Ciclopirox (HOE-296; LACQUER; Penlac), a hydroxypyrimidine analog, is an potent, synthetic and broad-spectrum antifungal agent used for topical dermatologic treatment of superficial mycoses. It acts as an iron chelator and also inhibits the membrane transfer system by interrupting the Na+ K+ ATPase. Ciclopirox is currently being investigated as an alternative treatment to ketoconazole for seborrhoeic dermatitis.

Physicochemical Properties

Molecular Formula	C12H17NO2
Molecular Weight	207.27
Exact Mass	207.125
Elemental Analysis	C, 69.54; H, 8.27; N, 6.76; O, 15.44
CAS #	29342-05-0
Related CAS #	Ciclopirox olamine;41621-49-2;Ciclopirox olamine;41621-49-2;Ciclopirox-d11;Ciclopirox-d11 sodium
PubChem CID	2749
Appearance	White to off-white solid powder.
Density	1.2±0.1 g/cm3
Boiling Point	350.0±25.0 °C at 760 mmHg
Melting Point	1440C
Flash Point	165.5±23.2 °C
Vapour Pressure	0.0±1.7 mmHg at 25°C
Index of Refraction	1.582
LogP	2.59
Hydrogen Bond Donor Count	1
Hydrogen Bond Acceptor Count	2
Rotatable Bond Count	1
Heavy Atom Count	15
Complexity	325
Defined Atom Stereocenter Count	0
SMILES	O([H])N1C(C([H])=C(C([H])([H])[H])C([H])=C1C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C1([H])[H])=O
InChi Key	SCKYRAXSEDYPSA-UHFFFAOYSA-N
InChi Code	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
Chemical Name	6-cyclohexyl-1-hydroxy-4-methylpyridin-2-one
Synonyms	Ciclopirox; Penlac; Batrafen; Ciclopiroxum; Loprox; HOE 296; HOE296; HOE-296; Ciclopirox olamine
HS Tariff Code	2934.99.9001
Storage	Powder-20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month
Shipping Condition	Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

