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Isavuconazonium sulfate (formerly BAL-8557; BAL8557; isavuconazole; Cresemba), the sulfate salt of Isavuconazonium, is the prodrug of isavuconazole (BAL4815) which is an approved triazole-based antifungal drug. It was approved by the U.S. FDA on March 6, 2015 for the treatment of invasive candidiasis/aspergillosis and invasive mucormycosis. Isavuconazole (BAL-4815; RO-0094815) is a water-soluble triazole and the active metabolite of Isavuconazonium. It is a novel and potent inhibitor of CYP3A4 with broad-spectrum antifungal activity.
Physicochemical Properties
| Molecular Formula | C35H36F2N8O9S2 |
| Molecular Weight | 814.83500 |
| Exact Mass | 814.201 |
| Elemental Analysis | C, 51.59; H, 4.45; F, 4.66; N, 13.75; O, 17.67; S, 7.87 |
| CAS # | 946075-13-4 |
| Related CAS # | 338990-84-4 (chloride);497235-79-7 (chloride HCl);742049-41-8 (cation);946075-13-4 (sulfate); |
| PubChem CID | 72196309 |
| Appearance | White to off-white solid powder |
| LogP | 5.06 |
| Hydrogen Bond Donor Count | 3 |
| Hydrogen Bond Acceptor Count | 17 |
| Rotatable Bond Count | 15 |
| Heavy Atom Count | 56 |
| Complexity | 1290 |
| Defined Atom Stereocenter Count | 2 |
| SMILES | S(O)([O-])(=O)=O.[C@@](C1C=C(F)C=CC=1F)(O)(CN1N=C[N+](C(C)OC(=O)N(C2N=CC=CC=2COC(=O)CNC)C)=C1)[C@H](C1SC=C(C2C=CC(C#N)=CC=2)N=1)C |
| InChi Key | LWXUIUUOMSMZKJ-KLFWAVJMSA-M |
| InChi Code | InChI=1S/C35H35F2N8O5S.H2O4S/c1-22(33-42-30(18-51-33)25-9-7-24(15-38)8-10-25)35(48,28-14-27(36)11-12-29(28)37)19-45-21-44(20-41-45)23(2)50-34(47)43(4)32-26(6-5-13-40-32)17-49-31(46)16-39-3;1-5(2,3)4/h5-14,18,20-23,39,48H,16-17,19H2,1-4H3;(H2,1,2,3,4)/q+1;/p-1/t22-,23?,35+;/m0./s1 |
| Chemical Name | 1-((2R,3R)-3-(4-(4-cyanophenyl)thiazol-2-yl)-2-(2,5-difluorophenyl)-2-hydroxybutyl)-4-(1-((methyl(3-(((methylglycyl)oxy)methyl)pyridin-2-yl)carbamoyl)oxy)ethyl)-1H-1,2,4-triazol-4-ium hydrogen sulfate |
| Synonyms | BAL8557;BAL 8557; Isavuconazonium sulfate; BAL-8557; Cresemba. |
| HS Tariff Code | 2934.99.9001 |
| 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) |
Biological Activity
| ln Vitro | With EC50 values of 0.001 μM, 0.037 μM, and 0.024 μM, respectively, isavuconazonium sulfate (0.006 nM–50 μM) suppresses the trophoblast activity of three T4-genotype strains of Acanthamoeba (Ma, CDC:V240, and MEEI 0184). Furthermore, three tested strains, Ma, CDC:V240, and MEEI 0184, showed vesicle-extinguishing activity at (100–200 μM; 48 h), with mean minimum vesicle extinguishing concentrations (MCC) of 167.1 μM, 136.0 μM, and 187.5 μM, respectively[2]. |
| ln Vivo | Isavuconazonium sulfate (215 mg/kg; p.o. ; three times daily for four days) exhibits anti-R.delemar virus activity in mucormycosis-infected ICR mice[4]. |
| Animal Protocol |
Animal Model: Neutropenic male ICR mouse model of intratracheal infection[4] Dosage: 215 mg/kg Administration: Oral gavage (p.o.); Three times a day for 4 days. Result: increased the survival rate of R. delemar-infected neutropenic mice. decreased amount of fungi in the mice's brains and lungs. |
| References |
[1]. Isavuconazonium sulfate: a new agent for the treatment of invasive aspergillosis and invasive mucormycosis[J]. Expert review of clinical pharmacology, 2016, 9(7): 887-897. [2]. Evaluation of Amebicidal and Cysticidal Activities of Antifungal Drug Isavuconazonium Sulfate against Acanthamoeba T4 Strains. Pharmaceuticals (Basel). 2021 Dec 11;14(12):1294. [3]. Isavuconazonium sulfate: a novel antifungal agent[J]. Current Fungal Infection Reports, 2015, 9: 302-313. [4]. Isavuconazole therapy protects immunosuppressed mice from mucormycosis[J]. Antimicrobial agents and chemotherapy, 2014, 58(4): 2450-2453. [5]. In Vitro Activity of Isavuconazole against Rasamsonia Species.Antimicrob Agents Chemother.2016 Oct 21;60(11):6890-6891. |
| Additional Infomation |
Isavuconazonium sulfate is an azaheterocycle sulfate salt that is a prodrug for isavuconazole, an antifungal agent used for the treatment of invasive aspergillosis and invasive mucormycosis. It has a role as a prodrug, an ergosterol biosynthesis inhibitor, an EC 1.14.13.70 (sterol 14alpha-demethylase) inhibitor and an orphan drug. It is an azaheterocycle sulfate salt, a triazole antifungal drug and a conazole antifungal drug. It contains an isavuconazonium. Isavuconazonium Sulfate is the sulfate ester form of isavuconazonium, a prodrug of the triazole antifungal agent isavuconazole, with broad-spectrum antifungal activity. Upon administration, isavuconazonium sulfate is hydrolyzed by plasma esterases to yield the active moiety isavuconazole. Isavuconazole binds to and inhibits the fungal cytochrome P450 family enzyme lanosterol 14-alpha-demethylase (CYP51), which catalyzes the demethylation of lanosterol to yield ergosterol, an important component of the fungal cell membrane. Inhibition of CYP51 leads to a decrease in fungal ergosterol production and disrupts synthesis of the fungal cell membrane, which decreases membrane integrity, increases cell membrane permeability and promotes the loss of essential intracellular elements. This results in fungal cell lysis and death. See also: Isavuconazole (has active moiety). Drug Indication Treatment of invasive aspergillosis, Treatment of mucormycosis Treatment of Candida infections |
Solubility Data
| Solubility (In Vitro) |
DMSO : 100 mg/mL ( 122.72 mM ) Water : 0.5~100 mg/mL (~0.61 mM ) Ethanol : 100 mg/mL |
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.08 mg/mL (2.55 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 20.8 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: ≥ 2.08 mg/mL (2.55 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 20.8 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. Solubility in Formulation 3: ≥ 2.08 mg/mL (2.55 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 20.8 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly. Solubility in Formulation 4: 10% DMSO+40% PEG300+5% Tween-80+45% Saline: ≥ 2.08 mg/mL (2.55 mM) Solubility in Formulation 5: 100 mg/mL (122.72 mM) in PBS (add these co-solvents sequentially from left to right, and one by one), clear solution; with ultrasonication. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.2272 mL | 6.1362 mL | 12.2723 mL | |
| 5 mM | 0.2454 mL | 1.2272 mL | 2.4545 mL | |
| 10 mM | 0.1227 mL | 0.6136 mL | 1.2272 mL |