3D Mol Similar

Voriconazole

: Iupac Name：(2R,3S)-2-(2,4-difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-1-(1,2,4-triazol-1-yl)butan-2-ol; CAS No.: 137234-62-9; Molecular Weight：349.317; Modify Date.: 2022-11-22 16:55; Introduction: Voriconazole was introduced in the US for the treatment of acute invasive aspergillosis,candidosis and other emerging fungal infections seen in immuno compromised patients. Itcan be synthesized in 3 steps by reaction of readily available 6-( 1 -bromoethyl)-4-chloro-5fluoropyrimidine with I-(2,4-difluorophenyl)-2-(1,2,4-triazol-I-yl) ethanone in the presenceof zinc metal. The resulting racemic mixture was submitted to a reductive dechlorinationstep followed by resolution with (R)-camphorsulfonic acid. Voriconazole is structurallyrelated to fluconazole (Pfizer, diflucan?) and acts by inhibiting the cytochrome P450-dependant enzyme 14a-sterol demethylase of ergosterol synthesis (thereby resulting inthe formation of a cell membrane with abnormal characteristics and accumulation of toxicsterol intermediates). Voriconazole was more active than itraconazole and fluconazoleagainst Cryptococcus neoformans and a variety of Candidas species such as C. albicans,C. glabrata C. krusei. It also exhibits similar or superior activity compared to amphotericinB and itraconazole against filamentous fungi such as Aspergillus, an important pathogenwhich is not susceptible to fluconazole. In clinical trials, voriconazole was effective in thetreatment of neutropenic patients with acute invasive aspergillosis, non-neutropenicpatients with chronic invasive aspergillosis and HIV patients with oropharyngealcandidiasis. Voriconazole is available as oral or intravenous formulations. Following oraladministration, absorption is rapid and the bioavailability is greater than 80%. Voriconazoleexhibits non linear pharmacokinetics, a large volume of distribution (2 L/Kg) and arelatively short half-life (6 h). It was extensively metabolized via hepatic cytochrome P450and has a drug interactions potential similar to itraconazole. Voriconazole was generallywell tolerated, the most common treatment-related adverse events were transient visualdisturbances. View more+

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1. Names and Identifiers

: 1.1 Name; Voriconazole; 1.2 Synonyms; (2R,3S)-2-(2,4-difluorophényl)-3-(5-fluoropyrimidin-4-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol (2R,3S)-2-(2,4-Difluorophenyl)-3 (2R,3S)-2-(2,4-Difluorophenyl)-3-(5-fluoro-4-pyrimidinyl)-1-(1H-1,2,4-triazol-1-yl)-2-butanol (2R,3S)-2-(2,4-difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol (2R,3S)-2-(2,4-Difluorphenyl)-3-(5-fluorpyrimidin-4-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol (2S,3R)-3-(6-Chloro-5-fluoro-4-pyrimidinyl)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-butanol hydrochloride (2S,3R)-3-(6-Chloro-5-fluoro-4-pyrimidinyl)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-butanol hydrochloride (1:1) (aR,bS)-a-(2,4-difluorophenyl)-5-fluoro-b-methyl-a-(1H-1,2,4-triazol-1-ylmethyl)-4-pyrimidineethanol (R-(R*,S*))-a-(2,4-difluorophenyl)-5-fluoro-b-methyl-a-(1H-1,2,4-triazol-1-ylmethyl)-4-pyrimidineethanol 2-(2,4-difluorophenyl)-3-(5-fluoro-4-pyrimidinyl)-1-(1,2,4-triazol-1-yl)butan-2-ol 2-(2,4-difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-1-(1,2,4-triazol-1-yl)butan-2-ol 4-Pyrimidineethanol, 6-chloro-α-(2,4-difluorophenyl)-5-fluoro-Β-methyl-α-(1H-1,2,4-triazol-1-ylmethyl)-, (αS,ΒR)-, hydrochloride (1:1) 4-Pyrimidineethanol, α-(2,4-difluorophenyl)-5-fluoro-Β-methyl-α-(1H-1,2,4-triazol-1-ylmethyl)-, (αR,ΒS)- EINECS 200-261-5 MFCD00905717 Vfend Voriconazole solution Voriconazole 2-(2,4-Difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol Voriconazole(UK 109496) Vorionazole; View all

1.3 CAS No.: 137234-62-9

1.4 CID: 71616

1.5 EINECS(EC#): 629-701-5

1.6 Molecular Formula: C16H14F3N5O (isomer)

1.7 Inchi: InChI=1S/C16H14F3N5O/c1-10(15-14(19)5-20-7-22-15)16(25,6-24-9-21-8-23-24)12-3-2-11(17)4-13(12)18/h2-5,7-10,25H,6H2,1H3/t10-,16+/m0/s1

