TABLE 2.
Potency of nitroheterocyclic compounds against intracellular L. donovani amastigotes in three different host cell typesa
| Drug | Exptb | Differentiated THP-1 cells |
PBMC-derived mϕ |
PEMs |
|||
|---|---|---|---|---|---|---|---|
| EC50 (μM [95% confidence interval]) | EC90 (μM [95% confidence interval]) | EC50 (μM [95% confidence interval]) | EC90 (μM [95% confidence interval]) | EC50 (μM [95% confidence interval]) | EC90 (μM [95% confidence interval]) | ||
| (R)-PA-824 | 1 | 2.91 (2.77–3.04) | 6.56 (4.66–8.47) | 4.59 (4.15–5.03)c | 5.76 (5.25–6.27)c | 1.16 (0.89–1.42) | 5.58 (3.25–7.92) |
| 1 | 2.63 (2.37–2.89)c | 4.92 (4.36–5.47)c | |||||
| 2 | 4.01 (3.94–4.09) | 8.39 (6.93–9.58) | 5.06 (4.55–5.57) | 7.27 (6.46–8.09) | 2.26 (2.09–2.44)d | 4.55 (3.46–5.64)d | |
| (S)-PA-824 | 1 | 27.83 (24.95–30.71) | >40 | 38.62 (37.53–39.70) | >40 | 13.03 (8.05–18.02) | NOe |
| 2 | 27.90 (25.32–30.49) | 50.82 (44.66–26.97) | 30.57 (26.73–34.41) | 37.82 (35.88–39.77) | 13.53 (11.67–15.39)d | NOd | |
| VL-2098 | 1 | 0.22 (0.21–0.23) | 0.36 (0.32–0.41) | 0.32 (0.31–0.34) | 0.48 (0.45–0.50) | 0.23 (0.20–0.26) | 0.45 (0.37–0.54) |
| 2 | NDf | ND | 0.39 (0.36–0.42) | 0.56 (0.52–0.61) | 0.23 (0.21–0.24)d | 0.45 (0.35–0.56)d | |
| 3 | ND | ND | 0.27 (0.21–0.33) | 0.41 (0.39–0.43) | ND | ND | |
| Fexinidazole | 3 | >80 | >80 | >80c | >80c | >80 | >80 |
| 3 | >80c | >80c | |||||
| Fexinidazole sulfone | 1 | 3.15 (2.06–4.25) | >20 | 7.57 (6.72–8.43)c | >40c | 5.59 (5.21–5.96) | >20 |
| 1 | 6.85 (4.56–9.13)c | >40c | |||||
| 3 | 8.43 (7.38–9.49) | >40 | 9.37 (4.66–14.07)c | >80c | 10.44 (6.88–14.00) | >40 | |
| 3 | 14.70 (10.73–18.68)c | >80c | |||||
| 4 | 2.24 (1.42–3.06) | >80 | 20.94 (17.02–24.86) | >80 | 10.27 (5.64–14.90) | >20 | |
a
Data is representative of 2 to 4 separate directly comparative experiments.
b
Experiment numbers indicate parallel testing of respective compounds in assays with the same number. Miltefosine was included as a positive control in experiment 4 and displayed EC50 values (95% confidence intervals in parentheses) of 8.58 μM (6.39 to 10.76) in differentiated THP-1 cells, 2.67 μM (1.78 to 3.57) in PBMC-derived mϕ, and 1.19 μM (0.83 to 1.54) in PEMs.
c
Cells were derived from two individual blood donors.
d
PEMs were harvested from CD-1 mice in this assay and BALB/c mice in all other assays.
e
NO, not obtained.
f
ND not determined.