Table 3.
In Vitro Antileishmanial Activity of TAs (82–109) with Modifications on Ring-B and Terminal Amine.
|
survival (%) at 0.1 μMa vs |
EC50 (nM)a vs |
||||||
|---|---|---|---|---|---|---|---|---|
| compound | R1 | R2 | R3 |
L. mexicana amastigote |
J774A.1 macrophage |
L. mexicana amastigote |
J774A.1 macrophage |
TI |
| 82 | H | Me |
|
26.3 ± 3.29 | 88.4 ± 29.4 | ND | ND | ND |
| 83 | H | Et |
|
42.1 ± 3.13 | 88.7 ± 22.0 | ND | ND | ND |
| 84 | Me | H |
|
89.0 ± 17.6 | 127 ± 83.3 | ND | ND | ND |
| 85 | Me | H |
|
48.6 ± 9.03 | 150 ± 60.4 | ND | ND | ND |
| 86 | Et | H |
|
33.9 ± 10.5 | 32.2 ± 9.96 | ND | ND | ND |
| 87 | Et | H |
|
34.6 ± 5.87 | 35.8 ± 11.9 | ND | ND | ND |
| 88 | Me | H |
|
15.4 ± 3.98 | 86.9 ± 27.5 | 48.0 ± 4.24 | 1131 ± 185 | 24 |
| 89 | Et | H |
|
11.3 ± 2.09 | 50.0 ± 22.1 | 37.5 ± 2.12 | 884 ± 163 | 24 |
| 90 | Me | Me |
|
18.2 ± 1.57 | 62.8 ± 7.71 | 55.0 ± 1.41 | 908 ± 159 | 16 |
| 91 | Me | Me |
|
33.5 ± 7.06 | 43.5 ± 14.4 | ND | ND | ND |
| 92 | Me | Me |
|
14.2 ± 1.0 | 53.2 ± 22.2 | 91.7 ± 48.3 | 1600 ± 900 | 17 |
| 93 | Et | Et |
|
27.5±3.37 | 26.7±5.21 | ND | ND | ND |
| 94 | Et | Et |
|
17.0±2.70 | 29.5±9.59 | ND | ND | ND |
| 95 | Et | Et |
|
17.1 ± 5.6 | 87.8 ± 10.7 | 73.3 ± 0.0 | 1424 ± 0.0 | 19 |
| 96 | Me | Me |
|
74.0 ± 7.9 | 54.2 ± 7.9 | ND | ND | ND |
| 97 | Me | Me |
|
92.2 ± 18.6 | 88.1 ± 23.4 | ND | ND | ND |
| 98 | Me | Me |
|
102 ± 25 | 77.2 ± 18.1 | ND | ND | ND |
| 99 | Me | Me |
|
108 ± 32 | 65.9 ± 3.7 | ND | ND | ND |
| 100 | Me | Me |
|
111 ± 30 | 66.2 ± 20.6 | ND | ND | ND |
| 101 |
|
|
40.9 ± 7.6 | 60.3 ± 13.4 | 130 ± 0.0 | 2934 ± 0.0 | 23 | |
| 102 |
|
|
24.7 ± 12.0 | 80.0 ± 6.71 | 74.0 ± 9.54 | 252±0.0 | 3.4 | |
| 103 |
|
|
33.4 ± 13.5 | 75.8 ± 25.7 | ND | ND | ND | |
| 104 |
|
|
16.1 ± 4.5 | 75.0 ± 16.9 | ND | ND | ND | |
| 105 |
|
|
112 ± 23 | 95.1 ± 16.9 | ND | ND | ND | |
| 106 |
|
|
103 ± 6 | 67.2 ± 19.5 | ND | ND | ND | |
| 107 |
|
|
84.9 ± 10.7 | 92.7 ± 51.2 | ND | ND | ND | |
| 108 |
|
|
89.8 ± 19.4 | 62.5 ± 19.1 | ND | ND | ND | |
| 109 |
|
|
102 ± 24 | 58.2 ± 9.5 | ND | ND | ND | |
| miltefosine | - | - | 0.020±0.010 | 39.2 ± 5.1 | 3460 ± 781 | >100000±0.0 | >29 | |
a
Data represent the mean ± standard deviation of results of at least two independent experiments; an error of 0.0 indicates identical values were obtained for each replicate; TI = Therapeutic Index (J774A.1 EC50/L. mexicana EC50); ND, not determined.