Identification

Name
Bifonazole
Accession Number
DB04794
Type
Small Molecule
Groups
Approved, Investigational
Description

Bifonazole is an azole antifungal drug. [Wikipedia]

Structure
Thumb
Synonyms
  • (+-)-1-(p,alpha-Diphenylbenzyl)imidazole
  • (+-)1-([1,1'-Biphenyl]-4-ylphenylmethyl)-1H-imidazole
  • 1-((4-Biphenylyl)phenylmethyl)-1H-imidazole
  • 1-(alpha-(4-Biphenylyl)benzyl)imidazole
  • 1-(p,alpha-Diphenylbenzyl)imidazole
  • Bay h 4502
  • Bifonazol
  • Bifonazolum
  • Mycospor
  • Trifonazole
International/Other Brands
Amycor (Merck) / Azolmen (Menarini) / Bayclear Plus (Bayer) / Bifonol (Mayado Seiyaku) / Canespor (Bayer) / Canesten (Bayer) / Mycospor (Bayer)
Categories
UNII
QYJ305Z91O
CAS number
60628-96-8
Weight
Average: 310.3917
Monoisotopic: 310.146998586
Chemical Formula
C22H18N2
InChI Key
OCAPBUJLXMYKEJ-UHFFFAOYSA-N
InChI
InChI=1S/C22H18N2/c1-3-7-18(8-4-1)19-11-13-21(14-12-19)22(24-16-15-23-17-24)20-9-5-2-6-10-20/h1-17,22H
IUPAC Name
1-[phenyl(4-phenylphenyl)methyl]-1H-imidazole
SMILES
C1=CN(C=N1)C(C1=CC=CC=C1)C1=CC=C(C=C1)C1=CC=CC=C1

Pharmacology

Indication

Used for the treatment of various topical fungal infections, including athlete's foot (tinea pedis).

Pharmacodynamics

Bifonazole is a type of antifungal medicine known as an imidazole. It kills fungi and yeasts by interfering with their cell membranes.

Mechanism of action

Bifonazole works by inhibiting the production of a substance called ergosterol, which is an essential component of fungal cell membranes.It acts to destabilize the fungal cyctochrome p450 51 enzyme (also known as Lanosterol 14-alpha demethylase). This is vital in the cell membrance structure of the fungus. Its inhibition leads to cell lysis. The disruption in production of ergosterol disrupts the cell membrane and causes holes to appear. The cell membranes of fungi are vital for their survival. They keep unwanted substances from entering the cells and stop the contents of the cells from leaking out. As bifonazole causes holes to appear in the cell membranes, essential constituents of the fungal cells can leak out. This kills the fungi.

TargetActionsOrganism
ALanosterol 14-alpha demethylase
inhibitor
Yeast
UCytochrome P450 2B6Not AvailableHuman
Absorption

Very low absorption following topical administration (0.6% of an applied dose). In cases of skin lesions absorption is increased (2.5%).

Volume of distribution
Not Available
Protein binding
Not Available
Metabolism

Hepatic.

Route of elimination
Not Available
Half life

1-2 hours

Clearance
Not Available
Toxicity
Not Available
Affected organisms
  • Fungi
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteraction
(R)-warfarinThe metabolism of (R)-warfarin can be decreased when combined with Bifonazole.
(S)-WarfarinThe metabolism of (S)-Warfarin can be decreased when combined with Bifonazole.
3,5-diiodothyropropionic acidThe metabolism of 3,5-diiodothyropropionic acid can be decreased when combined with Bifonazole.
4-hydroxycoumarinThe metabolism of 4-hydroxycoumarin can be decreased when combined with Bifonazole.
5-androstenedioneThe metabolism of 5-androstenedione can be decreased when combined with Bifonazole.
6-O-benzylguanineThe metabolism of 6-O-benzylguanine can be decreased when combined with Bifonazole.
AbemaciclibThe metabolism of Abemaciclib can be decreased when combined with Bifonazole.
AbirateroneThe metabolism of Abiraterone can be decreased when combined with Bifonazole.
AcenocoumarolThe metabolism of Acenocoumarol can be decreased when combined with Bifonazole.
AcetaminophenThe metabolism of Acetaminophen can be decreased when combined with Bifonazole.
Food Interactions
Not Available

References

Synthesis Reference

Regal, E., Draber, W., Buchel, K.H.and Plempel, M.; U.S. Patent 4,118,487; October 3,1978; assigned to Bayer A.G.

