 0.0065 | 0.020 | 7.2 | >23735 | >5933750 |
| 88 | 1-F | 3-F | 4’-SCF3 | 0.013 | 0.078 | 0.16 | 3.8 | 772 | 59384 |
| 89 | 1-F | 3-F | 4’-CF3 | 0.042 | 0.063 | 0.045 | 8.0 | 15617 | 371833 |
| 90 | 1-F | 3-F | 3’-OCF3 | 0.054 | 0.17 | 0.070 | 2.5 | >23735 | >439537 |
| 91 | 1-F | 3-F | 3’-CF3 | 0.084 | 0.21 | 0.13 | 15 | >24672 | >293714 |
| 92 | 1-F | 3-F | 2’-CF3 | 0.0030 | 0.0040 | 0.0063 | 4.3 | >24672 | >8224000 |
| 93 | 1-Cl | 2-Cl | 4’-Cl | 0.033 | 0.038 | 0.28 | 21 | >24711 | >748818 |
| 99 | 2-Cl | 3-OMe | 4’-OCF3 | 0.19 | 0.14 | 0.17 | 0.27 | >22232 | >117010 |
| 100 | 2-Cl | 3-OMe | 4’-CF3 | 0.08 | 0.14 | 0.45 | 0.43 | >23052 | >288150 |
| 101 | 2-F | 3-OMe | 4’-OCF3 | 1.5 | 1.9 | 2.9 | 2.8 | >100000 | >66667 |
| 102 | 2-F | 3-OMe | 4’-CF3 | 3.2 | 3.2 | 7.1 | 10.5 | >100000 | >31250 |
| 107 | 1-F | 3-F | 4’-OCF3 | 0.17 | 0.42 | 0.25 | 65 | >23735 | >139618 |
| 108 | 1-F | 3-F | 4’-CF3 | 0.41 | 0.60 | 0.48 | 189 | >24672 | >60175 |
| 109 | 1-F | 3-F | 4’-Cl | 0.069 | 0.19 | 2.4 | 235 | >26898 | >389826 |
| CQ | - | - | - | 15 | 163 | 171 | 208 | 37577 | 2505 |
| ATV | - | - | - | 0.10 | 0.10 | 0.20 | 8256 | 23160 | 231600 |
a
IC50 values are the average of at least three determinations, each carried out in triplicate (±10%). CQ: chloroquine; ATV: atovaquone; D6: P. falciparum CQ sensitive strain; Dd2: MDR P. falciparum strain with Old World genetic background; 7G8: MDR P. falciparum strain with New World genetic background; Tm90-C2B: MDR P. falciparum clinical isolate, ATV resistant.