Table 3.
In Vitro Blood-Stage Antiplasmodial Activity and Selectivity of Acridones (68−80)
 | |||||||||
|---|---|---|---|---|---|---|---|---|---|
| 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 | ||||||
| 68 | 1-F | 3-F | 4’-OCF3 | 0.12 | 3.3 | 4.1 | 20 | >37199 | >309992 |
| 69 | 1-F | 3-OMe | 4’-OCF3 | 0.69 | 1.3 | 1.3 | 9.8 | >36131 | >52364 |
| 70 | 1-OMe | 3-F | 4’-OCF3 | 17 | 17 | 35 | 157 | >36131 | >2125 |
| 71 | 2-F | 3-OMe | 4’-OCF3 | 99 | 164 | 130 | 187 | >100000 | >1010 |
| 72 | 1-F | 3-F | 4’-OCF3 | 58 | 16 | 41 | 92 | >37289 | >643 |
| 73 | 1-F | 3-F | 3’-OCF3 | 29 | 17 | 32 | 41 | >37289 | >1286 |
| 74 | 1-F | 3-F | 2’-OCF3 | 0.048 | 0.047 | 0.73 | 23 | 18673 | 389021 |
| 75 | 1-Cl | 3-Cl | 4’-OCF3 | 385 | 1402 | 1733 | 748 | >34495 | >89 |
| 76 | 1-Cl | 3-Cl | 3’-OCF3 | 1474 | 1690 | 750 | 3017 | >34495 | >23 |
| 77 | 2-F | 3-OMe | 4’-OCF3 | 45 | 91 | 156 | 139 | >36216 | >805 |
| 78 | 2-F | 3-OMe | 3’-OCF3 | 100 | 145 | 286 | 130 | >36216 | >362 |
| 79 | 2-Cl | 3-OMe | 4’-OCF3 | 82 | 83 | 166 | 78 | >34846 | >425 |
| 80 | 2-Cl | 3-OMe | 3’-OCF3 | 78 | 56 | 141 | 55 | >34846 | >447 |
| 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.