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| Targets |
Plasmodium
Ganaplacide hydrochloride targets Plasmodium phosphatidylinositol 4-kinase (PI4K), an enzyme essential for parasite survival and replication. Inhibition of PI4K disrupts the secretory pathway of the parasite, leading to impaired growth and eventual death. The compound's novel mechanism of action, centered on disruption of the Plasmodium secretory pathway, marks a significant advancement in the fight against malaria. Ganaplacide hydrochloride is parasiticidal against both asexual and sexual blood stages as well as the liver stages of the parasite. Its activity against drug-resistant parasites makes it a promising candidate for combination therapy and for addressing artemisinin resistance. |
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| ln Vitro |
Ganaplacide hydrochloride (KAF156) hydrochloride demonstrates blood schizonticide efficacy against drug-susceptible and drug-resistant strains of P. falciparum at 50% inhibitory concentrations of 6 to 17.4 nM [1].
In vitro, ganaplacide hydrochloride demonstrates potent antimalarial activity. The compound shows blood schizonticidal activity with 50% inhibitory concentrations of 6 to 17.4 nM against P. falciparum. It is active against a variety of malaria parasites including drug-resistant strains. Ganaplacide hydrochloride has parasiticidal activity against both asexual and sexual blood stages as well as the liver stages of the parasite. The compound also has cidal action against mature Plasmodium falciparum gametocytes, which is important for blocking transmission to mosquitoes. Its activity against artemisinin-resistant parasites demonstrates its potential for overcoming existing drug resistance. The compound's effects are mediated through inhibition of Plasmodium PI4K. |
| ln Vivo |
In order to stop the spread of the parasite to Anopheles mosquitoes, KAF156 has cidal action against mature Plasmodium falciparum gametocytes [1]. In a malaria mouse model used as a preventive measure, ganaplacide hydrochloride (KAF156) hydrochloride (1–15 mg/kg; oral) provides complete protection [1].
In vivo, ganaplacide hydrochloride has demonstrated efficacy in animal models of malaria. As an orally administered compound, it shows good bioavailability and antimalarial activity. The compound is effective against both blood-stage and liver-stage parasites in vivo. Its activity against artemisinin-resistant strains has been confirmed in animal models. Ganaplacide hydrochloride's ability to kill mature gametocytes contributes to transmission-blocking activity, which is important for preventing the spread of malaria. The compound's oral bioavailability makes it suitable for potential clinical use. Detailed in vivo efficacy studies are described in the primary literature. |
| Enzyme Assay |
For in vitro enzyme assays, ganaplacide hydrochloride is evaluated for its ability to inhibit Plasmodium PI4K activity. Enzyme assays are performed using recombinant Plasmodium PI4K and appropriate substrates, measuring ATP consumption or product formation. IC50 values are determined from dose-response curves. Selectivity assays against mammalian kinases are performed to assess specificity. The compound's effects on parasite growth are assessed in culture using P. falciparum strains, including drug-sensitive and drug-resistant lines. Growth inhibition is measured by incorporation of radiolabeled hypoxanthine or by fluorescence-based methods. Gametocyte killing assays assess activity against sexual stages. These cell-free and cell-based assays help characterize the compound's antimalarial potency and mechanism of action.
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| Cell Assay |
In vitro cellular assays for ganaplacide hydrochloride are performed using Plasmodium falciparum cultures. Parasites are cultured in human erythrocytes in RPMI 1640 medium supplemented with serum. The compound is added at various concentrations, and parasite growth is assessed after 48-72 hours using [3H]-hypoxanthine incorporation or SYBR Green fluorescence. IC50 values are calculated from dose-response curves. For liver-stage activity, assays using Plasmodium berghei or P. yoelii sporozoites infecting hepatoma cell lines are performed. Gametocyte activity is assessed using mature gametocyte cultures and measuring gametocyte viability or ATP levels. Cytotoxicity against mammalian cell lines is assessed to determine selectivity. Resistance selection studies are performed by culturing parasites under increasing drug concentrations.
