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Table 2 Calculated (ADMET predictor) and measured pKa and Log D7.4

From: An in vitro toolbox to accelerate anti-malarial drug discovery and development

Compound

Calculated pKa

Measured pKaa

Calculated

Log D7.4

Measured

Log D b7.4

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

  1. A acidic pKa, B basic pKa, CND could not determine, NA not applicable
  2. aValues for pKa represent the mean ± SD for n = 3 titrations
  3. 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%
  4. cNo ionization detected
  5. dSolubility-limited
  6. eMultiple overlapping pKa values
  7. fAqueous phase concentrations below the analytical LLQ
  8. gData for M5717 from [77] and for DSM421 from [78]