Ketoconazole

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Ketoconazole
Category Bioactive by-products
Catalog number BBF-04031
CAS 65277-42-1
Molecular Weight 531.43
Molecular Formula C26H28Cl2N4O4
Purity >98%

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Description

Ketoconazole inhibits cyclosporine oxidase and testosterone 6 beta-hydroxylase with IC50 of 0.19 mM and 0.22 mM, respectively. It is used primarily to treat fungal infections.

Specification

Synonyms Kuric; Nizoral; (2R,4S)-ketoconazole; Fungarest
Storage Store at 2-8°C
IUPAC Name 1-[4-[4-[[(2R,4S)-2-(2,4-dichlorophenyl)-2-(imidazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]piperazin-1-yl]ethanone
Canonical SMILES CC(=O)N1CCN(CC1)C2=CC=C(C=C2)OCC3COC(O3)(CN4C=CN=C4)C5=C(C=C(C=C5)Cl)Cl
InChI InChI=1S/C26H28Cl2N4O4/c1-19(33)31-10-12-32(13-11-31)21-3-5-22(6-4-21)34-15-23-16-35-26(36-23,17-30-9-8-29-18-30)24-7-2-20(27)14-25(24)28/h2-9,14,18,23H,10-13,15-17H2,1H3/t23-,26-/m0/s1
InChI Key XMAYWYJOQHXEEK-OZXSUGGESA-N
Source Synthetic

Properties

Appearance White to Off-white Solid
Application For the treatment of fungal infections.
Antibiotic Activity Spectrum fungi
Boiling Point 753.4°C at 760 mmHg
Melting Point 148-150°C
Density 1.38 g/cm3
Solubility Soluble in DMSO
LogP 4.35

Toxicity

Carcinogenicity No indication of carcinogenicity to humans (not listed by IARC).
Mechanism Of Toxicity Ketoconazole interacts with 14-α demethylase, a cytochrome P-450 enzyme necessary for the conversion of lanosterol to ergosterol. This results in inhibition of ergosterol synthesis and increased fungal cellular permeability. Other mechanisms may involve the inhibition of endogenous respiration, interaction with membrane phospholipids, inhibition of yeast transformation to mycelial forms, inhibition of purine uptake, and impairment of triglyceride and/or phospholipid biosynthesis. Ketoconazole can also inhibit the synthesis of thromboxane and sterols such as aldosterone, cortisol, and testosterone.
Toxicity Hepatotoxicity, LD50: 86 mg/kg (orally in rat); LD50 = 44 mg/kg (Intravenous, Mouse); LD50: 702 mg/kg (Oral, Mouse).

Reference Reading

1.Peel bond strength of soft lining materials with antifungal to a denture base acrylic resin.
Sánchez-Aliaga A1, Pellissari CV, Arrais CA, Michél MD, Neppelenbroek KH, Urban VM. Dent Mater J. 2016;35(2):194-203. doi: 10.4012/dmj.2014-269.
The effect of the addition of nystatin, miconazole, ketoconazole, chlorhexidine, and itraconazole into the soft lining materials Softone and Trusoft on their peel bond strength to a denture base acrylic resin was evaluated. Specimens of soft lining materials (n=7) were made without (control) or with the incorporation of antifungals at their minimum inhibitory concentrations to the biofilm of C. albicans and bonded to the acrylic resin. Peel testing was performed after immersion in distilled water at 37ºC for 24 h, 7 and 14 days. Data (MPa) were analyzed by 3-way ANOVA/Tukey-Kramer test (α=0.05) and the failure modes were classified. The addition of nystatin and ketoconazole did not affect the peel bond strength for up to 14 days. Most failures were predominantly cohesive within soft lining materials. With the exception of itraconazole, incorporating the antifungals into the soft lining materials did not result in values below those recommended for peel bond strength after 7 and 14 days of analysis.
2.Effects of berberine on pharmacokinetics of midazolam and rhodamine 123 in rats in vivo.
Xin HW1, Tang X1, Ouyang M1, Zhong JX1, Li WL1. Springerplus. 2016 Mar 29;5:380. doi: 10.1186/s40064-016-2013-z. eCollection 2016.
AIM: To evaluate whether berberine hydrochloride (BBR) could modify the pharmacokinetic profiles of midazolam (MDZ), a substrate of CYP3A, and rhodamine 123 (Rh123), a substrate of P-glycolprotein (P-gp), in male rats.
3.Antimicrobial activity of the pygidial gland secretion of the troglophilic ground beetle Laemostenus (Pristonychus) punctatus (Dejean, 1828) (Insecta: Coleoptera: Carabidae).
Nenadić M1, Soković M2, Glamočlija J2, Ćirić A2, Perić-Mataruga V2, Tešević V3, Vujisić L3, Todosijević M3, Vesović N1, Ćurčić S1. Bull Entomol Res. 2016 Mar 28:1-7. [Epub ahead of print]
The antimicrobial activity of the pygidial gland secretion released by adult individuals of the troglophilic ground beetle Laemostenus (Pristonychus) punctatus (Dejean, 1828), applying microdilution method with the aim to detect minimal inhibitory concentration, minimal bactericidal concentration and minimal fungicidal concentration, has been investigated. In addition, morphology of the pygidial glands is observed. We have tested 16 laboratory and clinical strains of human pathogens - eight bacterial both gram-positive and gram-negative species and eight fungal species. The pygidial secretion samples have showed antimicrobial properties against all strains of treated bacteria and fungi. Micrococcus flavus proved to be more resistant compared with other bacterial strains. More significant antimicrobial properties of the secretion are observed against Escherichia coli, which proved to be the most sensitive bacteria. Aspergillus fumigatus proved to be the most resistant, while Penicillium ochrochloron and Penicillium verrucosum var.
4.Melanins Protect Sporothrix brasiliensis and Sporothrix schenckii from the Antifungal Effects of Terbinafine.
Almeida-Paes R1, Figueiredo-Carvalho MH1, Brito-Santos F1, Almeida-Silva F1, Oliveira MM1, Zancopé-Oliveira RM1. PLoS One. 2016 Mar 31;11(3):e0152796. doi: 10.1371/journal.pone.0152796. eCollection 2016.
Terbinafine is a recommended therapeutic alternative for patients with sporotrichosis who cannot use itraconazole due to drug interactions or side effects. Melanins are involved in resistance to antifungal drugs and Sporothrix species produce three different types of melanin. Therefore, in this study we evaluated whether Sporothrix melanins impact the efficacy of antifungal drugs. Minimal inhibitory concentrations (MIC) and minimal fungicidal concentrations (MFC) of two Sporothrix brasiliensis and four Sporothrix schenckii strains grown in the presence of the melanin precursors L-DOPA and L-tyrosine were similar to the MIC determined by the CLSI standard protocol for S. schenckii susceptibility to amphotericin B, ketoconazole, itraconazole or terbinafine. When MICs were determined in the presence of inhibitors to three pathways of melanin synthesis, we observed, in four strains, an increase in terbinafine susceptibility in the presence of tricyclazole, a DHN-melanin inhibitor.

Spectrum

Predicted LC-MS/MS Spectrum - 10V, Positive

Experimental Conditions

Ionization Mode: Positive
Collision Energy: 10 eV
Instrument Type: QTOF (generic), spectrum predicted by CFM-ID
Mass Resolution: 0.0001 Da

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