1.8 InChIkey: BCEHBSKCWLPMDN-MGPLVRAMSA-N

1.9 Canonical Smiles: CC(C1=NC=NC=C1F)C(CN2C=NC=N2)(C3=C(C=C(C=C3)F)F)O

1.10 Isomers Smiles: C[C@@H](C1=NC=NC=C1F)[C@](CN2C=NC=N2)(C3=C(C=C(C=C3)F)F)O

2. Properties

2.1 Density: 1.42

2.1 Melting point: 127-130°C

2.1 Boiling point: 508.6°C at 760 mmHg

2.1 Refractive index: 1.616

2.1 Flash Point: 261.4°C

2.1 PSA: 76.72000

2.1 logP: 2.17690

2.1 Solubility: DMSO: >20mg/mL

2.2 Appearance: Solid

2.3 Storage: Store at +4°C

2.4 Chemical Properties: Cyrstalline Solid

2.5 pKa: 11.54±0.29(Predicted)

2.6 Water Solubility: DMSO: >20mg/mL

2.7 StorageTemp: 2-8°C

3. Use and Manufacturing

3.1 Definition: ChEBI: A triazole-based antifungal agent used for the treatment of esophageal candidiasis, invasive pulmonary aspergillosis, and serious fungal infections caused by Scedosporium apiospermum and Fusarium spp. It is an inhibitor of cytochrme P450 2C9 (CYP2C9) and CYP3A4.

3.2 Usage: broad-spectrum antifungal

4. Safety and Handling

4.1 Symbol: GHS02, GHS06, GHS08

4.1 Hazard Codes: Xn;

4.1 Signal Word: Danger

4.1 Risk Statements: R22;R36/38

4.1 Safety Statements: S26;S36

4.1 Packing Group: III

4.1 Hazard Class: 6.1

4.1 Hazard Declaration: H225-H301 + H311 + H331-H370

4.1 RIDADR: OTH

4.1 Caution Statement: P210-P260-P280-P301 + P310-P311

4.1 WGK Germany: 3

4.1 RTECS: UV9145000

5. MSDS

2.Hazard identification

2.1 Classification of the substance or mixture

no data available

2.2 GHS label elements, including precautionary statements

Pictogram(s)	no data available
Signal word	no data available
Hazard statement(s)	no data available
Precautionary statement(s)
Prevention	no data available
Response	no data available
Storage	no data available
Disposal	no data available

2.3 Other hazards which do not result in classification

no data available

View all

6. Synthesis Route

137234-62-9Total: 18 Synthesis Route

759-67-1 46 Suppliers

137234-62-9 432 Suppliers

Literatures:
Bioorganic and Medicinal Chemistry Letters, , vol. 6, # 16 p. 2031 - 2036
Yield: null

51336-94-8 123 Suppliers

137234-62-9 432 Suppliers

Literatures:
WO2011/96697 A2, ;
Yield: null

86404-63-9 187 Suppliers

137234-62-9 432 Suppliers

Literatures:
WO2014/60900 A1, ;
Yield: null

View all

7. Precursor and Product

precursor:

188416-28-6

1237497-00-5

1289559-75-6

1289559-65-4

321589-01-9

1289559-66-5

86404-63-9

137234-85-6

848469-32-9

759-67-1

1237496-99-9

137234-74-3

188416-34-4

51336-94-8

188416-35-5

906451-64-7

182230-43-9

137234-87-8

View all

8. Other Information

8.0 Merck: 14,10033

8.1 Product description: Voriconazole is a broad-spectrum triazole antifungal ,it is primarily used for the treatment of progressive, possibly life-threatening infections in immune deficiency patients. Indications include: immunosuppressed patients with severe fungal infections, acute invasive aspergillosis (the most common pathogen is Aspergillus fumigatus, followed by A. flavus, Aspergillus niger and Aspergillus soil), severe invasive infections caused by fluconazole-resistant Candida (including C. krusei) severe infection caused by Foot actinomycetes bacteria genus and Fusarium bacteria genus . Moderate to severe renal insufficiency is administered intravenously paying caution.

8.2 Pharmacological interactions: Combination With the CYP3A4 substrates, terfenadine, sirolimus, astemizole, cisapride, pimozide or quinidine , can increase blood concentrations of this drug, leading to QT prolongation, and occasionally torsades de pointes ventricular tachycardia.
Combination With Rifampicin, rifabutin, efavirenz, ritonavir (each 400mg, once every 12 hours), carbamazepine and phenobarbital, can significantly lower blood concentrations of voriconazole.
Combination with ergot alkaloids (ergotamine, dihydroergotamine) plasma concentrations of ergot drugs can cause increased ergot poisoning.

