T3DB: Ciclopirox

Identification Taxonomy Biological Properties Physical Properties Toxicity Profile Spectra Concentrations Links References Gene Regulation Targets (5)XML

Targets (5)

Record Information

Version

2.0

Creation Date

2009-07-21 20:28:34 UTC

Update Date

2014-12-24 20:25:55 UTC

Accession Number

T3D3012

Identification

Common Name

Ciclopirox

Class

Small Molecule

Description

Ciclopirox is only found in individuals that have used or taken this drug. It is a synthetic antifungal agent for topical dermatologic use. [Wikipedia] Unlike antifungals such as itraconazole and terbinafine, which affect sterol synthesis, ciclopirox is thought to act through the chelation of polyvalent metal cations, such as Fe³⁺ and Al³⁺. These cations inhibit many enzymes, including cytochromes, thus disrupting cellular activities such as mitochondrial electron transport processes and energy production. Ciclopirox also appears to modify the plasma membrane of fungi, resulting in the disorganization of internal structures. The anti-inflammatory action of ciclopirox is most likely due to inhibition of 5-lipoxygenase and cyclooxygenase. Ciclopirox may exert its effect by disrupting DNA repair, cell division signals and structures (mitotic spindles) as well as some elements of intracellular transport.

Compound Type

Antifungal Agent
Drug
Ester
Metabolite
Organic Compound
Synthetic Compound

Chemical Structure

MOL SDF PDB SMILES InChI

Synonyms

Synonym
6-Cyclohexyl-1-hydroxy-4-methyl-2(1H)-pyridinone
Batrafen
Ciclodan
Ciclopirox Olamin
Ciclopirox-Olamin
Ciclopiroxolamine
Ciclopiroxum
CNL8
HOE 296b
HOE-296b
Loprox
Mycoster
Penlac
Stieprox

Chemical Formula

C₁₂H₁₇NO₂

Average Molecular Mass

207.269 g/mol

Monoisotopic Mass

207.126 g/mol

CAS Registry Number

29342-05-0

IUPAC Name

6-cyclohexyl-1-hydroxy-4-methyl-1,2-dihydropyridin-2-one

Traditional Name

penlac

SMILES

CC1=CC(=O)N(O)C(=C1)C1CCCCC1

InChI Identifier

InChI=1S/C12H17NO2/c1-9-7-11(13(15)12(14)8-9)10-5-3-2-4-6-10/h7-8,10,15H,2-6H2,1H3

InChI Key

InChIKey=SCKYRAXSEDYPSA-UHFFFAOYSA-N

Chemical Taxonomy

Description

belongs to the class of organic compounds known as pyridinones. Pyridinones are compounds containing a pyridine ring, which bears a ketone.

Kingdom

Organic compounds

Super Class

Organoheterocyclic compounds

Class

Pyridines and derivatives

Sub Class

Hydropyridines

Direct Parent

Pyridinones

Alternative Parents

Substituents

Methylpyridine
Pyridinone
Dihydropyridine
Heteroaromatic compound
Lactam
Azacycle
Organic nitrogen compound
Organic oxygen compound
Organopnictogen compound
Organic oxide
Hydrocarbon derivative
Organooxygen compound
Organonitrogen compound
Aromatic heteromonocyclic compound

Molecular Framework

Aromatic heteromonocyclic compounds

External Descriptors

hydroxypyridone antifungal drug (CHEBI:453011 )
pyridone (CHEBI:453011 )
cyclic hydroxamic acid (CHEBI:453011 )

Biological Properties

Status

Detected and Not Quantified

Origin

Exogenous

Cellular Locations

Membrane

Biofluid Locations

Not Available

Tissue Locations

Not Available

Pathways

Not Available

Applications

Biological Roles

Chemical Roles

Not Available

Physical Properties

State

Solid

Appearance

White powder.

Experimental Properties

Property	Value
Melting Point	143°C
Boiling Point	Not Available
Solubility	1.41e+00 g/L
LogP	2.3

Predicted Properties

Property	Value	Source
Water Solubility	1.41 g/L	ALOGPS
logP	2.15	ALOGPS
logP	2.22	ChemAxon
logS	-2.2	ALOGPS
pKa (Strongest Acidic)	6.84	ChemAxon
pKa (Strongest Basic)	-6.2	ChemAxon
Physiological Charge	-1	ChemAxon
Hydrogen Acceptor Count	2	ChemAxon
Hydrogen Donor Count	1	ChemAxon
Polar Surface Area	40.54 Å²	ChemAxon
Rotatable Bond Count	1	ChemAxon
Refractivity	60.91 m³·mol⁻¹	ChemAxon
Polarizability	23.12 Å³	ChemAxon
Number of Rings	2	ChemAxon
Bioavailability	1	ChemAxon
Rule of Five	Yes	ChemAxon
Ghose Filter	Yes	ChemAxon
Veber's Rule	Yes	ChemAxon
MDDR-like Rule	Yes	ChemAxon

