Background
Methods
In vitro antiplasmodial activity against chloroquine-sensitive and resistant strains
Pharmacokinetic studies
Sample preparation
Liquid chromatography–mass spectrometry summary
Parameter | Compound 1 | Compound 2 |
---|---|---|
Q1 mass (Da) | 531.2 | 490.2 |
Q3 mass (Da) | 91.1 | 261.2 |
Dwell time (ms) | 40 | 40 |
Declustering potential (V) | 91 | 61 |
Collision energy (V) | 89 | 73 |
Entrance potential (V) | 10 | 10 |
Collision cell exit potential (V) | 4 | 2 |
Source temperature (°C) | 500 | 500 |
Curtain gas (psi) | 25 | 25 |
Gas 1 (psi) | 50 | 50 |
Gas 2 (psi) | 70 | 70 |
CAD gas | Medium | Medium |
Ion spray voltage (kV) | 5500 | 5500 |
Ionization mode | Positive | Positive |
Pharmacokinetic analysis
In vivo anti-malarial efficacy of compound 1 against a chloroquine-sensitive Plasmodium berghei strain
Results
Antiplasmodial action of the compounds in vitro
Test compounds | Sensitive strains | Resistant strains | RI |
P value | ||
---|---|---|---|---|---|---|
3D7 | D10 | K1 | Dd2 | |||
1 | 0.064 ± 0.02 | 0.047 ± 0.01 | 0.505 ± 0.10 | 0.463 ± 0.12 | 10.7 | 0.343 |
2 | 0.041 ± 0.02 | 0.122 ± 0.03 | 0.089 ± 0.01 | 0.076 ± 0.01 | 2.2 | 1 |
Chloroquine | 0.019 ± 0.00 | 0.023 ± 0.00 | 0.279 ± 0.002 | 0.180 ± 0.01 | 14.4 | n/a |
Pharmacokinetics
Parameters | Compound 1 | Compound 2 |
---|---|---|
T1/2 (h) | 4.3 ± 1.02 | 0.7 ± 0.2 |
Vss (l/kg) | 20.1 ± 6 | 154.1 ± 1 |
CL (ml/min/kg) | 27.6 ± 8 | 366 ± 46.6 |
AUC0–∞ (µM min) | 196 ± 29.9 | 25.2 ± 3.4 |
Anti-malarial effect of compound 1 on Plasmodium berghei-infected mice
Test group | Average % parasitemia | % reduction of parasitemia | ||
---|---|---|---|---|
Day 4 | Day 6 | Day 9 | Day 9 | |
Oral (20 mg/kg/day) | 5.3 ± 3.9 | 22.7 ± 10 | 24.2 ± 5.6 | 3.7 ± 5.6 |
Oral (40 mg/kg/day) | 5.9 ± 2 | 10.7 ± 5 | 48.6 ± 12 | −93.8 ± 49.3 |
IV (4 mg/kg/day) | 0.4 ± 0.4 | 1.8 ± 1.4 | 8.1 ± 5 | 61.9 ± 26 |
IV (8 mg/kg/day) | 0 | 0.9 ± 0.9 | 5.1 ± 1.7 | 82.9 ± 2.5 |
Oral CQ (10 mg/kg/day) | 0 | 0 | 2 ± 1.6 | 92.0 ± 0.4 |
Placebo | 2.5 ± 2.4 | 7.3 ± 2.4 | 25.1 ± 0.4 | – |