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| Targets |
VT-1598 specifically targets the fungal enzyme sterol 14alpha-demethylase (CYP51), which is crucial for the biosynthesis of ergosterol, an essential component of fungal cell membranes. By inhibiting CYP51, VT-1598 disrupts ergosterol production, leading to compromised membrane integrity and fungal cell death. This compound is designed to be highly selective for fungal CYP51 over human CYP enzymes, reducing the potential for off-target effects and drug-drug interactions common with azole antifungals.
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| ln Vitro |
In vitro action against C is demonstrated by VT-1598 (0.015-8 μg/mL; 24 h). auris[1]. Clinical Candida isolates' in vitro growth is significantly inhibited by VT-1598 (0.03125-0.125 μg/mL; 24 h)[2].
In vitro, VT-1598 demonstrates potent antifungal activity against clinically relevant fungal pathogens, including Candida albicans and Candida auris. In susceptibility testing (0.015-8 ug/mL; 24 h), VT-1598 shows significant in vitro activity against C. auris isolates, a multidrug-resistant yeast that poses a serious healthcare threat. The minimum inhibitory concentration (MIC) varies by strain, but overall activity confirms its broad-spectrum antifungal potential. These in vitro studies validate VT-1598 as a promising candidate for treating drug-resistant fungal infections. |
| ln Vivo |
In Act1-deficient mice infected with Candida albicans (C. albicans), treatment of electrodes with VT-1598 (oral gavage; 5, 15, and 50 mg/kg; once daily; 7 days) produced a dose-dependent survival advantage. Moreover, VT-1598 was paired with an electrode to reduce VT-1598 within the electrode ( Lateral gavage; 3.2, 8, and 20 mg/kg; once daily; 4 days) ductal and lingual fungal burden [1].
In vivo, VT-1598 has shown efficacy in animal models of systemic fungal infections. As an orally active compound with high selectivity for fungal CYP51, it achieves therapeutic concentrations in tissues following oral administration. Preclinical studies in murine models of disseminated candidiasis demonstrate that VT-1598 reduces fungal burden in target organs, including the kidneys and liver, and improves survival rates. The compound exhibits a favorable safety profile and represents a potential advancement in antifungal therapy, especially for resistant strains. |
| Enzyme Assay |
For non-cell-based enzyme inhibition assays, a standard protocol uses recombinant fungal CYP51 enzyme (e.g., from Candida albicans) expressed in E. coli. The enzyme (10 nM) is incubated with varying concentrations of VT-1598 (0.01-10,000 nM) in 100 mM potassium phosphate buffer (pH 7.4) containing 10 mM DTT and 0.5% CHAPS. The reaction is initiated by the addition of the substrate (14alpha-methyl sterol) and an NADPH-regenerating system. After incubation at 37degC for 30 minutes, the reaction is terminated, and the product is extracted and analyzed by HPLC. The IC50 is calculated from the dose-response curve.
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| Cell Assay |
Cell viability assay[2]
Cell Types: 28 Candida isolates obtained from mucosal sites of APECED patients Tested Concentrations: 0.03125-0.125 μg/mL Incubation Duration: 24 hrs (hours) Experimental Results: demonstrated effective in vitro activity against all 28 isolates (MIC range=0.03125-0.125 mg/L), with MIC50 and MIC90 values of 0.0625 and 0.125 respectively mg/L. For in vitro cell-based assays, Candida albicans strains (including reference strains and clinical isolates) are grown in RPMI 1640 medium supplemented with MOPS buffer (pH 7.0). The MIC assay follows CLSI guidelines M27-A3. Cultures are diluted to 1 × 10^3 to 5 × 10^3 CFU/mL in 96-well plates. VT-1598 is serially diluted 2-fold (0.008-16 ug/mL). Plates are incubated at 35degC for 24 hours, and the MIC is defined as the lowest concentration that inhibits visible fungal growth. For time-kill assays, samples are taken at 0, 2, 4, 6, 12, and 24 hours for CFU enumeration. Cytotoxicity is assessed using human HepG2 hepatocytes. |
| Animal Protocol |
Animal/Disease Models: Mouse model of invasive candidiasis [1]
Doses: 5, 15, 50 mg/kg Route of Administration: po (oral gavage); present in large amounts [2]. one time/day; 7 days Experimental Results: Median survival was observed to be longer in the VT-1598 15 mg/kg and 50 mg/kg groups (15 days and >21 days, respectively) than in the control group. The observed renal fungal burden in mice treated with the 15 mg/kg and 50 mg/kg doses (mean log10 CFU/g, 5.40 and 3.67, respectively) was lower than that in the vehicle control group. After 7 days of treatment, the average trough concentration in the 5 mg/kg group was 1.55 μg/mL, the average trough concentration in the 15 mg/kg group was 6.78 μg/mL, and the average trough concentration in the 50 mg/kg group was 14.2 μg/mL. Animal/Disease Models: Act1-deficient mice infected with Candida albicans[2] Doses: 3.2, 8 and 20 mg/kg Route of Administration: po (oral gavage); one time/day; 4 days Experimental Results: Plasma and tongue of Candida-infected mice The concentration is very high. For in vivo animal studies, a murine model of disseminated candidiasis is used. Female BALB/c mice (6-8 weeks old, n=10 per group) are infected via the lateral tail vein with 1-5 × 10^5 CFU of Candida albicans or Candida auris in 200 microL PBS. VT-1598 is administered orally by gavage at doses of 10-50 mg/kg once daily for 5-7 days, starting 1 hour post-infection. Control animals receive vehicle (0.5% methylcellulose) or fluconazole (10 mg/kg). Survival is monitored for 14 days. At study endpoint, kidneys are harvested, homogenized, and plated on Sabouraud dextrose agar for CFU quantification. Serum is collected for measurement of fungal biomarkers. |
| ADME/Pharmacokinetics |
VT-1598 is an orally bioavailable small molecule with a molecular weight of 584.52 g/mol. The compound exhibits good metabolic stability and low inhibition of human CYP450 enzymes (CYP2C9, CYP2C19, CYP3A4), minimizing drug-drug interaction potential. In preclinical species, it shows an elimination half-life of 6-12 hours, supporting once-daily dosing. The volume of distribution is moderate, with good tissue penetration including distribution to the brain. Oral bioavailability is approximately 50-80% in rodents. Detailed PK parameters can be obtained from the supplier.
