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171228-49-2 molecular structure
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4-{4-[4-(4-{[(3R,5R)-5-(2,4-difluorophenyl)-5-(1H-1,2,4-triazol-1-ylmethyl)oxolan-3-yl]methoxy}phenyl)piperazin-1-yl]phenyl}-1-[(2S,3S)-2-hydroxypentan-3-yl]-4,5-dihydro-1H-1,2,4-triazol-5-one

ChemBase ID: 72597
Molecular Formular: C37H42F2N8O4
Molecular Mass: 700.7773864
Monoisotopic Mass: 700.3297083
SMILES and InChIs

SMILES:
c1(ccc(cc1)N1CCN(CC1)c1ccc(cc1)OC[C@@H]1CO[C@](C1)(c1ccc(cc1F)F)Cn1ncnc1)n1c(=O)n(nc1)[C@H]([C@H](C)O)CC
Canonical SMILES:
CC[C@H](n1ncn(c1=O)c1ccc(cc1)N1CCN(CC1)c1ccc(cc1)OC[C@@H]1CO[C@@](C1)(Cn1cncn1)c1ccc(cc1F)F)[C@@H](O)C
InChI:
InChI=1S/C37H42F2N8O4/c1-3-35(26(2)48)47-36(49)46(25-42-47)31-7-5-29(6-8-31)43-14-16-44(17-15-43)30-9-11-32(12-10-30)50-20-27-19-37(51-21-27,22-45-24-40-23-41-45)33-13-4-28(38)18-34(33)39/h4-13,18,23-27,35,48H,3,14-17,19-22H2,1-2H3/t26-,27+,35-,37-/m0/s1
InChIKey:
RAGOYPUPXAKGKH-XAKZXMRKSA-N

Cite this record

CBID:72597 http://www.chembase.cn/molecule-72597.html

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NAMES AND DATABASE IDS

NAMES AND DATABASE IDS

Names Database IDs
IUPAC name
4-{4-[4-(4-{[(3R,5R)-5-(2,4-difluorophenyl)-5-(1H-1,2,4-triazol-1-ylmethyl)oxolan-3-yl]methoxy}phenyl)piperazin-1-yl]phenyl}-1-[(2S,3S)-2-hydroxypentan-3-yl]-4,5-dihydro-1H-1,2,4-triazol-5-one
IUPAC Traditional name
posaconazole
4-{4-[4-(4-{[(3R,5R)-5-(2,4-difluorophenyl)-5-(1,2,4-triazol-1-ylmethyl)oxolan-3-yl]methoxy}phenyl)piperazin-1-yl]phenyl}-2-[(2S,3S)-2-hydroxypentan-3-yl]-1,2,4-triazol-3-one
Synonyms
2,5-Anhydro-1,3,4-trideoxy-2-C-(2,4-difluorophenyl)-4-[[4-[4-[4-[1-[(1S,2S)-1-ethyl-2-hydroxypropyl]-1,5-dihydro-5-oxo-4H-1,2,4-triazol-4-yl]phenyl]-1-piperazinyl]phenoxy]methyl]-1-(1H-1,2,4-triazol-1-yl)-D-threo-pentitol
Sch 56592
Noxafil
Posaconazole
CAS Number
171228-49-2
PubChem SID
162037522
PubChem CID
468595

DATA SOURCES

DATA SOURCES

All Sources Commercial Sources Non-commercial Sources
Data Source Data ID
PubChem 468595 external link

CALCULATED PROPERTIES

CALCULATED PROPERTIES

JChem
Rotatable Bonds 12  Lipinski's Rule of Five false 
Acid pKa 14.826501  H Acceptors
H Donor LogD (pH = 5.5) 5.394681 
LogD (pH = 7.4) 5.4060388  Log P 5.406185 
Molar Refractivity 200.7058 cm3 Polarizability 70.79972 Å3
Polar Surface Area 111.79 Å2

PROPERTIES

PROPERTIES

Physical Property Safety Information Product Information Bioassay(PubChem)
Solubility
Chloroform expand Show data source
DMSO expand Show data source
Methanol (Sparingly) expand Show data source
Apperance
White Solid expand Show data source
Melting Point
170-172°C expand Show data source
Storage Condition
-20°C expand Show data source
-20°C Freezer expand Show data source
MSDS Link
Download expand Show data source
Salt Data
Free Base expand Show data source
Certificate of Analysis
Download expand Show data source