US4118487
General References
  1. Watanabe S, Takahashi H, Nishikawa T, Takiuchi I, Higashi N, Nishimoto K, Kagawa S, Yamaguchi H, Ogawa H: A comparative clinical study between 2 weeks of luliconazole 1% cream treatment and 4 weeks of bifonazole 1% cream treatment for tinea pedis. Mycoses. 2006 May;49(3):236-41. [PubMed:16681817]
  2. Cho KJ, Su W, Chen WC, Law YP, Fang HC, Liu CP, Cheng JS, Lee KC, Lo YK, Chang HT, Huang JK, Jan CR: Mechanism of bifonazole-induced [Ca2+]i increases in MDCK renal tubular cells. Chin J Physiol. 2001 Sep 30;44(3):97-101. [PubMed:11767287]
  3. Tanuma H, Doi M, Sato N, Nishiyama S, Abe M, Kume H, Katsuoka K: Bifonazole (Mycospor cream) in the treatment of moccasin-type tinea pedis. Comparison between combination therapy of bifonazole cream + 10% urea ointment (Urepearl) and occlusive dressing therapy with the same agents. Mycoses. 2000;43(3-4):129-37. [PubMed:10907343]
  4. Berg D, Regel E, Harenberg HE, Plempel M: Bifonazole and clotrimazole. Their mode of action and the possible reason for the fungicidal behaviour of bifonazole. Arzneimittelforschung. 1984;34(2):139-46. [PubMed:6372801]
External Links
Human Metabolome Database
HMDB0015583
PubChem Compound
2378
PubChem Substance
46507284
ChemSpider
2287
BindingDB
50128548
ChEBI
78692
ChEMBL
CHEMBL277535
Therapeutic Targets Database
DAP000877
PharmGKB
PA164746464
HET
TMI
Wikipedia
Bifonazole
ATC Codes
D01AC60 — Bifonazole, combinationsD01AC10 — Bifonazole

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
3CompletedTreatmentClotrimazole / Ovulen / Vulvovaginal Candidiasis1
3CompletedTreatmentOnychomycosis1
4CompletedTreatmentFoot Dermatoses1
4CompletedTreatmentVulvovaginal Candidiasis1
4Unknown StatusTreatmentMelasma1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
Not Available
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
PropertyValueSource
melting point (°C)142Regal, E., Draber, W., Buchel, K.H.and Plempel, M.; U.S. Patent 4,118,487; October 3,1978; assigned to Bayer A.G.
logP4.77BIOBYTE (1995)
Predicted Properties
PropertyValueSource
Water Solubility0.00245 mg/mLALOGPS
logP4.92ALOGPS
logP5.23ChemAxon
logS-5.1ALOGPS
pKa (Strongest Basic)6.69ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count1ChemAxon
Hydrogen Donor Count0ChemAxon
Polar Surface Area17.82 Å2ChemAxon
Rotatable Bond Count4ChemAxon
Refractivity97.94 m3·mol-1ChemAxon
Polarizability35.41 Å3ChemAxon
Number of Rings4ChemAxon
Bioavailability1ChemAxon
Rule of FiveNoChemAxon
Ghose FilterYesChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET features
PropertyValueProbability
Human Intestinal Absorption+0.9934
Blood Brain Barrier+0.9828
Caco-2 permeable+0.6357
P-glycoprotein substrateNon-substrate0.7794
P-glycoprotein inhibitor INon-inhibitor0.8037
P-glycoprotein inhibitor IINon-inhibitor0.8724
Renal organic cation transporterNon-inhibitor0.6194
CYP450 2C9 substrateNon-substrate0.7897
CYP450 2D6 substrateNon-substrate0.9115
CYP450 3A4 substrateNon-substrate0.7693
CYP450 1A2 substrateInhibitor0.7884
CYP450 2C9 inhibitorNon-inhibitor0.6395
CYP450 2D6 inhibitorInhibitor0.6381
CYP450 2C19 inhibitorInhibitor0.8503
CYP450 3A4 inhibitorInhibitor0.578
CYP450 inhibitory promiscuityHigh CYP Inhibitory Promiscuity0.9523
Ames testAMES toxic0.5674
CarcinogenicityNon-carcinogens0.9066
BiodegradationNot ready biodegradable0.9521
Rat acute toxicity2.3581 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.967
hERG inhibition (predictor II)Non-inhibitor0.6458
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397)

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted GC-MS Spectrum - GC-MSPredicted GC-MSNot Available
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSNot Available
MS/MS Spectrum - , positiveLC-MS/MSsplash10-0006-1390000000-1be085eadfe1ca8da91f
MS/MS Spectrum - , positiveLC-MS/MSsplash10-0006-0290000000-77357a487121e6eca52c
MS/MS Spectrum - , positiveLC-MS/MSsplash10-00kf-2690000000-8eaa22839544d8c21308
LC-MS/MS Spectrum - LC-ESI-QFT , positiveLC-MS/MSsplash10-0006-0190000000-e6d6c0b5fe503dddd253

Taxonomy

Description
This compound belongs to the class of organic compounds known as diphenylmethanes. These are compounds containing a diphenylmethane moiety, which consists of a methane wherein two hydrogen atoms are replaced by two phenyl groups.
Kingdom
Organic compounds
Super Class
Benzenoids
Class
Benzene and substituted derivatives
Sub Class
Diphenylmethanes
Direct Parent
Diphenylmethanes
Alternative Parents
Biphenyls and derivatives / N-substituted imidazoles / Heteroaromatic compounds / Azacyclic compounds / Organopnictogen compounds / Organonitrogen compounds / Hydrocarbon derivatives
Substituents
Diphenylmethane / Biphenyl / N-substituted imidazole / Heteroaromatic compound / Imidazole / Azole / Azacycle / Organoheterocyclic compound / Organic nitrogen compound / Organopnictogen compound
Molecular Framework
Aromatic heteromonocyclic compounds
External Descriptors
imidazoles, biphenyls (CHEBI:78692)

