TABLE 1.
Compounds with known or suspected modes of action against Toxoplasma gondiia
| MoA and compound class and no. | Reference(s) | In vitro IC50 | Host cell TD50 | In vivo survivability | In vivo chronic infection | Parasite burden | In vivo toxicity |
|---|---|---|---|---|---|---|---|
| Interference with invasion or egress | |||||||
| Pyrazolopyrimidines | 24, 129, 130 | ||||||
| Compound 1 | 0.003 μM (24) | ||||||
| Compound 2 | Not established (129) | 100,000 RH strain tachyzoites injected i.p.; treatment did not increase survival (129) | 1,000 RH strain tachyzoites injected i.p.; treatment decreased parasite load in liver and lungs by ∼10- to 100-fold and in brain by <5-fold at 4 dpi (129) | ||||
| Compound 3 | 0.060 μM (130) | >10 μM HepG2 and CRL-8155 cells (130) | Unreported no. of ME49 cysts injected i.p.; treatment decreased cyst count by 88.7% (130) | “High inoculum” of RH strain tachyzoites injected i.p.; 99% reduction in spleen tachyzoites; 95% reduction in brain tachyzoites (130) | >500 mg/kg/day in mice (PK information available for rats, dogs, calves, monkeys) (130) | ||
| Pyridinylpyrroles | 19, 21, 22 | ||||||
| Compound 4 | 0.32–200 μM (19, 21, 22) | >10 μM HFF cells (19, 21, 22) | 1,000–3,000 RH strain tachyzoites injected i.p.; treatment increased survival by 90% (19) | ND | 1,000–3,000 RH strain tachyzoites injected i.p.; no parasites detected in brain, lung, spleen, or peritoneal fluid during treatment; at 5–10 days posttreatment, parasites detected in brain, lung, spleen (19) | >50 mg/kg/day (19, 22) | |
| Benzophenones | 20, 131, 132 | ||||||
| Compound 5 | 0.14 μM (131) | 0.21 μM HFF cells, 5.89 μM HeLa cells (131) | ND | ND | ND | ND | |
| Benzoylbenzimidazoles | 25 | ||||||
| Compound 6 | >1 μM for all tested compounds | >30 μM for all tested compounds | ND | ND | ND | ND | |
| Diaryl ureas | 28 | ||||||
| Compound 7 | <0.5 μM | >10 μM HFF cells | ND | ND | ND | ND | |
| Dinitroanilines | 27, 133 | ||||||
| Compound 8 | 0.036 μM (27) | >0.5 μM HFF cells (27) | ND | ND | ND | ND | |
| 5-Aminopyrazole-4-carboxamides | 134 | ||||||
| Compound 9 | 0.089 μM | >40 μM CLR-8155 cells | ND | ND | 105 RH strain tachyzoites injected i.p.; no parasites detected in peritoneal fluid, >5-fold reduction in brain tissue | >10 mg/kg/day | |
| Inhibition of DNA synthesis | |||||||
| 6-Benzylthioinosines | 42, 135–140 | ||||||
| Compound 10 | 9.3 μM (136) | >50 μM HFF cells (136) | 200 RH or TgAK-3 strain tachyzoites injected i.p. increased survival by 2 days | ND | ND | ND | |
| Compound 11 | 4.3 μM (136) | >50 μM HFF cells (136) | Increased survival by 2–3 days (136) | ND | ND | >300 mg/kg (136) | |
| Compound 12 | 7.3 μM (136) | >50 μM HFF cells (136) | Increased survival by 2–3 days (136) | ND | ND | >300 mg/kg (136) | |
| Triazines and 2,4-diaminopyrido[2,3-d]pyrimidines | 37, 114, 141–148 | ||||||
| Compound 13 | 0.058 μM (143) | ND | ND | ND | ND | ND | |
| Compound 14 | 0.02 μM (37) | ND | ND | ND | 10,000 RH strain tachyzoites injected i.p.; 99% reduction in parasites in peritoneal fluid (37) | ND | |
| Compound 15 | ~0.05 μM (114) | >100 μM HFF cells (114) | ND | ND | 10,000 RH strain tachyzoites injected i.p.; significant reduction of tachyzoites in peritoneal fluid (114) | ND | |
| Sulfonamides (exptl) | 39, 149 | ||||||
| Compound 16 | 0.05 μM (39) | ND | ND | ND | ND | ND | |
| Compound 17 | ND (149) | ND | 5,000 RH strain tachyzoites injected i.p.; treatment group had 10–50% survival (149) | ND | 5,000 RH strain tachyzoites injected i.p. (mice that survived acute trial used for parasite burden assay); no parasites detected in heart or kidneys (149) | ND | |
| 2,4-Diaminopteridines | 150 | ||||||
| Compound 18 | 0.077 μM | ND | ND | ND | ND | ND | |
| Phthalazinone derivatives | 41 | ||||||
| Compound 19 | 1 μM | ND | ND | ND | ND | ND | |
| Urea derivatives | 151 | ||||||
| Compound 20 | 0.402 μM | ND | ND | ND | ND | ND | |
| 1-[4-(4-Nitrophenoxy)phenyl]propane-1-one | 152 | ||||||
| Compound 21 | 36.2 μM | 67.0 μM HeLa cells | ND | ND | 100,000 RH strain tachyzoites injected i.p.; 40% reduction in tachyzoite burden in peritoneal cavity at 4 dpi | ND | |
| Inhibition of steroid synthesis | |||||||
| Bisphosphonates | 53, 153–158 | ||||||
| Compound 22 | 0.28 μM (154) | >826 μM KB cells (154) | 5 C56 strain bradyzoites administered orally; 80% survival (154) | ND | ND | ND | |
