Table 1.
In vitro biochemical and cellular activities of test compounds and controls. (n.a. = not active (cruzain IC50 > 50 μM); BNZ = benzindazole; POSA = posaconazole).
| compound | cruzain activity | TcCYP51 activity | T. cruzi growth inhibition | ||
|
kinact/Ki (s−1·M−1) |
in vitro KD (nM) |
cellular activity (Y/N, conc.)a | MTCb (μM) | HCSc EC90 (μM) |
|
| 1 | 118,000 | >2,000 | N (1.6 μM) | 8 | 0.10 |
| 2 | 120,000 | — | — | 10 | — |
| 3 | 16,000 | >2,000 | N (2.0 μM) | 8 | 1.85 |
| 4 | 67,300 | ≤5 | Y (0.2 μM) | 0.6 | 0.10 |
| 5 | — | ≤5 | Y (5.0 μM) | ≤10d | — |
| 6 | n.a. | >2,000 | N (2.0 μM) | >10 | >10 |
| 7 | n.a. | >2,000 | N (0.1 μM) | >10 | >10 |
| 8 | n.a. | ≤5 | Y (0.1 μM) | 0.25 | 0.11 |
| 9 | 81,500 | — | — | 5e | 0.017 |
| 12 | n.a. | 620 ± 260 | — | >10 | >10 |
| 13 | n.a. | 75 ± 26 | — | 1f | 3.9 |
| BNZ | — | — | — | 10 | 7.2 |
| POSA | — | ≤5 | Y (0.1 μM) | 0.003 | 2.7 |
aCompound affects ergosterol biosynthesis at indicated concentration as determined by GC/MS analysis. bMinimum effective concentration that clears J774 host cells of parasites at day 40 of the experiment, following 28 days of treatment. cConcentration that reduces parasite load in C2C12 cells by 90% relative to untreated controls. dConcentrations lower than 10 μM were not examined. eExperiment performed in BESM host cell rather than J774 cells. fRead at day 12 following 7 days treatment.