Table 9 CYP inhibition in human liver microsomes
From: An in vitro toolbox to accelerate anti-malarial drug discovery and development
Compound | IC50 (µM) (% inhibition at max conc)/Ki (µM) | |||||
|---|---|---|---|---|---|---|
CYP1A2 | CYP2C9 | CYP2C19 | CYP2D6 | CYP3A4 (test) | CYP3A4 (midaz) | |
Ionized or partially ionized bases at physiological pH | ||||||
 Cycloguanil | > 20 (nmi) | > 20 (nmi) | > 20 (nmi) | 6.0/3.7 | > 20 (nmi) | > 20 (nmi) |
 Doxycyclin | CNDa | > 20 (nmi) | > 20 (nmi) | > 20 (nmi) | > 20 (22%) | > 20 (nmi) |
 Pyronaridine | > 20 (30%) | > 20 (nmi) | > 20 (nmi) | 1.2/0.75 | > 20 (nmi) | > 20 (28%) |
 Proguanil | > 20 (nmi) | > 20 (nmi) | > 20 (27%) | 3.5/2.2 | > 20 (24%) | > 20 (nmi) |
 Primaquine | < 0.25/< 0.15 | > 20 (20%) | > 20 (34%) | > 20 (33%) | > 20 (nmi) | > 20 (31%) |
 Chloroquine | > 20 (nmi) | > 20 (nmi) | > 20 (nmi) | 6.1/3.8 | > 20 (nmi) | > 20 (24%) |
 Chlorproguanil | > 20 (nmi) | > 20 (nmi) | > 20 (39%) | 1.4/0.87 | > 20 (41%) | > 20 (nmi) |
 Azithromycin | > 20 (nmi) | > 20 (nmi) | > 20 (29%) | > 20 (nmi) | > 20 (nmi) | > 20 (nmi) |
 AQ-13 | > 20 (nmi) | > 20 (nmi) | > 20 (nmi) | 13/8.3 | > 20 (nmi) | > 20 (nmi) |
 Desethylamodiaquine | > 18 (nmi) | > 18 (nmi) | > 18 (nmi) | 2.6/1.6 | CNDa | > 18 (nmi) |
 Quinine | > 20 (nmi) | > 20 (nmi) | > 20 (nmi) | 6.0/3.7 | > 20 (nmi) | > 20 (nmi) |
 Clindamycin | > 20 (nmi) | > 20 (nmi) | > 20 (32%) | > 20 (nmi) | > 20 (nmi) | > 20 (nmi) |
 KAF156 | > 20 (nmi) | 19/14 | > 20 (40%) | 1.2/0.75 | 2.7/1.6 | 2.5/1.8 |
 M5717 | > 20 (nmi) | > 20 (nmi) | > 20 (nmi) | > 20 (nmi) | > 20 (nmi) | > 20 (nmi) |
 OZ277 | > 20 (nmi) | > 20 (nmi) | > 20 (nmi) | > 20 (nmi) | > 20 (46%) | > 20 (26%) |
 Mefloquine | > 20 (nmi) | > 20 (nmi) | > 20 (nmi) | 16/10 | > 20 (29%) | > 20 (nmi) |
 Amodiaquine | > 20 (27%) | > 20 (nmi) | > 20 (nmi) | 0.88/0.55 | > 20 (nmi) | > 20 (nmi) |
 NPC1161B | 6.5/3.8 | > 20 (37%) | 9.6/5.7 | > 20 (39%) | 13.6/8.2 | > 20 (37%) |
 Ferroquine | > 20 (nmi) | > 20 (nmi) | > 20 (nmi) | 0.83/0.52 | > 20 (42%) | 7.3/5.2 |
 Naphthoquine | > 20 (33%) | > 20 (nmi) | > 20 (nmi) | 1.1/0.68 | > 20 (38%) | > 20 (41%) |
 Tafenoquine | > 20 (20%) | 14/10 | > 20 (42%) | > 20 (35%) | 3.8/2.3 | > 20 (40%) |