| Compound 23 | 0.55 μM (154) | >892 μM KB cells (154) | 5 C56 strain bradyzoites administered orally; 80% survival (154) | ND | ND | ND | |
| ACAT inhibitors | 51 | ||||||
| Compound 24 | ∼3 μM | >100 μM HFF cells | ND | ND | ND | ND | |
| Aryloxyphenoxy derivatives | 48, 159 | ||||||
| Compound 25 | 2.03 μM (55) | >50 μM Vero cells (48) | ND | ND | ND | ND | |
| Azasterols | 54, 55, 160 | ||||||
| Compound 26 | 0.12 μM (55) | ND | ND | ND | ND | ND | |
| Quinuclidines | 52 | ||||||
| Compound 27 | 0.19 μM | >15 μM LLC-MK2 cells | ND | ND | ND | ND | |
| Fatty acid synthesis inhibition | |||||||
| Acylsulfonamides | 63 | ||||||
| Compound 28 | 0.02 ± 0.07 μM | >1,000 μM HFF cells | ND | ND | ND | ND | |
| Benzimidazoles | 62 | ||||||
| Compound 29 | 2.5 μM | <10 μM HFF or PC3-Luc cells | ND | ND | ND | ND | |
| Thiolactomycin analogues | 60 | ||||||
| Compound 30 | 1.6 μM | >15 μM LLC-MK2 cells | ND | ND | ND | ND | |
| Inhibition of virulence factors or host interactions | |||||||
| Pyridinylimidazoles | 69, 70, 161 | ||||||
| Compound 31 | 0.8–5 μM (70) | ND | 1,000 RH strain tachyzoites injected i.p.; 40% survival in treatment group (70) | ND | ND | ∼>60 mg/kg/day (70) | |
| Compound 32 | ∼3 μM (69) | ND | ND | 1,000 RH-GFP strain tachyzoites injected i.p.; significant reduction in peritoneal exudate (69) | >10 mg/kg/day (69) | ||
| Inhibition of transcription | |||||||
| Cyclic tetrapeptides | 74, 75, 162 | ||||||
| Compound 33 | 0.01 μM (MIC) (75) | ND | ND | ND | ND | ND | |
| Compound 34 | 0.0076 μM (74) | 0.107 μM HFF cells (74) | ND | ND | ND | ND | |
| Hydroxamic acids | 77 | ||||||
| Compound 35 | 0.039 μM | >10 μM HS68 cells | ND | ND | ND | ND | |
| Garcinol | 78 | ||||||
| Compound 36 | 1.79 μM | >10 μM HFF cells | ND | ND | ND | ND | |
| Inhibition of reproduction or differentiation | |||||||
| Gossypol and derivatives | 84 | ||||||
| Compound 37 | 5–10 μM | ∼40 μM HFF cells | ND | ND | ND | ND | |
| Lactacystin | 81 | ||||||
| Compound 38 | 2 μM (significant inhibition of intracellular tachyzoite replication) | 2 μM (HFF cells showed little to no signs of toxicity) | ND | ND | ND | ND | |
| 3-Bromopyruvate | 163 | ||||||
| Compound 39 | <10 μM | >10 μM LLC-MK2 cells | ND | ND | ND | ND | |
| Effects on ROS regulation | |||||||
| Quinones | 88, 164–169 | ||||||
| Compound 40 | 0.10 μM (164) | >10 μM HFF cells (164) | 2,500 RH strain tachyzoites or 10 C56 strain bradyzoites given orally; 0–20% survival in treatment group (164) | ND | ND | <100 mg/kg/day (164) | |
| Compound 41 | 0.11 μM (164) | >10 μM HFF cells (164) | 2,500 RH strain tachyzoites or 10 C56 strain bradyzoites given orally; 40–50% survival in treatment group (164) | ND | ND | ∼100 mg/kg/day (164) | |
| Compound 42 | ND (168) | ND | (Coadministered with sulfadiazine) 1,000 RH strain tachyzoites injected i.p., 70% survival in treatment group; when 10 EGS strain cysts given orally, 90% survival in treatment group (168) | 5 P strain cysts given orally, cyst burden reduced ∼58% with treatment (168) | ND | <100 mg/kg/day (165) | |
| Quinolines | 87, 170 | ||||||
| Compound 43 | 0.0786 μM (87) | 3.4 μM HS68 cells (87) | ND | ND | ND | ND | |
| Alkaloids | 86, 97, 169, 171–177 | ||||||
| Compound 44 | 0.0007 μM (173) | 0.001 μM THP-1 cells (173) | ND | ND | ND | ND | |
| Compound 45 | 0.0007 μM (173) | 0.392 μM THP-1 cells (173) | ND | ND | ND | ND | |
| Cationic dyes | 85 | ||||||
| Compound 46 | 0.26 μM | 0.55 μM mouse peritoneal macrophages | ND | ND | ND | ND |
a
Individual compound information is listed with the index number assigned to the specific molecule's structure. For cases in which multiple IC50 values were reported in the literature, the lowest observed IC50 is reported. Anti-Toxoplasma compounds are categorized by MoA and grouped by structure. Structures for each compound can be found in Table S1 in the supplemental material. The term in vivo survivability assay data refer to experiments where model organisms (mice) were exposed to a lethal infectious dose of parasite, often via i.p. injection. The strain and dose of the parasite and the recipient host differed between studies, making comparisons between studies problematic. In vivo chronic infection and parasite burden data refer to tissue or fluid counts of parasites isolated from a host following a nonlethal infection or bradyzoite cyst burden in brain tissue (most often determined via PCR). ND, not determined; dpi, days postinfection; HFF, human foreskin fibroblasts.