DETAILS

DETAILS

Selleck Chemicals Selleck Chemicals TRC TRC
Selleck Chemicals - S1257 external link
Research Area
Description Infection
Biological Activity
Description Posaconazole (Noxafil) is a sterol C14ɑ demethylase inhibitor with an IC50 of 0.25 nM.
Targets C14ɑ demethylase
IC50 0.25 nM [1]
In Vitro Posaconazole has potent trypanocidal activity. Amiodarone acts synergistically with Posaconazole. Posaconazole also affects and disrupts Ca2+ homeostasis in T. cruzi. Posaconazole blocks the biosynthesis of ergosterol, which is essential for parasite survival. Posaconazole has a clear, dose-dependent effect on proliferation of the epimastigote (extracellular) stages, with a minimal inhibitory concentration of 20 nM and an IC50 of 14 nM. Against the clinically relevant intracellular amastigote form of the parasite, Posaconazole is even more potent. Posaconazole has the minimal inhibitory concentration and IC50 values of 3 nM and 0.25 nM. [1] Posaconazole is active against isolates of Candida and Aspergillus spp. that exhibit resistance to Fluconazole, Voriconazole, and Amphotericin B and is much more active than the other triazoles against zygomycetes. [2]
In Vivo Treatment of infected animals with amiodarone alone reduces parasitemia, increased survival 60 days pi (0% for untreated controls vs 40% for amiodarone-treated animals) and, when given in combination with Posaconazole, delays the development of parasitemia. [1] Coadministration of Posaconazole and Boost Plus increases drug exposure compared to the administration of Posaconazole alone in the fasted state. Food, particularly meals high in fat content, significantly increases Posaconazole bioavailability. Systemic exposure to Posaconazole increases 4- and 2.6-fold when it is consumed with a high-fat and nonfat meal, respectively. [3] Posaconazole and Amiodarone may constitute an effective anti-T. cruzi therapy with low side effect. [4] At twice-daily doses of ≥15 mg/kg of body weight, Posaconazole prolongs the survival of the mice and reduces tissue burden. [5]
Clinical Trials Posaconazole has entered in a phase II clinical trial in the treatment of mycoses.
Features Posaconazole is the most advanced candidate for the treatment of Chagas disease.
Protocol
Cell Assay [1]
Cell Lines Epimastigote form of T. cruzi amastigotes
Concentrations 0 nM -4 nM
Incubation Time 96 hours
Methods The epimastigote form of the parasite is cultivated in liver infusion tryptose medium, supplemented with 10% new born calf serum at 28 °C with strong (120 rpm) agitation. Cultures are initiated at a cell density of 2 × 106 epimastigotes/mL, and Posaconazole is added at a cell density of 0.5?1.0 × 107 epimastigotes/mL. Cell densities are measured by using an electronic particle counter as well as by direct counting with a hemocytometer. Cell viability is followed by Trypan blue exclusion, using light microscopy. Amastigotes are cultured in Vero cells maintained in minimal essential medium supplemented with 1% fetal calf serum in a humidified atmosphere (95% air?5% CO2) at 37 °C. Cells are infected with 10 tissue culture-derived trypomastigotes per cell for 2 hours and then washed three times with phosphate-buffered saline (PBS) to remove nonadherent parasites. Fresh medium with and without Posaconazole is added, and the cells are incubated for 96 hours with a medium change at 48 hours. The percent of infected cells and the numbers of parasites per cell are determined directly using light microscopy, and a statistical analysis of the results is carried out. IC50 values are calculated by nonlinear regression, using the program GraFit. Fractional inhibitory concentrations (FIC) are calculated. Cytoplasmic free Ca2+ concentrations in control and drug-treated extracellular epimastigotes are determined by fluorimetric methods using Fura-2. Subcellular Ca2+ levels and mitochondrial membrane potentials are monitored on individual Vero cells infected with T. cruzi amastigotes by using time-scan confocal microscopy. Briefly, Vero cells heavily infected (72 hours) with T. cruzi amastigotes are plated onto 22 × 40 mm glass coverslips (0.15 mm thickness) and incubated simultaneously with 10 μM cell-permeant Rhod-2 and 10 μg/mL Rhodamine-123 for 50 minutes at 37 °C in culture medium and then washed and incubated with Ringer's solution, with or without amiodarone. Under the conditions used fluorescence of Rhod-2 comes mainly from intracellular Ca2+-rich compartments, like mitochondria, since its low affinity for Ca2+ limits its fluorescence in the Ca2+-poor cytoplasm of the Vero cells or amastigotes. Rhodamine-123 is a mitochondrion-specific cationic dye, which distributes across the inner mitochondrial membranes strictly according to their membrane potential.
Animal Study [1]
Animal Models Female NMRI?IVIC mice with acute Chagas' disease
Formulation Control
Doses 20 mg/kg/d
Administration Oral
References
[1] Benaim G, et al. J Med Chem. 2006, 49(3), 892-389.
[2] Sabatelli F, et al. Antimicrob Agents Chemother. 2006, 50(6), 2009-2015.
[3] Sansone-Parsons A, et al. Antimicrob Agents Chemother. 2006, 50(5), 1881-1883.
[4] Veiga-Santos P, et al. Int J Antimicrob Agents. 2012, 40, 61-71.
[5] Sun QN, et al. Antimicrob Agents Chemother. 2002, 46(7), 2310-2312.
Toronto Research Chemicals - P689600 external link
Orally active triazole antifungal.

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