Table 5:
Probing expanded diversity at R1. Values highlighted in red are considered improved in comparison to initial lead compound 1.
| Cpd | R1 | LD AMMAC EC50 (μM)a | LD MAC EC50 (μM)b | SI MACc |
HEPG2 EC50 (μM) | Solubilityd (μM) |
AMPe (nm/sec) |
HSAf Binding (%) |
PFIg |
|---|---|---|---|---|---|---|---|---|---|
| 1 |
|
2.5 | 15.8 | 6.3 | 63.1 | 107 | 345 | 96.4 | 8.4 |
| 29 |
|
20.0 | >50 | >2.5 | 79.4 | 240 | 590 | 97.5 | 8.5 |
| 30 |
|
12.6 | 31.6 | 2.5 | 63.1 | 64 | 370 | 97.3 | 8.4 |
| 31 |
|
10.0 | >50 | >5.0 | >100 | 194 | 260 | 95.5 | 8.0 |
| 32 |
|
25.1 | >50 | >2.0 | >100 | 182 | 470 | 93.4 | 7.2 |
| 33 |
|
20.0 | >50 | >2.5 | >100 | 219 | 200 | 96.6 | 8.5 |
| 34 |
|
12.6 | 31.6 | >2.5 | 50.1 | 45 | 550 | 98.2 | 9.0 |
| 35 |
|
15.8 | 39.8 | >2.5 | 50.1 | 19 | 370 | 97.2 | 8.9 |
| 36 |
|
25.1 | >50 | >2.0 | >100 | ≥450 | 570 | 92.1 | 7.3 |
| 37 |
|
25.1 | >50 | >2.0 | >100 | ≥446 | 130 | 81.1 | 4.6 |
| 38 |
|
31.6 | >50 | >1.6 | >100 | ≥381 | 490 | 90.2 | 6.5 |
| 39 |
|
15.8 | >50 | >3.2 | >100 | ≥433 | 230 | 76.7 | 5.3 |
| 40 |
|
>50 | >50 | >1.0 | >100 | ≥351 | <10 | 77.5 | 4.8 |
| 41 |
|
>50 | >50 | >1.0 | >100 | ≥421 | 520 | 90.2 | 6.7 |
(a)
EC50 for growth inhibition of L. donovani intracellular amastigotes infecting THP-1 macrophages;
(b)
EC50 for cytotoxicity against host THP-1 macrophages;
(c)
SI MAC = selectivity index in macrophages, calculated as SI MAC = (LD MAC EC50)/(LD AMMAC EC50);
(d)
kinetic aqueous solubility as determined by high-throughput CLND (chemoluminescent nitrogen detection);
(e)
artificial membrane permeability;
(f)
human serum albumin binding;
(g)
PFI = ChromLogD7.4 + Aromatic rings.