8.3 Uses: broad-spectrum antifungal

8.4 Chemical Properties: Cyrstalline Solid

8.5 Uses: An antifungal (systemic). An ergosterol biosynthesis inhibitor.

8.6 Uses: antibacterial

8.7 Uses: An antifungal. An Ergosterol Biosynthesis inhibitor

8.8 Definition: ChEBI: A triazole-based antifungal agent used for the treatment of esophageal candidiasis, invasive pulmonary aspergillosis, and serious fungal infections caused by Scedosporium apiospermum and Fusarium spp. It is an inhibitor of cytochr me P450 2C9 (CYP2C9) and CYP3A4.

8.9 Uses: Voriconazole is a triazole, antifungal agent that inhibits a broad range of pathogenic yeasts, including Candida (MIC = 0.03-8 μg/ml), and filamentous fungi such as Aspergillus, Scedosporium, and Fusarium. Its inhibitory action results from its ability to inhibit the synthesis of ergosterol, the major sterol of the fungal cell membrane.

8.10 Brand name: Vfend (Pfizer).

8.11 Biological Activity: Triazole antifungal agent. Displays potent activity against Candida , Cryptococcus and Aspergillus species.

8.12 Target: Value

8.13 Pharmacological interactions: Combination With the CYP3A4 substrates, terfenadine, sirolimus, astemizole, cisapride, pimozide or quinidine , can increase blood concentrations of this drug, leading to QT prolongation, and occasionally torsades de pointes ventricular tachycardia.
Combination With Rifampicin, rifabutin, efavirenz, ritonavir (each 400mg, once every 12 hours), carbamazepine and phenobarbital, can significantly lower blood concentrations of voriconazole.
Combination with ergot alkaloids (ergotamine, dihydroergotamine) plasma concentrations of ergot drugs can cause increased ergot poisoning.

8.14 Description: Voriconazole was introduced in the US for the treatment of acute invasive aspergillosis, candidosis and other emerging fungal infections seen in immuno compromised patients. It can be synthesized in 3 steps by reaction of readily available 6-( 1 -bromoethyl)-4-chloro-5 fluoropyrimidine with I-(2,4-difluorophenyl)-2-(1,2,4-triazol-I-yl) ethanone in the presence of zinc metal. The resulting racemic mixture was submitted to a reductive dechlorination step followed by resolution with (R)-camphorsulfonic acid. Voriconazole is structurally related to fluconazole (Pfizer, diflucan^?) and acts by inhibiting the cytochrome P450- dependant enzyme 14a-sterol demethylase of ergosterol synthesis (thereby resulting in the formation of a cell membrane with abnormal characteristics and accumulation of toxic sterol intermediates). Voriconazole was more active than itraconazole and fluconazole against Cryptococcus neoformans and a variety of Candidas species such as C. albicans, C. glabrata C. krusei. It also exhibits similar or superior activity compared to amphotericin B and itraconazole against filamentous fungi such as Aspergillus, an important pathogen which is not susceptible to fluconazole. In clinical trials, voriconazole was effective in the treatment of neutropenic patients with acute invasive aspergillosis, non-neutropenic patients with chronic invasive aspergillosis and HIV patients with oropharyngeal candidiasis. Voriconazole is available as oral or intravenous formulations. Following oral administration, absorption is rapid and the bioavailability is greater than 80%. Voriconazole exhibits non linear pharmacokinetics, a large volume of distribution (2 L/Kg) and a relatively short half-life (6 h). It was extensively metabolized via hepatic cytochrome P450 and has a drug interactions potential similar to itraconazole. Voriconazole was generally well tolerated, the most common treatment-related adverse events were transient visual disturbances.; View all

8.15 Originator: Pfizer (UK)

8.16 Indications: Voriconazole (Vfend), a derivative of fluconazole, is a second-generation triazole that has improved antifungal activity against Aspergillus and Fusarium spp., P. boydii, Penicillium marneffei, and fluconazole-resistant Candida spp. Like fluconazole, voriconazole has high oral bioavailability and good cerebrospinal fluid penetration, but unlike fluconazole, it undergoes extensive hepatic metabolism and is highly protein bound. No significant amount of bioactive drug is excreted into the urine. Dosage reduction is necessary with severe hepatic insufficiency but not with renal insufficiency.

