TABLE 3.
Compounds with demonstrated activity against Toxoplasma gondii that were identified via various screen typesa
| Screen type and compound no. | Reference(s) | IUPAC name | Targeted protein | Predicted or demonstrated MoA | In vitro IC50 (μM) | Host cell TD50 (μM) | In vivo (mouse) therapeutic dose (mg/kg/day) | In vivo toxicity (mg/kg/day) |
|---|---|---|---|---|---|---|---|---|
| Phenotypic screens | ||||||||
| 67 | 104 | Benzyl ((S)-1-oxo-1-(((S)-3-oxopent-4-en-2-yl)amino)-3-phenylpropan-2-yl)carbamate | TgDJ-1 | Prevents attachment and invasion | ∼2–6 | ND | ND | ND |
| 68 | 101 | 2-Methyl-3-(4-(4-(trifluoromethoxy)phenoxy)phenyl)quinolin-4(1H)-one | Cytochrome bc1 complex | Inhibits mitochondrial respiratory chain | 0.0001 | 9.3 | >1 | >50 |
| 69 | 101 | 6-Fluoro-7-methoxy-2-methyl-3-(4-(4-(trifluoromethoxy)-phenoxy)phenyl)- quinolin-4(1H)-one | Cytochrome bc1 complex | Inhibits mitochondrial respiratory chain | 0.000007 | >50 | >0.33 | >50 |
| 70 | 195 | Ethyl 6-fluoro-7-methoxy-3-(4-(4-(trifluoromethoxy)phenoxy)phenyl)quinoline-2-carboxylate | Cytochrome bc1 complex | Inhibits mitochondrial respiratory chain | 5 | >320 | ND | ND |
| 71 | 98 | 2-(4-Fluorophenyl)-3-(20-hydroxybiphen-3-yl)-6-(thien-3-yl)imidazo[1,2-b]pyridazine | ND | ND | ∼0.61 | >50 | ND | ND |
| 72 | 98 | 3-(20-Hydroxybiphen-3-yl)-2-tert-butyl-6-(thien-3-yl)imidazo[1,2-a]pyridine | ND | ND | ∼0.08 | >50 | ND | ND |
| 73 | 98 | 2-(2-Methoxyphenyl)-3-(2'-hydroxybiphen-3-yl)-6-(thien-3-yl)imidazo[1,2-b]pyridazine | ND | ND | ∼0.36 | ∼32.0 | ND | ND |
| 74 | 98 | 3-(20-Hydroxybiphen-3-yl)-2-(2-methoxyphenyl)-6-(thien-3-yl)imidazo[1,2-a]pyridine | ND | ND | ∼0.27 | >50 | ND | ND |
| 75 | 98 | 3-((Biphen-3-yl)-2-(2-methoxyphenyl)imidazo[1,2-a]pyridin-6-yl)methanol | ND | ND | ∼0.63 | ∼42.2 | ND | ND |
| 76 | 196 | N-[(E)-(1-propan-2-ylbenzimidazol-2-yl)methylideneamino]-1H-benzimidazol-2-amine | ND | Inhibits motility and invasion | ∼1.36 | >10 | ND | ND |
| 77 | 196 | (5E)-5-(2,4-dinitrophenoxy)iminoquinolin-8-one | ND | ND | ∼1.34 | >10 | 4.4 | ND |
| 78 | 196 | 3-Benzyl-6-[1-(2-ethoxyphenyl)-5-methyltriazol-4-yl]-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazole | ND | ND | ∼0.57 | >10 | ND | ND |
| 79 | 196 | 4-N-Benzyl-2-N-(2-methylphenyl)quinazoline-2,4-diamine hydrochloride | ND | Inhibits motility | ∼1.12 | >10 | ND | ND |
| 80 | 99 | N-4-Ethyl-benzoyl-2-hydroxybenzamide | Adaptin-3β | Inhibits secretion of micronemes, rhoptries, and dense granules | I0.031b | >10 | 50 | ND |
| 81 | 100 | N-[4-(Diethylamino)benzoyl]-2-hydroxybenzamide | Adaptin-3β | Inhibits secretion of micronemes, rhoptries, and dense granules | 0.016b | >10 | 20 | ND |
| Targeted screens | ||||||||
| 82 | 119 | 1-(tert-Butyl)-3-(3-methylbenzyl)-4-amino-1H-pyrazolo[3,4-d]pyrimidine | TgCDPK1 | Inhibits invasion, gliding motility, microneme secretion, and egress | 0.11 | ND | 5 | ND |
| 83 | 119 | 1-(tert-Butyl)-3-(3-chlorobenzyl)-4-amino-1H-pyrazolo[3,4-d]pyrimidine | TgCDPK1 | Inhibits invasion, gliding motility, microneme secretion, and egress | 0.03 | ND | 5 | ND |
