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| Targets |
Quilseconazole targets fungal lanosterol 14alpha-demethylase (Cyp51), a cytochrome P450 enzyme that is essential for ergosterol biosynthesis in fungi. Ergosterol is a critical structural component of the fungal cell membrane, analogous to cholesterol in mammalian cells. By inhibiting Cyp51, quilseconazole disrupts ergosterol synthesis, leading to membrane integrity loss, impaired cell growth, and ultimately fungal cell death. The compound binds tightly to cryptococcal Cyp51 but shows only weak inhibitory activity against human CYP450 enzymes, including human Cyp51. This selectivity is a key feature that contributes to its favorable safety profile and makes it a valuable tool for studying fungal Cyp51 as a therapeutic target. The compound's ability to cross the blood-brain barrier further enhances its utility for treating central nervous system fungal infections.
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| ln Vitro |
Quilseconazole demonstrates potent in vitro antifungal activity against Cryptococcus species, including Cryptococcus neoformans and Cryptococcus gattii. The compound is highly effective in inhibiting fungal growth in standard susceptibility testing. Its mechanism of action involves binding to fungal Cyp51 and preventing ergosterol synthesis. The compound shows minimal effects on human CYP enzymes, indicating a favorable selectivity profile. In vitro studies have characterized the compound's potency, selectivity, and spectrum of antifungal activity against various fungal pathogens. The compound's activity is comparable to or better than existing antifungal agents, making it a promising candidate for further development. Detailed IC50 and MIC values have been determined in susceptibility testing against clinical isolates.
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| ln Vivo |
In vivo activity of quilseconazole has been evaluated in animal models of fungal infection. The compound is orally active and can cross the blood-brain barrier, making it particularly suitable for the treatment of cryptococcal meningitis. In animal models, quilseconazole has demonstrated efficacy in reducing fungal burden and improving survival outcomes. Its oral bioavailability and ability to achieve therapeutic concentrations in the central nervous system are key advantages over existing antifungal therapies. The compound's selectivity for fungal Cyp51 over human CYP450 enzymes contributes to its safety in vivo. Efficacy studies have been conducted in mouse models of cryptococcal infection, where quilseconazole has shown significant reduction in fungal load in the brain and other tissues. The compound's favorable pharmacokinetic and pharmacodynamic properties support its potential for clinical development.
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| Enzyme Assay |
In vitro enzyme/receptor binding assays for quilseconazole involve measuring the inhibition of fungal Cyp51 (lanosterol 14alpha-demethylase) activity. The enzyme is incubated with varying concentrations of the test compound and a substrate (typically lanosterol or a labeled analog), and the production of the demethylated product is quantified by HPLC or LC-MS/MS. Alternatively, binding affinity can be measured using differential scanning fluorimetry or isothermal titration calorimetry to assess the interaction between the compound and the Cyp51 protein. Selectivity assays compare the compound's activity against human CYP450 enzymes (including human Cyp51) to confirm its specificity for the fungal target. IC50 values are calculated from dose-response curves using non-linear regression analysis. Assays are typically performed in 96-well plate format with appropriate positive controls (known Cyp51 inhibitors) and vehicle controls.
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| Cell Assay |
In vitro cellular assays for quilseconazole are performed using fungal cell cultures to assess antifungal activity. Standard broth microdilution assays are conducted according to Clinical and Laboratory Standards Institute (CLSI) guidelines to determine the minimum inhibitory concentration (MIC) against various fungal strains, including Cryptococcus neoformans and Cryptococcus gattii. Fungal cells are cultured in appropriate medium and exposed to varying concentrations of the test compound for 24-48 hours. The MIC is defined as the lowest concentration that inhibits visible fungal growth. Time-kill assays may be performed to determine the fungicidal or fungistatic nature of the compound. Cytotoxicity against mammalian cells is assessed in parallel using standard viability assays (e.g., MTT or CellTiter-Glo) to confirm selectivity. The compound's ability to cross the blood-brain barrier can be assessed using in vitro models such as the hCMEC/D3 brain endothelial cell line.
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| Animal Protocol |
In vivo animal studies for quilseconazole are conducted using mouse models of cryptococcal infection. Typically, 6-8 week old female BALB/c or C57BL/6 mice are infected intravenously or intranasally with Cryptococcus neoformans or Cryptococcus gattii. Following infection, animals are randomized into treatment groups and administered quilseconazole via oral gavage at various doses and schedules. Efficacy is evaluated by measuring survival rates, fungal burden in tissues (brain, lungs, and spleen) determined by colony-forming unit (CFU) counts, and histopathological examination of infected organs. Pharmacokinetic studies assess drug concentrations in plasma and brain tissue to confirm blood-brain barrier penetration. Body weight and clinical observations are monitored as safety indicators. Efficacy is compared to vehicle-treated controls and standard-of-care antifungal agents.