Spectra

Spectrum Type	Description	Splash Key	Deposition Date	View
Predicted GC-MS	Predicted GC-MS Spectrum - GC-MS (Non-derivatized) - 70eV, Positive	splash10-02vi-1900000000-b0302ddc025a747a3484	2017-09-01	View Spectrum
Predicted GC-MS	Predicted GC-MS Spectrum - GC-MS (Non-derivatized) - 70eV, Positive	Not Available	2021-10-12	View Spectrum
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 10V, Positive	splash10-0a4i-0390000000-1d9227c74bcc86583df3	2016-08-02	View Spectrum
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 20V, Positive	splash10-0a4i-2690000000-963d9e37afedc3b4a600	2016-08-02	View Spectrum
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 40V, Positive	splash10-05mo-9600000000-de9b944829cc25a5681b	2016-08-02	View Spectrum
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 10V, Negative	splash10-0a4i-3090000000-ac55f8f5496920dc9ca4	2016-08-03	View Spectrum
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 20V, Negative	splash10-0a4i-0490000000-6cd8e595360c6bddf33a	2016-08-03	View Spectrum
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 40V, Negative	splash10-0a6r-5900000000-7869913422c2e64d2101	2016-08-03	View Spectrum
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 10V, Positive	splash10-0a4i-0090000000-69c98b0c95a4f7a6ef58	2021-10-11	View Spectrum
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 20V, Positive	splash10-0a4i-4490000000-d28507b6dbcfe8f98141	2021-10-11	View Spectrum
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 40V, Positive	splash10-066r-9700000000-4dafee1a9eed2bbabe7b	2021-10-11	View Spectrum
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 10V, Negative	splash10-0a4i-0090000000-bc1578d935014f0ac50f	2021-10-11	View Spectrum
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 20V, Negative	splash10-05is-6930000000-c7140620c24b41758ee7	2021-10-11	View Spectrum
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 40V, Negative	splash10-0f6x-9400000000-8c3e2f33da6d3911ea34	2021-10-11	View Spectrum

Toxicity Profile

Route of Exposure

Rapidly absorbed after oral administration. Mean absorption of ciclopirox after application to nails of all twenty digits and adjacent 5 millimeters of skin once daily for 6 months in patients with dermatophytic onychomycoses was less than 5% of the applied dose. Ciclopirox olamine also penetrates into hair and through the epidermis and hair follicles into sebaceous glands and dermis.

Mechanism of Toxicity

Unlike antifungals such as itraconazole and terbinafine, which affect sterol synthesis, ciclopirox is thought to act through the chelation of polyvalent metal cations, such as Fe³⁺ and Al³⁺. These cations inhibit many enzymes, including cytochromes, thus disrupting cellular activities such as mitochondrial electron transport processes and energy production. Ciclopirox also appears to modify the plasma membrane of fungi, resulting in the disorganization of internal structures. The anti-inflammatory action of ciclopirox is most likely due to inhibition of 5-lipoxygenase and cyclooxygenase. ciclopirox may exert its effect by disrupting DNA repair, cell division signals and structures (mitotic spindles) as well as some elements of intracellular transport.

Metabolism

Glucuronidation is the main metabolic pathway of ciclopirox. Route of Elimination: Most of the compound is excreted either unchanged or as glucuronide. After oral administration of 10 mg of radiolabeled drug (14C-ciclopirox) to healthy volunteers, approximately 96% of the radioactivity was excreted renally within 12 hours of administration. Ninety-four percent of the renally excreted radioactivity was in the form of glucuronides. Half Life: 1.7 hours for 1% topical solution.

Toxicity Values

LD50: >10 ml/kg (Oral, Rat) (2)

Lethal Dose

Not Available

Carcinogenicity (IARC Classification)

No indication of carcinogenicity to humans (not listed by IARC).

Uses/Sources

Used as a topical treatment in immunocompetent patients with mild to moderate onychomycosis of fingernails and toenails without lunula involvement, due to Trichophyton rubrum.

