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. Author manuscript; available in PMC: 2020 Jul 12.
Published in final edited form as: J Med Chem. 2020 May 26;63(11):6179–6202. doi: 10.1021/acs.jmedchem.0c00539

Table 1.

In Vitro Blood-Stage Antiplasmodial Activity and Selectivity of Acridones (18−42)

graphic file with name nihms-1593349-t0002.jpg
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
T31 - - - 0.022 0.041 0.43 228 >54510 >2477727
18 1-Cl 2-Cl 4’-OCF3 3.2 6.8 14 1053 10992 3435
19 2-Cl 3-Cl 4’-OCF3 21 7.7 14 16 >34418 >1639
20 1-Cl 3-Cl 4’-OCF3 0.52 0.88 1.2 23 >34418 >66188
21 H 3-Cl 4’-OCF3 2.6 2.4 14 142 >37340 >14361
22 1-F 3-F 4’-OCF3 0.0047 0.0030 0.0073 3.2 >245700 >52276595
23 1-F 3-F 4’-Cl 0.010 0.28 0.68 73 >27953 >2795300
24 1-F H 4’-OCF3 0.24 0.06 0.43 12 196 816
25 H 3-F 4’-OCF3 3.2 4.8 2.2 20 9432 2947
26 1-F 3-Cl 4’-OCF3 0.028 0.045 0.042 5.6 >35754 >1276928
27 1-Cl 3-F 4’-OCF3 0.050 0.18 0.28 31 798 15960
28 1-Cl 3-OMe 4’-OCF3 5.0 2.9 10 18 >34763 >6953
29 1-F 3-OMe 4’-OCF3 0.65 0.31 1.6 21 755 1161
30 1-F 3-OMe 4’-Cl 0.51 0.39 2.8 47 548 1074
31 1-OMe 3-Cl 4’-OCF3 28 22 79 28 >34768 >1242
32 1-OMe 3-F 4’-OCF3 54 32 63 80 25903 480
33 1-OMe 3-F 4’-Cl 18 15 82 150 22462 1248
34 1-Cl 2-OMe 4’-OCF3 17 24 51 151 >34767 >2045
35 2-OMe 3-Cl 4’-OCF3 157 221 410 137 >34767 >221
36 1-OMe H 4’-OCF3 40 57 72 52 >100000 >2500
37 H 3-OMe 4’-OCF3 0.33 0.25 1.3 1.0 >37751 >114397
38 2-Cl 3-OMe 4’-OCF3 0.37 0.83 1.61 0.58 >34767 >93965
39 2-F 3-OMe 4’-OCF3 1.3 1.2 2.1 1.7 27908 21468
40 2-Cl 3-OMe 3’-OCF3 2.5 1.8 2.8 2.4 >34767 >13907
41 2-F 3-OMe 2’-OCF3 0.042 0.066 0.076 0.031 14838 353286
42 2-Cl 3-OMe graphic file with name nihms-1593349-t0003.jpg 0.69 0.76 1.5 0.85 >33600 >48696
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.