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| ADME/Pharmacokinetics |
Quilseconazole exhibits favorable pharmacokinetic properties, including good oral bioavailability and the ability to cross the blood-brain barrier. The compound is orally active, making it suitable for convenient dosing regimens. Its ability to penetrate the central nervous system is a key advantage for treating cryptococcal meningitis and other fungal infections of the brain. The compound is metabolized by hepatic cytochrome P450 enzymes, though its weak inhibition of human CYP450 isoforms suggests a low risk of drug-drug interactions. Quilseconazole has a molecular formula of C22H14F7N5O2 and a molecular weight of 513.37 g/mol. It is soluble in DMSO (10 mM). The compound's pharmacokinetic profile supports once-daily or twice-daily dosing in preclinical studies. Comprehensive pharmacokinetic parameters have been characterized in animal models.
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| Toxicity/Toxicokinetics |
Quilseconazole exhibits a favorable safety profile due to its high selectivity for fungal Cyp51 over human CYP450 enzymes. The compound shows minimal effects on human CYP enzymes, reducing the risk of off-target toxicity and drug-drug interactions. In preclinical toxicology studies, the compound has demonstrated acceptable safety margins at therapeutic doses. Standard toxicology assessments include evaluation of clinical observations, body weight, food consumption, hematology, clinical chemistry, organ weights, and histopathology in rodent and non-rodent species. The compound's ability to cross the blood-brain barrier is beneficial for efficacy but also requires careful evaluation of central nervous system safety. Quilseconazole is strictly for research use and has not received regulatory approval for human therapeutic use. Comprehensive toxicological data are available from preclinical studies conducted as part of the compound's development program.
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| References | |
| Additional Infomation |
Quilseconazole (VT-1129) is a potent, orally active, and highly selective inhibitor of fungal Cyp51 (lanosterol 14alpha-demethylase) developed by Viamet Pharmaceuticals. It is designed to treat fungal infections, particularly cryptococcal meningitis, by inhibiting ergosterol synthesis in fungal cells. The compound has a molecular formula of C22H14F7N5O2 and a molecular weight of 513.37 g/mol. Quilseconazole binds tightly to cryptococcal Cyp51 but shows weak inhibitory activity against human CYP450 enzymes, providing a favorable selectivity profile. The compound can cross the blood-brain barrier, a critical feature for treating central nervous system fungal infections. Quilseconazole has demonstrated potent in vitro activity against Cryptococcus neoformans and Cryptococcus gattii. It has not received regulatory approval for any indication and is available for research purposes only. The compound represents a promising new class of antifungal agents targeting fungal Cyp51 with improved selectivity and CNS penetration.
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| Molecular Formula |
C22H14F7N5O2
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|---|---|
| Molecular Weight |
513.367688655853
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| Exact Mass |
513.103
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| CAS # |
1340593-70-5
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| Related CAS # |
1809323-18-9 (besylate);1340593-70-5;
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| PubChem CID |
91886002
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| Appearance |
White to off-white solid powder
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| LogP |
4.3
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
13
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| Rotatable Bond Count |
7
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| Heavy Atom Count |
36
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| Complexity |
727
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| Defined Atom Stereocenter Count |
1
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| SMILES |
FC(C1C=CC(C2C=CC(=CC=2)OC(F)(F)F)=CN=1)([C@](C1C=CC(=CC=1F)F)(CN1C=NN=N1)O)F
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| InChi Key |
NCEHACHJIXJSPD-FQEVSTJZSA-N
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| InChi Code |
InChI=1S/C22H14F7N5O2/c23-15-4-7-17(18(24)9-15)20(35,11-34-12-31-32-33-34)21(25,26)19-8-3-14(10-30-19)13-1-5-16(6-2-13)36-22(27,28)29/h1-10,12,35H,11H2/t20-/m0/s1
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| Chemical Name |
(2R)-2-(2,4-difluorophenyl)-1,1-difluoro-3-(tetrazol-1-yl)-1-[5-[4-(trifluoromethoxy)phenyl]pyridin-2-yl]propan-2-ol
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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 |
| 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 (~194.79 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (4.87 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 (4.87 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (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 corn oil and mix evenly. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.9479 mL | 9.7396 mL | 19.4791 mL | |
| 5 mM | 0.3896 mL | 1.9479 mL | 3.8958 mL | |
| 10 mM | 0.1948 mL | 0.9740 mL | 1.9479 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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