Table 2.
Calculated (ADMET predictor) and measured pKa and Log D7.4
| Compound | Calculated pKa | Measured pKaa | Calculated Log D7.4 |
Measured Log Db7.4 |
|---|---|---|---|---|
| Ionized or partially ionized bases at physiological pH | ||||
| Cycloguanil | 10.5 (B) | 11.4 ± 0.3 (B) | − 1.80 | − 1.10 |
| Doxycyclin | 9.13 (B), 3.35 (A), 9.98 (A) | CNDe | − 0.75 | − 0.20 |
| Pyronaridine | 7.65 (B), 6.39 (B), 5.20 (B), 10.1 (A) | CNDe | 5.61 | 0.23 |
| Proguanil | 10.0 (B), 6.64 (B) | CNDc | 0.21 | 0.27 |
| Primaquine | 9.92 (B), 3.88 (B) | 10.2 ± 0.12 (B), 3.3 ± 0.02 (B) | 0.40 | 0.54 |
| Chloroquine | 9.86 (B), 7.25 (B) | 9.9 ± 0.1 (B), 8.4 ± 0.1 (B) | 2.42 | 0.93 |
| Chlorproguanil | 9.79 (B), 6.29 (B) | CNDc | 0.84 | 1.10 |
| Azithromycin | 8.72 (B), 7.63 (B) | CNDe | 1.64 | 1.10 |
| AQ-13 | 9.63 (B), 7.28 (B) | 7.6 ± 0.2 (B) | 1.89 | 1.30 |
| Desethylamodiaquine | 10.3 (B), 6.21 (B), 8.14 (A) | 8.5 ± 0.05 (B), 7.1 ± 0.01 (B) | 3.51 | 1.30 |
| Quinine | 7.95 (B), 3.87 (B) | 8.5 ± 0.05 (B), 4.2 ± 0.03 (B) | 1.99 | 1.80 |
| Clindamycin | 7.44 (B) | 7.1 ± 0.07 (B) | 1.62 | 1.90 |
| KAF156 | 8.08 (B), 3.83 (B) | 8.4 ± 0.06 (B), 4.5 ± 0.02 (B) | 1.80 | 2.06 |
| M5717 | 8.67 (B), 6.23 (B), 2.54 (B), 10.9 (A) | 8.7 ± 0.11 (B), 6.8 ± 0.04 (B)g | 2.49 | 2.50 g |
| OZ277 | 9.38 (B) | 8.9 ± 0.16 (B) | 1.28 | 2.60 |
| Mefloquine | 8.52 (B) | 8.5 ± 0.04 (B) | 2.66 | 2.70 |
| Amodiaquine | 7.95 (B), 6.25 (B), 10.3 (A) | 7.0 ± 0.02 (B) | 4.27 | 2.95 |
| NPC1161B | 9.94 (B), 3.61 (B) | 9.3 ± 0.03 (B), 6.0 ± 0.01 (B) | 3.24 | CNDf |
| Ferroquine | 8.08 (B), 6.74 (B) | 8.4 ± 0.06 (B), 7.5 ± 0.02 (B) | 5.41 | 3.39 |
| Naphthoquine | 8.48 (B), 6.48 (B), 10.7 (A) | CNDd | 5.36 | 4.18 |
| Tafenoquine | 10.0 (B), 4.00 (B) | 8.7 ± 0.09 (B), 6.0 ± 0.10 (B) | 2.61 | 4.24 |
| MMV253 | 8.03 (B), 4.63 (B), 3.03 (B), 2.52 (B) | 8.0 ± 0.03 (B), 5.5 ± 0.03 (B) | 3.76 | 4.42 |
| MMV052 | 8.75 (B) | 8.3 ± 0.06 (B) | 4.58 | 5.40 |
| Piperaquine | 7.60 (B), 5.93 (B), 5.15 (B), 4.36 (B) | CNDe | 5.59 | CNDf |
| Halofantrine | 9.20 (B) | CNDd | 5.78 | CNDf |
| TDD-E209 | 7.40 (B) | CNDd | 5.84 | CNDf |
| Lumefantrine | 8.66 (B) | CNDd | 7.34 | CNDf |
| Ionized acids at physiological pH | ||||
| Sulfadoxine | 2.01 (B), 6.40 (A) | 6.2 ± 0.01 (A) | − 0.28 | − 0.780 |
| Sulfamethoxazole | 6.15 (A) | 6.1 ± 0.01 (A) | − 0.25 | − 0.780 |
| Artesunate | 4.51 (A) | 4.7 ± 0.04 (A) | − 0.38 | − 0.120 |
| Atovaquone | 4.28 (A) | CNDd | 2.58 | 5.30 |
| Zwitterionic or partially zwitterionic at physiological pH | ||||
| P218 | 7.22 (B), 4.26 (A) | 7.3 ± 0.003 (B), 4.9 ± 0.002 (A) | 0.49 | 0.080 |
| JPC3210 | 8.20 (B), 10.5 (A) | 5.3 ± 0.04 (A) | 5.42 | 5.30 |
| Neutral at physiological pH | ||||
| Dapsone | 3.06 (B), 2.18 (B) | CNDe | 0.97 | 0.86 |
| Dihydroartemisinin | NA | NA | 2.16 | 2.30 |
| DSM421 | 3.04 (B) | CNDc | 3.51 | 2.36 g |
| Pyrimethamine | 6.57 (B) | 6.9 ± 0.10 (B) | 2.47 | 2.41 |
| MMV048 | 4.18 (B) | 4.0 ± 0.07 (B) | 2.81 | 2.50 |
| Artemisone | 5.22 (B) | CNDc | 1.36 | 2.82 |
| Artemether | NA | NA | 2.80 | 3.70 |
| SJ733 | 3.16 (B), 10.7 (A) | 4.1 ± 0.03 (B) | 3.34 | 3.90 |
| DSM265 | 3.23 (B) | CNDc | 4.59 | 4.03 |
| KAE609 | 3.95 (B), 10.7 (A), 10.1 (A) | 5.1 ± 0.02 (B) | 4.36 | CNDf |
| OZ439 | 6.38 (B) | CNDd | 5.03 | CNDf |
| ELQ300 | NA | NA | 5.28 | CNDf |
A acidic pKa, B basic pKa, CND could not determine, NA not applicable
aValues for pKa represent the mean ± SD for n = 3 titrations
bValues for Log D represent the average ratio for n = 2–3 replicate measurements of each partitioning phase (i.e. buffer or octanol); replicate measurements for each phase differed by less than 10%
cNo ionization detected
dSolubility-limited
eMultiple overlapping pKa values
fAqueous phase concentrations below the analytical LLQ