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| Animal Protocol |
Animal/Disease Models: Mice (causal prophylactic rodent malaria model)[1]
Doses: 1-15 mg/kg Route of Administration: po Experimental Results: A single oral dose of 10 mg of KAF156/kg administered 2 h before infection was fully protective. In vivo animal experiments with ganaplacide hydrochloride are conducted using mouse models of malaria. The P. berghei mouse model is commonly used for assessing blood-stage activity. Mice are infected with P. berghei parasites and treated with ganaplacide hydrochloride orally at various doses. Parasitemia is monitored by Giemsa-stained blood smears. For liver-stage activity, the P. berghei sporozoite challenge model is used, where mice are infected with sporozoites and treated before or after infection. For transmission-blocking studies, mice are infected with P. berghei expressing GFP or luciferase, and gametocyte carriage and mosquito infection rates are assessed. Efficacy against artemisinin-resistant strains is evaluated using resistant parasite lines. Survival and cure rates are monitored throughout the study. |
| ADME/Pharmacokinetics |
Pharmacokinetic properties of ganaplacide hydrochloride have been characterized to support its development as an antimalarial agent. The compound is orally administered and exhibits good bioavailability. As an imidazopyrimidine small molecule, it has favorable drug-like properties including good membrane permeability and metabolic stability. Detailed PK parameters such as half-life, Cmax, Tmax, AUC, volume of distribution, and clearance have been determined in preclinical studies. The compound's pharmacokinetic profile supports once-daily or twice-daily dosing in animal models. Protein binding and tissue distribution have also been characterized. Formulation development has been optimized for oral administration. The compound's PK properties are described in the primary literature and regulatory submissions.
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| Toxicity/Toxicokinetics |
The toxicological profile of ganaplacide hydrochloride has been evaluated in preclinical safety studies. As a potential antimalarial therapeutic, comprehensive toxicity assessments have been conducted including acute, subchronic, and chronic toxicity studies in rodents and non-rodent species. Parameters assessed include body weight, food consumption, clinical signs, hematology, clinical chemistry, organ weights, and histopathology. Genotoxicity and reproductive toxicity studies have also been performed. The compound's safety margin has been established relative to its antimalarial efficacy. The most common adverse effects and target organs of toxicity have been identified. The compound is intended for research use and clinical development, with appropriate safety monitoring in human studies.
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| References |
[1]. Kuhen KL, et al. KAF156 is an antimalarial clinical candidate with potential for use in prophylaxis, treatment, and prevention of disease transmission. Antimicrob Agents Chemother. 2014;58(9):5060-5067.
[2]. Leong FJ, et al. A first-in-human randomized, double-blind, placebo-controlled, single- and multiple-ascending oral dose study of novel Imidazolopiperazine KAF156 to assess its safety, tolerability, and pharmacokinetics in healthy adult volunteers. Antimicrob Agents Chemother. 2014;58(11):6437-6443. |
| Additional Infomation |
Ganaplacide hydrochloride represents a significant advancement in antimalarial drug development with its novel mechanism of action targeting Plasmodium PI4K. Its activity against artemisinin-resistant parasites makes it a promising candidate for combination therapy and for addressing the growing problem of drug resistance. The compound's efficacy against both blood and liver stages and its transmission-blocking activity through gametocyte killing provide multiple benefits for malaria control. Ganaplacide hydrochloride is being developed for the treatment of uncomplicated malaria, potentially in combination with other antimalarial agents. Its favorable oral bioavailability and safety profile support its advancement through clinical development. The compound serves as a valuable tool for malaria research and drug discovery.
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| Molecular Formula |
C22H24CLF2N5O
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|---|---|
| Molecular Weight |
447.908670425415
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| Exact Mass |
447.163
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| CAS # |
2751586-94-2
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| Related CAS # |
Ganaplacide;1261113-96-5
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| PubChem CID |
154925625
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| Appearance |
White to yellow solid powder
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| Hydrogen Bond Donor Count |
3
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| Hydrogen Bond Acceptor Count |
6
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| Rotatable Bond Count |
4
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| Heavy Atom Count |
31
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| Complexity |
604
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| Defined Atom Stereocenter Count |
0
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| SMILES |
Cl.FC1C=CC(=CC=1)C1=C(NC2C=CC(=CC=2)F)N2CCN(C(CN)=O)C(C)(C)C2=N1
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| InChi Key |
XCXQBXGWYRFISY-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C22H23F2N5O.ClH/c1-22(2)21-27-19(14-3-5-15(23)6-4-14)20(26-17-9-7-16(24)8-10-17)28(21)11-12-29(22)18(30)13-25;/h3-10,26H,11-13,25H2,1-2H3;1H
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| Chemical Name |
2-amino-1-[3-(4-fluoroanilino)-2-(4-fluorophenyl)-8,8-dimethyl-5,6-dihydroimidazo[1,2-a]pyrazin-7-yl]ethanone;hydrochloride
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month Note: Please store this product in a sealed and protected environment, avoid exposure to moisture. |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
DMSO : 100 mg/mL (223.26 mM)
H2O : 33.33 mg/mL (74.41 mM) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (5.58 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 2.5 mg/mL (5.58 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. View More
Solubility in Formulation 3: ≥ 2.5 mg/mL (5.58 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.2326 mL | 11.1630 mL | 22.3259 mL | |
| 5 mM | 0.4465 mL | 2.2326 mL | 4.4652 mL | |
| 10 mM | 0.2233 mL | 1.1163 mL | 2.2326 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
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