Minimum Risk Level

Not Available

Health Effects

Not Available

Symptoms

Not Available

Treatment

Not Available

Normal Concentrations

Not Available

Abnormal Concentrations

Not Available

External Links

DrugBank ID

HMDB ID

PubChem Compound ID

ChEMBL ID

ChemSpider ID

KEGG ID

Not Available

UniProt ID

Not Available

OMIM ID

ChEBI ID

453011

BioCyc ID

Not Available

CTD ID

Not Available

Stitch ID

Ciclopirox

PDB ID

Not Available

ACToR ID

Not Available

Wikipedia Link

Ciclopirox

References

Synthesis Reference

Lohaus, G.and Dittmar, W.; U.S. Patents 3,972,888; August 3, 1976; and 3,883,545; May 13, 1975; both assigned to Hoechst A .G.

MSDS

Link

General References

Niewerth M, Kunze D, Seibold M, Schaller M, Korting HC, Hube B: Ciclopirox olamine treatment affects the expression pattern of Candida albicans genes encoding virulence factors, iron metabolism proteins, and drug resistance factors. Antimicrob Agents Chemother. 2003 Jun;47(6):1805-17. [12760852 ]
Wishart DS, Knox C, Guo AC, Cheng D, Shrivastava S, Tzur D, Gautam B, Hassanali M: DrugBank: a knowledgebase for drugs, drug actions and drug targets. Nucleic Acids Res. 2008 Jan;36(Database issue):D901-6. Epub 2007 Nov 29. [18048412 ]
Sigle HC, Thewes S, Niewerth M, Korting HC, Schafer-Korting M, Hube B: Oxygen accessibility and iron levels are critical factors for the antifungal action of ciclopirox against Candida albicans. J Antimicrob Chemother. 2005 May;55(5):663-73. Epub 2005 Mar 24. [15790671 ]
Qadripur SA: [Antimycotic therapy. 2. Antimycotic chemotherapeutic agents: imidazole derivatives, tolciclate, haloprogin, ciclopiroxolamin]. Fortschr Med. 1983 Mar 10;101(9):355-63. [6303928 ]
Beikert FC, Le MT, Koeninger A, Technau K, Clad A: Recurrent vulvovaginal candidosis: focus on the vulva. Mycoses. 2011 Nov;54(6):e807-10. doi: 10.1111/j.1439-0507.2011.02030.x. Epub 2011 May 25. [21615545 ]

Gene Regulation

Up-Regulated Genes

Not Available

Down-Regulated Genes

Gene	Gene Symbol	Gene ID	Interaction	Chromosome	Details

Targets

Target Details

1. Arachidonate 15-lipoxygenase

General Function:: Phosphatidylinositol-4,5-bisphosphate binding
Specific Function:: Non-heme iron-containing dioxygenase that catalyzes the stereo-specific peroxidation of free and esterified polyunsaturated fatty acids generating a spectrum of bioactive lipid mediators. Converts arachidonic acid into 12-hydroperoxyeicosatetraenoic acid/12-HPETE and 15-hydroperoxyeicosatetraenoic acid/15-HPETE. Also converts linoleic acid to 13-hydroperoxyoctadecadienoic acid. May also act on (12S)-hydroperoxyeicosatetraenoic acid/(12S)-HPETE to produce hepoxilin A3. Probably plays an important role in the immune and inflammatory responses. Through the oxygenation of membrane-bound phosphatidylethanolamine in macrophages may favor clearance of apoptotic cells during inflammation by resident macrophages and prevent an autoimmune response associated with the clearance of apoptotic cells by inflammatory monocytes. In parallel, may regulate actin polymerization which is crucial for several biological processes, including macrophage function. May also regulate macrophage function through regulation of the peroxisome proliferator activated receptor signaling pathway. Finally, it is also involved in the cellular response to IL13/interleukin-13. In addition to its role in the immune and inflammatory responses, may play a role in epithelial wound healing in the cornea maybe through production of lipoxin A4. May also play a role in endoplasmic reticulum stress response and the regulation of bone mass.
Gene Name:: ALOX15
Uniprot ID:: P16050
Molecular Weight:: 74803.795 Da

References

Overington JP, Al-Lazikani B, Hopkins AL: How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6. [17139284 ]
Imming P, Sinning C, Meyer A: Drugs, their targets and the nature and number of drug targets. Nat Rev Drug Discov. 2006 Oct;5(10):821-34. [17016423 ]

