Table 2.
Antitrypanosomal, cytotoxic, and anticholinesterase activity and BBB permeability of the N-cyanoalkyl, N-aminoalkyl, and N-guanidinoalkyl 4-aminoquinoline derivatives 6b,e, 7, 8, 11c,e, 12c–e, 13c,e, 14e, 15c,e, and 16e and reference compounds 1 and nifurtimoxa
| Compd | T. brucei IC50 (μM) | T. brucei IC90 (μM) | L6 cells IC50 (μM) | SITbb | EeAChE IC50 (nM) | Pe (10−6 cm s−1)c (prediction) |
|---|---|---|---|---|---|---|
| 6b | 1.37 ± 0.02 | 1.54 ± 0.01 | 21.0 ± 1.6 | 15.3 | 11.8 ± 1.3 | 2.9 ± 0.4 (CNS±) |
| 6e | 0.33 ± 0.06 | 0.70 ± 0.09 | 10.9 ± 0.9 | 33 | 10.6 ± 0.8 | 5.4 ± 0.3 (CNS+) |
| 7 | 0.83 ± 0.04 | 1.70 ± 0.21 | 2.40 ± 0.19 | 2.9 | 48.4 ± 2.7 | 5.9 ± 0.4 (CNS+) |
| 8 | 1.75 ± 0.19 | 4.88 ± 0.27 | 14.3 ± 0.5 | 8.2 | 13.3 ± 0.8 | 15.0 ± 1.0 (CNS+) |
| 11c | 3.81 ± 1.13 | 10.3 ± 2.7 | 34.8 ± 1.6 | 9.1 | 53.9 ± 3.0 | 11.2 ± 0.2 (CNS+) |
| 11e | 0.98 ± 0.05 | 1.38 ± 0.09 | 5.73 ± 0.16 | 4.2 | 44.9 ± 1.6 | 7.6 ± 0.35 (CNS+) |
| 12c | 7.92 ± 0.17 | 12.2 ± 0.2 | 34.7 ± 0.6 | 4.4 | d | 16.7 ± 0.9 (CNS+) |
| 12d | 6.89 ± 0.13 | 8.75 ± 0.24 | 27.8 ± 1.6 | 4.0 | 46.0 ± 6.0 | 14.7 ± 0.8 (CNS+) |
| 12e | 1.57 ± 0.17 | 2.56 ± 0.07 | 8.00 ± 0.44 | 5.1 | 24.3 ± 4.5 | 5.4 ± 0.4 (CNS+) |
| 13c | 2.13 ± 0.05 | 3.12 ± 0.14 | 7.28 ± 0.86 | 3.4 | 23.9 ± 2.6 | 7.4 ± 0.1 (CNS+) |
| 13e | 4.07 ± 0.12 | 5.55 ± 0.10 | 16.6 ± 0.6 | 4.1 | 15.6 ± 1.5 | 6.9 ± 0.5 (CNS+) |
| 14e | 2.31 ± 0.36 | 4.88 ± 0.18 | 7.62 ± 0.81 | 3.3 | 14.5 ± 1.6 | 5.8 ± 0.3 (CNS+) |
| 15c | 0.85 ± 0.09 | 1.30 ± 0.20 | <1.20 | <1.4 | 23.9 ± 2.6 | 5.9 ± 0.3 (CNS+) |
| 15e | 0.12 ± 0.01 | 0.25 ± 0.04 | 15.9 ± 0.8 | 133 | 30.5 ± 1.9 | 6.5 ± 0.3 (CNS+) |
| 16e | 0.63 ± 0.08 | 0.96 ± 0.02 | 11.9 ± 1.2 | 19 | 16.4 ± 1.5 | 6.7 ± 0.4 (CNS+) |
| 1e | 0.61 ± 0.03 | 2.94 ± 0.20 | 7.80 ± 0.47 | 13 | 0.30 ± 0.01 | 23.8 ± 2.7 (CNS+)f |
| Nifurtimox | 4.4 ± 0.7g | 32.0 ± 1.1 | 7.3 | d | d |
In vitro activity against bloodstream form of T. brucei (pH 7.4), rat myoblast L6 cells, and Electrophorus electricus AChE, expressed as the concentration that inhibited growth or enzyme activity by 50% (IC50) and 90% (IC90, for T. brucei). Data are the mean of triplicate experiments ± SEM.
SITb: selectivity index as the ratio of cytotoxic to anti-T. brucei IC50 values.
Permeability values from the PAMPA-BBB assay. Values are expressed as the mean ± SD of three independent experiments.
Not determined.
Trypanocidal and cytotoxicity activity values taken from Ref. 29.
Taken from Ref. 38.
Taken from Ref. 44.