| 84 | 119 | 3-(2,3-Dichlorobenzyl)-1-isopropyl-4-amino-1H-pyrazolo[3,4-d]pyrimidine | TgCDPK1 | Inhibits invasion, gliding motility, microneme secretion, and egress | 0.25 | ND | 5 | ND |
| 85 | 119 | 1-(tert-Butyl)-3-(3,5-difluorobenzyl)-4-amino-1H-pyrazolo[3,4-d]pyrimidine | TgCDPK1 | Inhibits invasion, gliding motility, microneme secretion, and egress | 0.61 | ND | 5 | ND |
| 86 | 120, 197 | 1-((1-Methylpiperidin-4-yl)methyl)-3-(6-ethoxynaphthalen-2-yl)- 4-amino-1H-pyrazolo[3,4-d]pyrimidine | TgCDPK1 | Inhibits invasion, gliding motility, microneme secretion, and egress | 0.14 | ND | 40 | >100 |
| 87 | 113 | 2,4-Diamino-5-methyl-6-(2¢,6¢-dimethylphenylthio)pyrrolo[2,3-d]pyrimidine | TgDHFR | Growth inhibition | 1.92 | >260 | 50 | ND |
| 88 | 113 | 2,4-Diamino-5-methyl-6-(2¢,6¢-dimethylphenylthio)pyrrolo[2,3-d]pyrimidine hydrochloride salt | TgDHFR | Growth inhibition | 2.15 | >260 | 50 | ND |
| 89 | 115 | 2-Phenylthio-indole | TgNTPase-I, TgNTPase-II | Growth inhibition | ∼7 | >50 | ND | ND |
| 90 | 115 | 2-(2-Naphthalenylthio)-1H-indole | TgNTPase-I, TgNTPase-II | Growth inhibition | ∼3.6 | >50 | ND | ND |
| 91 | 115 | 2-(1-Naphthalenylthio)-1H-indole | TgNTPase-I, TgNTPase-II | Growth inhibition | ∼3.2 | >50 | ND | ND |
| Cheminformatic screens | ||||||||
| 92 | 87 | 5-Nitroso-8-hydroxyquinoline | ND | Oxidative stress | 0.08 | ND | ND | ND |
| 93 | 124 | 3-[(E)-2-(1,3-Benzodioxol-5-yl)ethenyl]-1H-quinoxalin-2-one | ROP18 | Destruction of parasitophorous vacuole | 0.002 | ND | ND | ND |
| Drug repurposing screens | ||||||||
| 94 | 126 | N-(2-Ethoxyphenyl)-2-[4-(furan-2-carbonyl)piperazin-1-yl]acetamide | ND | ND | 0.19 | >30 | ND | ND |
| 95 | 126 | N-[4-(Dibutylsulfamoyl)phenyl]furan-2-carboxamide | ND | ND | 1.07 | >30 | ND | ND |
| 96 | 126 | 7-Chloro-4-pyrrolidin-1-ylquinoline | ND | ND | 1.49 | >30 | ND | ND |
| 97 | 126 | N',N'-Dimethyl-N-(2-phenylquinolin-4-yl)ethane-1,2-diamine | ND | ND | 1.95 | >30 | ND | ND |
| 98 | 126 | 6-Bromo-2-methyl-3-propyl-1H-quinolin-4-one | ND | ND | 3.05 | >30 | ND | ND |
| 99 | 126 | N-[4-[(4-Ethylpiperazin-1-yl)methyl]phenyl]-1H-pyrrolo[3,2-h]quinoline-2-carboxamide | ND | ND | 3.85 | >30 | ND | ND |
| 100 | 126 | 2-(2-Methoxyanilino)-3-piperidin-1-ylnaphthalene-1,4-dione | ND | ND | 4.54 | >30 | ND | ND |
| 101 | 127 | 2-[(E)-2-(4-Ethoxyphenyl)ethenyl]-1,3-benzoxazin-4-one | ND | ND | 0.27 | >39.8 | ND | ND |
| 102 | 127 | 2-Amino-4-(3,5-ditert-butyl-4-hydroxyphenyl)-5-oxo-4,6,7,8-tetrahydrochromene-3-carbonitrile | ND | ND | 1.33 | >36.2 | ND | ND |
| 103 | 127 | Methyl N-[(E)-[phenyl(pyridin-2-yl)methylidene]amino]carbamodithioate | ND | ND | 1.63 | >42.9 | ND | ND |
| 104 | 198 | 3-(4-Chlorophenyl)1-(1,1-dimethylethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine | ND | ND | 0.2 | >5 | ND | ND |
a
The lowest observed IC50s are reported in cases in which multiple values were found in the literature. Structure data for each compound in the table can be found in Table S3 in the supplemental material. In vivo therapeutic dose data refer to the best concentration tested in the literature for toxicity and efficacy in a model organism. ND, not determined.
b
The IC90 value (rather than IC50) is reported for this compound.