Target Details

2. Prostaglandin G/H synthase 1

General Function:: Prostaglandin-endoperoxide synthase activity
Specific Function:: Converts arachidonate to prostaglandin H2 (PGH2), a committed step in prostanoid synthesis. Involved in the constitutive production of prostanoids in particular in the stomach and platelets. In gastric epithelial cells, it is a key step in the generation of prostaglandins, such as prostaglandin E2 (PGE2), which plays an important role in cytoprotection. In platelets, it is involved in the generation of thromboxane A2 (TXA2), which promotes platelet activation and aggregation, vasoconstriction and proliferation of vascular smooth muscle cells.
Gene Name:: PTGS1
Uniprot ID:: P23219
Molecular Weight:: 68685.82 Da

References

Overington JP, Al-Lazikani B, Hopkins AL: How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6. [17139284 ]
Imming P, Sinning C, Meyer A: Drugs, their targets and the nature and number of drug targets. Nat Rev Drug Discov. 2006 Oct;5(10):821-34. [17016423 ]

Target Details

3. Prostaglandin G/H synthase 2

General Function:: Prostaglandin-endoperoxide synthase activity
Specific Function:: Converts arachidonate to prostaglandin H2 (PGH2), a committed step in prostanoid synthesis. Constitutively expressed in some tissues in physiological conditions, such as the endothelium, kidney and brain, and in pathological conditions, such as in cancer. PTGS2 is responsible for production of inflammatory prostaglandins. Up-regulation of PTGS2 is also associated with increased cell adhesion, phenotypic changes, resistance to apoptosis and tumor angiogenesis. In cancer cells, PTGS2 is a key step in the production of prostaglandin E2 (PGE2), which plays important roles in modulating motility, proliferation and resistance to apoptosis.
Gene Name:: PTGS2
Uniprot ID:: P35354
Molecular Weight:: 68995.625 Da

References

Overington JP, Al-Lazikani B, Hopkins AL: How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6. [17139284 ]
Imming P, Sinning C, Meyer A: Drugs, their targets and the nature and number of drug targets. Nat Rev Drug Discov. 2006 Oct;5(10):821-34. [17016423 ]

Target Details

4. Multidrug and toxin extrusion protein 1

General Function:: Monovalent cation:proton antiporter activity
Specific Function:: Solute transporter for tetraethylammonium (TEA), 1-methyl-4-phenylpyridinium (MPP), cimetidine, N-methylnicotinamide (NMN), metformin, creatinine, guanidine, procainamide, topotecan, estrone sulfate, acyclovir, ganciclovir and also the zwitterionic cephalosporin, cephalexin and cephradin. Seems to also play a role in the uptake of oxaliplatin (a new platinum anticancer agent). Able to transport paraquat (PQ or N,N-dimethyl-4-4'-bipiridinium); a widely used herbicid. Responsible for the secretion of cationic drugs across the brush border membranes.
Gene Name:: SLC47A1
Uniprot ID:: Q96FL8
Molecular Weight:: 61921.585 Da

Binding/Activity Constants

Type	Value	Assay Type	Assay Source
IC50	>500 uM	Not Available	BindingDB 81379

References

Wittwer MB, Zur AA, Khuri N, Kido Y, Kosaka A, Zhang X, Morrissey KM, Sali A, Huang Y, Giacomini KM: Discovery of potent, selective multidrug and toxin extrusion transporter 1 (MATE1, SLC47A1) inhibitors through prescription drug profiling and computational modeling. J Med Chem. 2013 Feb 14;56(3):781-95. doi: 10.1021/jm301302s. Epub 2013 Jan 22. [23241029 ]

Target Details

5. Sodium/potassium-transporting ATPase subunit alpha-1

General Function:: Steroid hormone binding
Specific Function:: This is the catalytic component of the active enzyme, which catalyzes the hydrolysis of ATP coupled with the exchange of sodium and potassium ions across the plasma membrane. This action creates the electrochemical gradient of sodium and potassium ions, providing the energy for active transport of various nutrients.
Gene Name:: ATP1A1
Uniprot ID:: P05023
Molecular Weight:: 112895.01 Da

References

Niewerth M, Kunze D, Seibold M, Schaller M, Korting HC, Hube B: Ciclopirox olamine treatment affects the expression pattern of Candida albicans genes encoding virulence factors, iron metabolism proteins, and drug resistance factors. Antimicrob Agents Chemother. 2003 Jun;47(6):1805-17. [12760852 ]

Ciclopirox (T3D3012)

Structure for T3D3012: Ciclopirox

Targets

References

References

References

Binding/Activity Constants

References

References