Targets

Kind
Protein
Organism
Yeast
Pharmacological action
Yes
Actions
Inhibitor
General Function
Sterol 14-demethylase activity
Specific Function
Catalyzes C14-demethylation of lanosterol which is critical for ergosterol biosynthesis. It transforms lanosterol into 4,4'-dimethyl cholesta-8,14,24-triene-3-beta-ol.
Gene Name
ERG11
Uniprot ID
P10613
Uniprot Name
Lanosterol 14-alpha demethylase
Molecular Weight
60674.965 Da
References
  1. Carrillo-Munoz AJ, Giusiano G, Ezkurra PA, Quindos G: Antifungal agents: mode of action in yeast cells. Rev Esp Quimioter. 2006 Jun;19(2):130-9. [PubMed:16964330]
  2. Rossello A, Bertini S, Lapucci A, Macchia M, Martinelli A, Rapposelli S, Herreros E, Macchia B: Synthesis, antifungal activity, and molecular modeling studies of new inverted oxime ethers of oxiconazole. J Med Chem. 2002 Oct 24;45(22):4903-12. [PubMed:12383016]
  3. Berg D, Plempel M: Bifonazole, a biochemist's view. Dermatologica. 1984;169 Suppl 1:3-9. [PubMed:6396116]
  4. Berg D, Regel E, Harenberg HE, Plempel M: Bifonazole and clotrimazole. Their mode of action and the possible reason for the fungicidal behaviour of bifonazole. Arzneimittelforschung. 1984;34(2):139-46. [PubMed:6372801]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
General Function
Steroid hydroxylase activity
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally un...
Gene Name
CYP2B6
Uniprot ID
P20813
Uniprot Name
Cytochrome P450 2B6
Molecular Weight
56277.81 Da
References
  1. Berman HM, Westbrook J, Feng Z, Gilliland G, Bhat TN, Weissig H, Shindyalov IN, Bourne PE: The Protein Data Bank. Nucleic Acids Res. 2000 Jan 1;28(1):235-42. [PubMed:10592235]

Enzymes

Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Oxygen binding
Specific Function
Catalyzes the formation of aromatic C18 estrogens from C19 androgens.
Gene Name
CYP19A1
Uniprot ID
P11511
Uniprot Name
Aromatase
Molecular Weight
57882.48 Da
References
  1. Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S, Winnenburg R, Schroeder M, Preissner R: SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan;38(Database issue):D237-43. doi: 10.1093/nar/gkp970. Epub 2009 Nov 24. [PubMed:19934256]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Steroid hydroxylase activity
Specific Function
Metabolizes several precarcinogens, drugs, and solvents to reactive metabolites. Inactivates a number of drugs and xenobiotics and also bioactivates many xenobiotic substrates to their hepatotoxic ...
Gene Name
CYP2E1
Uniprot ID
P05181
Uniprot Name
Cytochrome P450 2E1
Molecular Weight
56848.42 Da
References
  1. Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S, Winnenburg R, Schroeder M, Preissner R: SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan;38(Database issue):D237-43. doi: 10.1093/nar/gkp970. Epub 2009 Nov 24. [PubMed:19934256]
  2. Tassaneeyakul W, Birkett DJ, Miners JO: Inhibition of human hepatic cytochrome P4502E1 by azole antifungals, CNS-active drugs and non-steroidal anti-inflammatory agents. Xenobiotica. 1998 Mar;28(3):293-301. [PubMed:9574817]
  3. Monostory K, Hazai E, Vereczkey L: Inhibition of cytochrome P450 enzymes participating in p-nitrophenol hydroxylation by drugs known as CYP2E1 inhibitors. Chem Biol Interact. 2004 Apr 15;147(3):331-40. doi: 10.1016/j.cbi.2004.03.003. [PubMed:15135088]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Vitamin d3 25-hydroxylase activity
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It performs a variety of oxidation react...
Gene Name
CYP3A4
Uniprot ID
P08684
Uniprot Name
Cytochrome P450 3A4
Molecular Weight
57342.67 Da
References
  1. Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S, Winnenburg R, Schroeder M, Preissner R: SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan;38(Database issue):D237-43. doi: 10.1093/nar/gkp970. Epub 2009 Nov 24. [PubMed:19934256]
  2. Monostory K, Hazai E, Vereczkey L: Inhibition of cytochrome P450 enzymes participating in p-nitrophenol hydroxylation by drugs known as CYP2E1 inhibitors. Chem Biol Interact. 2004 Apr 15;147(3):331-40. doi: 10.1016/j.cbi.2004.03.003. [PubMed:15135088]

Drug created on September 11, 2007 11:49 / Updated on November 02, 2018 06:05