 MMV253 | > 20 (nmi) | > 20 (nmi) | CNDa | > 20 (35%) | > 20 (37%) | CNDa |
 MMV052 | > 20 (nmi) | > 20 (nmi) | > 20 (nmi) | > 20 (nmi) | > 20 (nmi) | > 20 (nmi) |
 Piperaquine | > 20 (nmi) | CNDa | > 20 (nmi) | > 20 (nmi) | > 20 (nmi) | 4.5/3.2 |
 Halofantrine | > 20 (nmi) | > 20 (nmi) | > 20 (nmi) | 0.27/0.19 | > 20 (19%) | > 20 (24%) |
 TDD-E209b | > 20 (nmi) | > 20 (nmi) | > 20 (nmi) | > 20 (nmi) | > 20 (43%) | > 20 (33%) |
 Lumefantrine | > 20 (nmi) | > 20 (nmi) | > 20 (nmi) | 2.9/1.8 | > 20 (nmi) | > 20 (nmi) |
Ionized acids at physiological pH | ||||||
 Sulfadoxine | > 20 (nmi) | > 20 (nmi) | > 20 (nmi) | > 20 (nmi) | > 20 (nmi) | > 20 (nmi) |
  Sulfamethoxazole | CNDa | > 20 (nmi) | > 20 (nmi) | > 20 (nmi) | > 20 (nmi) | > 20 (nmi) |
 Artesunate | 20/12 | > 20 (nmi) | > 20 (nmi) | > 20 (nmi) | 20 (nmi) | > 20 (nmi) |
 Atovaquone | > 20 (nmi) | > 20 (26%) | > 20 (nmi) | > 20 (nmi) | > 20 (nmi) | > 20 (nmi) |
Zwitterionic or partially zwitterionic at physiological pH | ||||||
 P218 | > 20 (nmi) | > 20 (nmi) | > 20 (nmi) | > 20 (nmi) | > 20 (nmi) | > 20 (nmi) |
 JPC3210 | > 20 (nmi) | > 20 (nmi) | > 20 (nmi) | 0.70/0.43 | > 20 (nmi) | > 20 (nmi) |
Neutral at physiological pH | ||||||
 Dapsone | > 20 (nmi) | > 20 (nmi) | > 20 (nmi) | > 20 (nmi) | > 20 (nmi) | > 20 (nmi) |
 Dihydroartemisinin | 11/6.2 | > 20 (nmi) | > 20 (nmi) | > 20 (nmi) | > 20 (nmi) | > 20 (nmi) |
 DSM421b | > 20 (nmi) | > 20 (16%) | > 20 (nmi) | > 20 (33%) | > 20 (nmi) | CNDa |
 Pyrimethamine | > 20 (nmi) | > 20 (nmi) | > 20 (nmi) | > 20 (36%) | > 20 (nmi) | > 20 (nmi) |
 MMV048 | > 20 (nmi) | > 20 (nmi) | > 20 (nmi) | > 20 (16%) | > 20 (nmi) | CNDa |
 Artemisone | NA | NA | NA | NA | NA | NA |
 Artemether | > 20 (nmi) | > 20 (nmi) | > 20 (nmi) | > 20 (nmi) | > 20 (37%) | > 20 (39%) |
 SJ733 | > 20 (nmi) | > 20 (33%) | > 20 (38%) | 16/9.6 | > 20 (37%) | > 20 (33%) |
 DSM265b | > 20 (nmi) | > 20 (25%) | > 20 (19%) | 7.1/4.4 | > 20 (34%) | CND |
 KAE609 | 4.5/2.7 | 5.5/4.0 | < 0.25/< 0.15 | 5.9/3.7 | > 20 (30%) | > 20 (nmi) |
 OZ439 | > 20 (nmi) | > 20 (nmi) | > 20 (nmi) | > 20 (nmi) | 5.1/3.1 | 12/8.6 |
 ELQ300 | > 20 (nmi) | 7.5/5.4 | > 20 (41%) | 8.0/5.0 | > 20 (nmi) | CNDa |