Luliconazole (also known as NND-502; NND502; Luzu) is an imidazole-based antifungal drug that is used for the topical treatment of interdigital tinea pedis. Luliconazole is a broad-spectrum antifungal agent that inhibits growth of all filamentous fungi except zygomycetes at low concentrations (MIC, ≦0.004–0.125 µg/ml), with dermatophytes being most susceptible (MIC, ≦0.004–0.008 µg/ml). As a 1% topical cream, it is indicated for the treatment of athlete's foot, jock itch, and ringworm caused by dermatophytes such as Trichophyton rubrum, Microsporum gypseum and Epidermophyton floccosum.

Physicochemical Properties

Molecular Formula	C14H9CL2N3S2
Molecular Weight	354.28
Exact Mass	352.961
Elemental Analysis	C, 47.46; H, 2.56; Cl, 20.01; N, 11.86; S, 18.10
CAS #	187164-19-8
Related CAS #	187164-19-8
PubChem CID	3003141
Appearance	Off-white solid powder
Density	1.5±0.1 g/cm3
Boiling Point	499.1±55.0 °C at 760 mmHg
Flash Point	255.6±31.5 °C
Vapour Pressure	0.0±1.3 mmHg at 25°C
Index of Refraction	1.734
LogP	3.98
Hydrogen Bond Donor Count	0
Hydrogen Bond Acceptor Count	4
Rotatable Bond Count	2
Heavy Atom Count	21
Complexity	476
Defined Atom Stereocenter Count	1
SMILES	ClC1C([H])=C(C([H])=C([H])C=1[C@]1([H])C([H])([H])S/C(=C(/C#N)\N2C([H])=NC([H])=C2[H])/S1)Cl
InChi Key	YTAOBBFIOAEMLL-REQDGWNSSA-N
InChi Code	InChI=1S/C14H9Cl2N3S2/c15-9-1-2-10(11(16)5-9)13-7-20-14(21-13)12(6-17)19-4-3-18-8-19/h1-5,8,13H,7H2/b14-12+/t13-/m0/s1
Chemical Name	(2E)-[(4R)-4-(2,4-Dichlorophenyl)-1,3-dithiolan-2-ylidene](1H-imidazol-1-yl)acetonitrile
Synonyms	PR2699; NND502;PR 2699; NND502;PR2699; NND 502; Luzu; Lulicon
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	Using RPMI 1640 medium and a standardized microdilution method, the MICs of LLCZ against the organism were found to be 0.002 μg/ml for T. mentagrophytes TIMM1189 and 0.002 μg/ml for TIMM2789. The standardized broth microdilution method is used to determine the minimum inhibitory concentrations (MIC) of luliconazole against Trichophyton spp. (T. rubrum, T. mentagrophytes, and T. tonsurans) and Candida albicans. Compared to reference agents, leviconzole exhibits greater potency against Trichophyton spp. (MIC range: 0.00012-0.002 μg/ml), with T. rubrum showing the highest susceptibility (MIC range: 0.00012-0.00024 μg/ml). The MIC values of liconazole against T. mentagrophytes range from 0.00012 to 0.002 μg/ml. Luliconazole exhibits high anti-Candida albicans activity as well (MIC range: 0.031-0.13 μg/ml). Furthermore, luliconazole has a very low minimum inhibitory concentration (MIC) against Malassezia restricta (MIC range: 0.004-0.016 μg/ml)[1].
ln Vivo	Beginning on gestation day 7, liconazole (subcutaneous injection; 1, 5, and 25 mg/kg/day) is administered until lactation day 20, the end of lactation. There are maternal and embryofetal toxicity issues with liconazole at 25 mg/kg (higher prenatal pup mortality, smaller live litter sizes, and higher postnatal pup mortality). At 5 mg/kg, leviconazole shows no toxicity to developing embryos. Furthermore, has no treatment effects on rats' postnatal development at 25 mg/kg/day[2]. The topical application of liconazole (dosage: 0.02%–1%; 7–14 days) exhibits dose-dependent therapeutic efficacy on skin. Its efficacy is consistent at 0.02% concentration, and at 0.1% it is comparable to the 1% bifonazole creama tinea corporis model (4–8 days) and the tinea pedis model (7–14 days)[3].
Animal Protocol	Animal Model: specific-pathogen-free (SPF) for men Models of tinea corporis and tinea pedis created by Hartley Guinea Pigs[2] Dosage: 0.02%-1% Administration: Appliance on skin; 0.02%-1%; 7-14 days Result: was strong enough to treat dermatophytosis in vivo for a brief period of time.
ADME/Pharmacokinetics	Absorption, Distribution and Excretion Although luliconazole is administered topically, clinical studies have shown that after the first dose in patients with tina pedis, a maximum plasma concentration of 0.40 ± 0.76 ng/mL (mean ± SD) occurred in 16.9 ± 9.39 hours (mean ± SD). The route of elimination of luliconazole has yet to be determined. The volume of distribution was not quantified. The clearance of luliconazole has yet to be determined. Metabolism / Metabolites The metabolism of luliconazole has yet to be determined. Biological Half-Life The half life of luliconazole has yet to be determined.
Toxicity/Toxicokinetics	Effects During Pregnancy and Lactation ◉ Summary of Use during Lactation Topical luliconazole has not been studied during breastfeeding. Because it is poorly absorbed after topical use and is highly plasma protein bound, it is a low risk to the nursing infant. 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. ◉ 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 Plasma protein binding of luliconazole is >99%.
References	[1]. Antimicrob Agents Chemother. 2012 Jun;56(6):3138-43. [2]. Med Mycol. 2009;47(6):640-7. [3]. J Infect Chemother.2004 Aug;10(4):216-9. [4]. Med Mycol.2010 May;48(3):491-7.
Additional Infomation	Luliconazole is a dichlorobenzene. Luliconazole is a topical antifungal agent that acts by unknown mechanisms but is postulated to involve altering the synthesis of fungi cell membranes. It was approved by the FDA (USA) in November 2013 and is marketed under the brand name Luzu. Luliconazole is also approved in Japan. Luliconazole is an Azole Antifungal. The mechanism of action of luliconazole is as a Cytochrome P450 2C19 Inhibitor. Drug Indication Luliconazole is indicated for the treatment of interdigital tinea pedis, tinea cruris, or tinea corporis infections caused by Trichophyton rubrum and Epidermophyton floccosum. Mechanism of Action The exact mechanism of action for luliconazole's anti-fungal activity is still not known, but luliconazole is thought to inhibit the enzyme lanosterol demethylase. Lanosterol demethylase is needed for the synthesis of ergosterol, which is a major component of the fungus cell membranes. Pharmacodynamics Luliconazole kills the organisms Trichophyton rubrum and Epidermophyton floccosum, most likely by altering their fungal cell membranes.

Solubility Data

Solubility (In Vitro)

DMSO : 50 ~71 mg/mL ( 141.13 ~200.4 ) Ethanol : ~5 mg/mL

Solubility (In Vivo)

Solubility in Formulation 1: ≥ 2.5 mg/mL (7.06 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 (7.06 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 (7.06 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: 10% DMSO+40% PEG300+5% Tween-80+45% Saline: ≥ 2.5 mg/mL (7.06 mM)  (Please use freshly prepared in vivo formulations for optimal results.)

Preparing Stock Solutions		1 mg	5 mg	10 mg
	1 mM	2.8226 mL	14.1131 mL	28.2263 mL
	5 mM	0.5645 mL	2.8226 mL	5.6453 mL
	10 mM	0.2823 mL	1.4113 mL	2.8226 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.