TABLE 1.
Comparison of the efficacies of antimalarial hybrids, their component drugs, and 1:1 mixturesa
| Component 1 | Component 2 | Activity in culture (IC50) | Activity in animal model | Activity with respect to components 1 and 2 in culture (component no.) | Activity with respect to mixture (1:1) in culture | Reference |
|---|---|---|---|---|---|---|
| Aminoquinoline | Trioxane | ∼40 to 48 nmol/liter | ND | ND | ND | 41 |
| Aminoquinoline | Trioxane or trioxolane | 22 to 536 nM | ED50, CD50, 0.7 to >25 mg/kg/day | ND | ND | 42 |
| Aminoquinoline | Aminopeptidase inhibitor | 150 nM to 1.4 μM | ND | ND | ND | 43 |
| Aminoquioline | Hexanoic acid derivative (GR inhibitor) | 107 to 259 nM | ND | ND | ND | 44 |
| Primaquine | Statine | 0.4 to 6.2 μM | ND | ND | ND | 45 |
| Aminoquinoline | Isatin derivative | 33 nM to 1.5 μM | ND | ND | ND | 46 |
| Trifluoromethyl-artemisinin | Mefloquine | 2.4 to 17.2 nM | Effective at 35 μmol/kg/day | Higher (2) | ND | 47 |
| Primaquine | Statine (PS777621, plasmepsin inhibitor) | 0.1 to 4.5 μM | ND | Higher (2) | ND | 48 |
| Chloroquine | Imipramine | 2.9 to 5.3 nM | Effective at 64 mg/kg/day | Higher (1) | ND | 36 |
| Ferroquine | Thiosemi-carbazone | 0.1 to 96 μM | ND | Lower (1) | ND | 49 |
| Artemisinin | Quinine | 9.0 to 10 nM | ND | Higher (1 & 2) | Higher (3-fold) | 28 |
| Aminoquinoline | Trioxolane | 4.0 to 32.0 nM | ED50, CD50, 0.7 to >25 mg/kg/day | Higher | Higher | 29 |
| Aminoquinoline | Tetraoxane | 2.0 to 33 nM | Most effective at 320 mg/kg/day, partly effective at 80 mg/kg/day | Higher (1) | ND | 50 |
| Aminoquinoline | Triazine | 4.4 to 256 ng/ml | Partly effective at 50 mg/kg/day | Lower (1) | ND | 51 |
| Atovaquone and derivatives | Statine | 0.61 to 5.3 nM | ND | ND | ND | 52 |
| Aminoquinoline/aminoacridine | Clotrimazole derivatives | 3.0 nM to 1.4 μM | Some compounds effective at 50 mg/kg/day; ED50 of one compound, 6.3 mg/kg/day | Variable with strains (1), higher (2) | ND | 53 |
| Chloroquine | Astemizole | 0.02 to 0.61 μM | Effective at 80 to 200 mg/kg | Higher (1), higher (2) | ND | 54 |
| Artemisinin | Dipeptidyl vinyl sulfone | 2.08 to 4.81 nM | ND | Higher (1), higher (2) | ND | 55 |
| Chalcone | Thiolactone/Isatin | 0.68 to 14.9 μM | ND | Higher (2) | ND | 56 |
| Artemisinin (1,2,4-trioxane pharmacophore) | Ferroquine (ferrocenel-quinoline) | 16 to 43 nM | 10 mg/kg/day | Comparable to artemisinin, ferroquine, & trioxaquine; higher than chloroquine | ND | 57 |
| Artemisinin | Primaquine | 9.1 to 12.5 nM | 9 mg/kg/day | Lower (1), higher (2) | ND | 30 |
| Chloroquine | Thiazolidinone | 0.02 to >22 μM | Two compounds effective at 10 mg/kg/day | Variable with strains (1) | ND | 58 |
| Artemisinin/naphthoquinone | Aminoquinoline | 0.02 to 0.64 μM | ND | Comparable (1), comparable (2) | ND | 59 |
| Stilbene | Chalcone | 1.4 to 6.4 μM | ND | Higher (1), higher (1) | Higher | 31 |
| Chloroquine | Chalcone | 29 to 314 nM | ND | Variable with strains (1) | ND | 60 |
| Coumarin | Trioxane | 39 to >500 ng/ml | One compound partly effective at 96 mg/kg/day | ND | ND | 61 |
| Chloroquine | Chalcone | 3.6 to 380 ng/ml | Two compounds effective at 100 mg/kg/day | Lower (1) | ND | 62 |
| Amodiaquine | Phenyl furoxan | 0.630 μM | ND | Higher | ND | 63 |
| Chloroquine | Primaquine | 0.08 to 0.64 μM | Effective at 60 mg/kg/day | Variable with strains (1 & 2) | Higher (strain K1), lower (strains 3D7 & Dd2) | 64 |
| Artemisinin | Quinoline | 5.0 to 21.5 nM | ED50, <0.8 to 1.4 mg/kg/day | Lower (1), higher (2) | ND | 65 |
| Aminoquinoline | Triazine | 0.17 to 1.7 nM | ND | Variable with strains (1) | ND | 66 |
| Tetraoxane | Dipeptidyl vinyl sulfone | 10.7 to 175 nM | ND | Variable with strains (1) | ND | 67 |
| Chloroquine | Hydroxy-pyridone | 0.004 to 71.6 μM | ND | Higher (1) | ND | 68 |
| Quinoline | Triazole | 1.4 to 109 μM | ND | Lower (1) | ND | 69 |
| Artemisinin | Triazine | 5.5 to 85 nM | ND | Comparable (1), higher (2) | Lower (strain NF54), comparable (strain Dd2) | 70 |
| Artemisinin | Acridine | 2.6 to 430 nM | ND | Lower (1) | ND | 35 |
| Quinoline | Diarylether | 20.3 to >1,200 nM | ND | Lower (1) | ND | 71 |
| Tetraoxane | Pyrimidine | 9.8 to 81.2 nM | ND | ND | ND | 72 |
| Trioxane | Egonol and/or ferrocene | 0.3 to 88 nM | ND | Higher (1), lower (2) | ND | 73 |
| Quinoline | Pyrimidine | 22 to 4,310 nM | ND | Lower (1), lower (2) | ND | 74 |
| Artesunate | Indoloquinoline | 0.4 to 3.2 nM | One compound effective at 40 mg/kg/day | Higher (1), higher (1) | ND | 75 |
| Chloroquine | Hydroxi-pyridone | 0.04 to 0.46 μM | Partly effective at 8 mg/kg/day | Variable with strains (1) | ND | 76 |
| Aminoquinoline | Pyrazolopyrimidine | 0.005 to 1.6 μM | Variable with strains (1) | ND | 77 | |
| Primaquine | Pyrimidine | 1.93 to 6.46 μM | ND | Lower (1) | ND | 78 |
| Quinoline | Sulfonamide | 0.05 to 1.63 μM | Partly effective at 10 mg/kg/day | Higher (1), higher (1) | ND | 79 |
| Trioxane | Ferrocene | 7.2 to 30.2 nM | ND | Lower (1), higher (2) | ND | 80 |
| Aminoquinoline | s-Triazine | 0.22 to 8.3 μM | ND | Higher (1) | ND | 81 |
| Aminoquinoline | Atorvastatin | 0.4 to 6.39 μM | ND | Higher (1), higher (2) | ND | 82 |
a
CD50, 50% cytotoxic dose; ED50, 50% effective dose; GR, glucocorticoid receptor; kg, kilograms of body weight; ND, not determined.