Posaconazole-hydrate-SCH56592-hydrate-DataSheet-生命科學(xué)試劑-MedChemExpress

1、Hotline: 400-820-3792Inhibitors Agonists Screening Librarieswww.MedChemEPosaconazole hydrateCat. No.: HY-17373ACAS No.: 1198769-38-8Synonyms: SCH56592 hydrate分式: CHFNO分量: 718.79作靶點(diǎn): Fungal作通路: Anti-infection儲存式: Please store the product under the recommended conditions inthe COA.BIOLOGICAL ACTIVITY物

2、活性 Posaconazole合物是Lanosterol-14去甲基酶抑制劑，IC50為0.25 nM。IC50 & Target antifungal體外研究 Posaconazole has potent trypanocidal activity. Amiodarone acts synergistically with Posaconazole.Posaconazole also affects and disrupts Ca2+ homeostasis in T. cruzi. Posaconazole blocks the biosynthesisof ergosterol, wh

3、ich is essential for parasite survival. Posaconazole has a clear, dose-dependent effect onproliferation of the epimastigote (extracellular) stages, with a minimal inhibitory concentration of 20 nM andan IC50 of 14 nM. Against the clinically relevant intracellular amastigote form of the parasite, Pos

4、aconazoleis even more potent. Posaconazole has the minimal inhibitory concentration and IC50 values of 3 nM and0.25 nM 1. Posaconazole is active against isolates of Candida and Aspergillus spp. that exhibit resistanceto Fluconazole, Voriconazole, and Amphotericin B and is much more active than the o

5、ther triazoles againstzygomycetes 2.體內(nèi)研究Treatment of infected animals with amiodarone alone reduces parasitemia, increases survival 60 days pi (0%for untreated controls vs 40% for amiodarone-treated animals) and, when given in combination withPosaconazole, delays the development of parasitemia 1. Co

6、administration of Posaconazole and Boost Plusincreases 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 exposureto Posaconazole increases 4- and 2.6-fold

7、 when it is consumed with a high-fat and nonfat meal, respectively3. Posaconazole and Amiodarone may constitute an effective anti-T. cruzi therapy with low side effect 4.1/3 Master of Small Molecules 您邊的抑制劑師www.MedChemEAt twice-daily doses of 15 mg/kg of body weight, Posaconazole prolongs the surviv

8、al of the mice andreduces tissue burden 5.PROTOCOLCell Assay 1 The epimastigote form of the parasite is cultivated in liver infusion tryptose medium,12 supplemented with10% new born calf serum at 28C with strong (120 rpm) agitation. Cultures are initiated at a cell density of2106 epimastigotes mL-1,

9、 and drugs are added at a cell density of 0.5-1.0 107 epimastigotes mL-1. Celldensities are measured by using an electronic particle counter as well as by direct counting with ahemocytometer. Cell viability is followed by Trypan blue exclusion, using light microscopy. Amastigotes arecultured in Vero

10、 cells maintained in minimal essential medium supplemented with 1% fetal calf serum in ahumidified atmosphere (95% air-5% CO2) at 37C, as described previously. Cells are infected with 10 tissueculture-derived trypomastigotes per cell for 2 h and then washed three times with phosphate-buffered saline

11、(PBS) to remove nonadherent parasites. Fresh medium with and without drugs is added, and the cells areincubated for 96 h with a medium change at 48 h. The percent of infected cells and the numbers of parasitesper cell are determined directly using light microscopy, and a statistical analysis of the

12、results is carried outas described previously. IC50 values are calculated by nonlinear regression, using the program GraFit.Cytoplasmic free Ca2+ concentrations in control and drug-treated extracellular epimastigotes are determinedby fluorimetric methods, using Fura-2, again as described previously.

13、 Subcellular Ca2+ levels andmitochondrial membrane potentials are monitored on individual Vero cells infected with T. cruzi amastigotesby using time-scan confocal microscopy, as described in detail elsewhere. Briefly, Vero cells heavily infected(72 h) with T. cruzi amastigotes are plated onto 2240 m

14、m glass coverslips (0.15 mm thickness) andincubated simultaneously with 10 M cell-permeant Rhod-2 and 10 g/mL Rhodamine-123 for 50 min at37C in culture medium and then washed and incubated with Ringers solution, with or without amiodarone.Under the conditions used, fluorescence of Rhod-2 comes mainl

15、y from intracellular Ca2+-rich compartments,like mitochondria, since its low affinity for Ca2+ limits its fluorescence in the Ca2+-poor cytoplasm of the Verocells or amastigotes. Rhodamine-123 is a mitochondrion-specific cationic dye, which distributes across theinner mitochondrial membranes strictl

16、y according to their membrane potential.MCE has not independently confirmed the accuracy of these methods. They are for reference only.Animal In vivo studies are carried out by using the murine model of acute Chagas disease in which female NMRI-Administration 1 IVIC mice (20-25 g) are infected with

17、105 or 103 bloodstream trypomastigotes and drug treatment is started24 h later. Treatments are given for 30 consecutive days at 20 mg/kg/d for posaconazole (30 doses) and/orat 50 mg/kg every other day for amiodarone (15 doses). Negative controls (i.e. untreated animals) receiveonly the vehicle, whil

18、e positive controls are treated with the anti-T. cruzi compound, nifurtimox, at 50 mg/kg/dfor 30 days. Survival is followed daily and parasitemia weekly, the latter by direct microscopic examination.Animals are observed for 60 days postinfection, after which time parasitological cures are evaluated

19、by usinga combination of hemoculture, xenodiagnosis, and blood PCR tests. For PCR, primers TcZ1 (5-CGAGCTCTTGCCCACACGGGTGCT-3) and TcZ2 (5-CCTCCAAGCAGCGGATAGTTCAGG-3) are used todetect T. cruzi satellite DNA (TcZ DNA).MCE has not independently confirmed the accuracy of these methods. They are for re

20、ference only.2/3 Master of Small Molecules 您邊的抑制劑師www.MedChemE戶使本產(chǎn)品發(fā)表的科研獻(xiàn) Med Mycol. 2018 Jun 1;56(4):452-457.See more customer validations on HYPERLINK / www.MedChemEREFERENCES1. Benaim G, et al. Amiodarone has intrinsic anti-Trypanosoma cruzi activity and acts synergistically with posaconazole. J

21、Med Chem.2006 Feb 9;49(3):892-9.2. Sabatelli F, et al. In vitro activities of posaconazole, fluconazole, itraconazole, voriconazole, and amphotericin B against a largecollection of clinically important molds and yeasts. Antimicrob Agents Chemother. 2006 Jun;50(6):2009-15.3. Sansone-Parsons A, et al. Effe