8.17 Manufacturing Process: A solution of 3-(4-chloro-5-fluoropyrimidin-6-yl)-2-(2,4-difluorophenyl)-1-(1H- 1,2,4-triazol-1-yl)butan-2-ol, enantiomeric pair B (0.307 g, 0.8 mmol) in ethanol (20 ml) was hydrogenated at atmospheric pressure and at room temperature in the presence of 10% palladium-on-charcoal (30 mg) and sodium acetate (0.082 g, 1 mmol). After 5 hours a further 10 mg of 10% palladium-on-charcoal was added and hydrogenation was continued for an additional 1 hour. The catalyst was removed by filtration and the filtrate was concentrated in vacuo. 'Flash' chromatography of the residue on silica using 97:3 ethyl acetate/methanol as the eluent provided, after combination and evaporation of appropriate fractions and trituration with diethyl ether, the 2- (2,4-difluorophenyI)-3-(5-fluoropyrimidin-4-yl)-1-(1H-1,2,4-triazol-I-yl)butan- 2-ol enantiomeric pair B, (0.249 g, 89%), m.p. 127°C.
2-(2,4-DifluorophenyI)-3-(5-fluoropyrimidin-4-yl)-1-(1H-1,2,4-triazol-1- yl)butan-2-ol enantiomeric pair A was prepared by a similar method using 3- (4-chloro-5-fluoropyrimidin-6-yl)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1- yl)butan-2-ol, enantiomeric pair A as a starting material. This gave the product with m.p. 137°C.; View all

8.18 Therapeutic Function: Antifungal

8.19 Antimicrobial activity: The spectrum includes most fungi that cause human disease: dimorphic fungi (Blast. dermatitidis, Coccidioides spp., Hist. capsulatum, Paracocc. brasiliensis, Pen. marneffei and Spor. schenckii), molds (Aspergillus spp., Fusarium spp. and Scedosporium spp.), dematiaceous fungi and yeasts (Candida spp., Cryptococcus spp. and Trichosporon spp.).

8.20 Acquired resistance: Some fluconazole- and itraconazole-resistant strains of Candida and Aspergillus spp. show reduced susceptibility to voriconazole.

8.21 General Description: Voriconazole is a synthetically prepared, broad-spectrum triazole derivative of fluconazole, which shows in vitro activity against many yeasts and a broad-spectrum of mold and dermatophyte isolates. Its mode of action involves the inhibition of cytochrome P450 (CYP)-dependent enzyme, 14-α-sterol demethylase, and hence it is involved in disrupting the cell membrane and terminate the fungal growth.

9. Computational chemical data

Molecular Weight: 349.317g/mol
Molecular Formula: C₁₆H₁₄F₃N₅O
Compound Is Canonicalized: True
XLogP3-AA: 1.5
Exact Mass: 349.11504457
Monoisotopic Mass: 349.11504457
Complexity: 448
Rotatable Bond Count: 5
Hydrogen Bond Donor Count: 1
Hydrogen Bond Acceptor Count: 8
Topological Polar Surface Area: 76.7
Heavy Atom Count: 25
Defined Atom Stereocenter Count: 2
Undefined Atom Stereocenter Count: 0
Defined Bond Stereocenter Count: 0
Undefined Bond Stereocenter Count: 0
Isotope Atom Count: 0
Covalently-Bonded Unit Count: 1
CACTVS Substructure Key Fingerprint: AAADccB7oYAAAAAAAAAAAAAAAAAAAWAAAAA8QAAAAAAAAAAB8AAAHwAICAAADUzBngw/kJYIEgCiAzRnZACSgCsxgKAd2CA4TJiKLqLA2dGEdAhuwANY2CeQ0OIOgAAAAAAAAAAAAAAAAAAAAAAAAAAAAA==

10. Question & Answer

What is Voriconazole and its Role in Treating Fungal Infections? Jun 16 2024
Voriconazole, a broad‐spectrum triazole, is effective against various yeasts and moulds, including Aspergillus species. It can be administered orally and intravenously. Approved by the US FDA in May ..
What are the characteristics and uses of Voriconazole? May 09 2024
Voriconazole is a broad-spectrum triazole antifungal drug, mainly used for the treatment of severe fungal infections (such as Candida and Aspergillus), and can also prevent fungal infections in high-..
What is Voriconazole and how does it work? Nov 22 2022
Voriconazole is a novel second-generation triazole broad-spectrum antifungal drug used to treat invasive aspergillosis, candidemia in neutropenic patients, and serious invasive infections caused by fl..
What are the benefits, side effects, and cost of Voriconazole? Sep 21 2022
Voriconazole is a broad-spectrum triazole antifungal drug that inhibits the activity of lanosterol 14α-demethylase and 24-methylene-dihydrolanosterol demethylase, enzymes involved in the synthesis of..

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