Biological Activity

ln Vitro	In an investigation aimed at deciphering the mechanism of Ciclopirox, a number of Saccharomyces cerevisiae mutants were examined and evaluated. According to findings from the interpretation of the effects of the drug treatment and mutation, Ciclopirox may work by interfering with DNA repair, mitotic spindles, and other cell division signals and structures, as well as certain aspects of intracellular transport[2]. A broad-spectrum antifungal with anti-inflammatory qualities, ciclopirox is effective against Malassezia spp., the yeast linked to seborrheic dermatitis[3].
ln Vivo	The effect of Ciclopirox on endogenous HIF-1 target gene-VEGF was investigated using different animal organ models including mouse skin wound model, rat kidney model and chicken chorioallantoic membrane model. According to the results, CPX functionally activated HIF-1, induced VEGF expression and accelerated angiogenesis.
Cell Assay	Sabouraud glucose medium (2%) is used for cell culture growth, and RPMI 2% glucose medium and 2% Sabouraud glucose medium are used for MIC determinations. For cell culture growth curves, 220 mL of 2% Sabouraud glucose medium containing different concentrations of Ciclopirox are inoculated with 105 cells/mL, and the mixture is shaken at 160 rpm and 37 °C for 1-10 hours. Growth is measured photometrically at 630 nm. FeCl3 or 2,2-bipyridine is added to the medium at different concentrations for inhibition studie.
Animal Protocol	Different animal organ models including mouse skin wound model, rat kidney model and chicken chorioallantoic membrane model
ADME/Pharmacokinetics	Absorption, Distribution and Excretion 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. 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. Metabolism / Metabolites Glucuronidation is the main metabolic pathway of ciclopirox. 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. Biological Half-Life 1.7 hours for 1% topical solution.
Toxicity/Toxicokinetics	Effects During Pregnancy and Lactation ◉ Summary of Use during Lactation Topical ciclopirox has not been studied during breastfeeding. Because only about 1.3% is absorbed after topical application, it is considered a low risk to the nursing infant.[1] Avoid application to the nipple area and ensure that the infant's skin does not come into direct contact with the areas of skin that have been treated. Only water-miscible cream or gel products should be applied to the breast because ointments may expose the infant to high levels of mineral paraffins via licking.[2] ◉ Effects in Breastfed Infants Relevant published information was not found as of the revision date. ◉ Effects on Lactation and Breastmilk Relevant published information was not found as of the revision date. Protein Binding Protein binding is 94-97% following topical administration.
References	[1]. Antimicrob Agents Chemother, 2003. 47(6): p. 1805-17. [2]. Mol Cells, 2003. 15(1): p. 55-61. [3]. J Dermatolog Treat, 2007. 18(2): p. 88-96. [4]. FASEB J.2003 Apr;17(6):761-3 [5]. Br J Pharmacol.2005 Jun;145(4):469-76.
Additional Infomation	Ciclopirox is a cyclic hydroxamic acid that is 1-hydroxypyridin-2(1H)-one in which the hydrogens at positions 4 and 6 are substituted by methyl and cyclohexyl groups, respectively. A broad spectrum antigfungal agent, it also exhibits antibacterial activity against many Gram-positive and Gram-negative bacteria, and has anti-inflammatory properties. It is used a a topical treatment of fungal skin and nail infections. It has a role as an antibacterial agent and an antiseborrheic. It is a pyridone, a cyclic hydroxamic acid and a hydroxypyridone antifungal drug. Ciclopirox olamine (used in preparations called Batrafen, Loprox, Mycoster, Penlac and Stieprox) is a synthetic antifungal agent for topical dermatologic treatment of superficial mycoses. In particular, the agent is especially effective in treating Tinea versicolor. The mechanism of action of ciclopirox is as a Protein Synthesis Inhibitor. The physiologic effect of ciclopirox is by means of Decreased DNA Replication, and Decreased Protein Synthesis, and Decreased RNA Replication. Ciclopirox is a synthetic, broad-spectrum antifungal agent with additional antibacterial and anti-inflammatory activities. Ciclopirox exerts its action by binding to and chelating trivalent cations, such as Fe3+ and Al3+, thereby inhibiting the availability of essential co-factors for enzymes. This may lead to a loss of activity of enzymes that are essential for cellular metabolism, organization of cell wall structure and other crucial cell functions. In addition, ciclopirox exerts its anti-inflammatory activity by inhibiting 5-lipoxygenase and cyclooxygenase (COX). 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. A cyclohexane and pyridinone derivative that is used for the treatment of fungal infections of the skin and nails, and for treatment of VAGINAL YEAST INFECTIONS. See also: Ciclopirox Olamine (has salt form); Ciclopirox; clobetasol propionate (component of); Ciclopirox; fluconazole; terbinafine (component of). Drug Indication Used as a topical treatment in immunocompetent patients with mild to moderate onychomycosis of fingernails and toenails without lunula involvement, due to Trichophyton rubrum. FDA Label Mechanism of Action 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.

Solubility Data

Solubility (In Vitro)

DMSO : 41~100 mg/mL ( 197.8~482.46 mM ) Ethanol : 41 mg/mL

Solubility (In Vivo)

Solubility in Formulation 1: ≥ 2.5 mg/mL (12.06 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 2.5 mg/mL (12.06 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. Solubility in Formulation 3: ≥ 2.5 mg/mL (12.06 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly. Solubility in Formulation 4: 5%DMSO + Corn oil: 3mg/ml (14.47mM)  (Please use freshly prepared in vivo formulations for optimal results.)

Preparing Stock Solutions		1 mg	5 mg	10 mg
	1 mM	4.8246 mL	24.1231 mL	48.2462 mL
	5 mM	0.9649 mL	4.8246 mL	9.6492 mL
	10 mM	0.4825 mL	2.4123 mL	4.8246 mL

*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.