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| Toxicity/Toxicokinetics |
Formal toxicology studies for VT-1598 indicate a favorable safety profile. In repeated-dose toxicity studies in rats, the compound is well tolerated at oral doses up to 100 mg/kg/day for 28 days with no significant adverse effects on body weight, food consumption, or clinical chemistry parameters. No target organ toxicity was identified at therapeutic doses. In genotoxicity assays, VT-1598 is negative in the Ames test and the in vivo micronucleus assay. Cardiovascular safety pharmacology shows no significant hERG inhibition (IC50 >30 microM), suggesting low risk of QT prolongation.
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| References |
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| Additional Infomation |
VT-1598 is a research compound and is not approved for clinical use. It is a tetrazole-based antifungal that represents the next generation of CYP51 inhibitors with improved selectivity for fungal over human enzymes. The compound also contains a click chemistry reagent (an alkyne group) that can participate in copper-catalyzed azide-alkyne cycloaddition reactions, potentially enabling conjugation to targeting moieties. VT-1598 is of particular interest for the treatment of multidrug-resistant Candida auris infections, for which limited therapeutic options exist. The compound is for research use only.
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| Molecular Formula |
C31H20F4N6O2
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|---|---|
| Molecular Weight |
584.523119926453
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| Exact Mass |
584.158
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| CAS # |
2089320-99-8
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| Related CAS # |
VT-1598 tosylate;2089321-00-4
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| PubChem CID |
126715974
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| Appearance |
Off-white to light yellow solid powder
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| Density |
1.3±0.1 g/cm3
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| Boiling Point |
770.9±70.0 °C at 760 mmHg
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| Flash Point |
420.0±35.7 °C
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| Vapour Pressure |
0.0±2.8 mmHg at 25°C
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| Index of Refraction |
1.614
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| LogP |
6.56
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
11
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| Rotatable Bond Count |
10
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| Heavy Atom Count |
43
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| Complexity |
1030
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| Defined Atom Stereocenter Count |
1
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| SMILES |
C1=CC(=CC=C1COC2=CC=C(C=C2)C#CC3=CN=C(C=C3)C([C@](CN4C=NN=N4)(C5=C(C=C(C=C5)F)F)O)(F)F)C#N
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| InChi Key |
UDGASIIGNCBLSI-PMERELPUSA-N
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| InChi Code |
InChI=1S/C31H20F4N6O2/c32-25-10-13-27(28(33)15-25)30(42,19-41-20-38-39-40-41)31(34,35)29-14-9-23(17-37-29)4-1-21-7-11-26(12-8-21)43-18-24-5-2-22(16-36)3-6-24/h2-3,5-15,17,20,42H,18-19H2/t30-/m0/s1
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| Chemical Name |
4-[[4-[2-[6-[(2R)-2-(2,4-difluorophenyl)-1,1-difluoro-2-hydroxy-3-(tetrazol-1-yl)propyl]pyridin-3-yl]ethynyl]phenoxy]methyl]benzonitrile
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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 (~171.08 mM)
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| Solubility (In Vivo) |
Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.
Injection Formulations
Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)(e.g. IP/IV/IM/SC) *Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution. Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline) Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil) Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals). View More
Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)] Oral Formulations
Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium) Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals). View More
Oral Formulation 3: Dissolved in PEG400 (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.7108 mL | 8.5540 mL | 17.1081 mL | |
| 5 mM | 0.3422 mL | 1.7108 mL | 3.4216 mL | |
| 10 mM | 0.1711 mL | 0.8554 mL | 1.7108 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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