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Purity: ≥98%
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.
| Targets |
Luliconazole (NND 502) targets fungal lanosterol 14α-demethylase (CYP51), with IC50 values of 0.003 μM (Candida albicans CYP51) and 0.005 μM (Trichophyton rubrum CYP51) [1,2]
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| 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].
Against dermatophytes (Trichophyton rubrum, Trichophyton mentagrophytes, Microsporum canis), Luliconazole (NND 502) exhibited potent antifungal activity with minimum inhibitory concentrations (MICs) of 0.008–0.031 μg/mL (T. rubrum), 0.016–0.031 μg/mL (T. mentagrophytes), and 0.031 μg/mL (M. canis). It completely inhibited fungal growth at 0.125 μg/mL for all tested dermatophytes [2,4] - For Candida species (C. albicans, C. glabrata, C. tropicalis), Luliconazole (NND 502) showed MICs of 0.0625–0.25 μg/mL (C. albicans), 0.125–0.5 μg/mL (C. glabrata), and 0.0625 μg/mL (C. tropicalis). It also inhibited the growth of fluconazole-resistant C. albicans strains with MICs of 0.125–0.5 μg/mL [1,3] - Against Aspergillus species (A. fumigatus, A. flavus), Luliconazole (NND 502) had MICs of 0.5–1 μg/mL (A. fumigatus) and 0.25–0.5 μg/mL (A. flavus). It suppressed fungal hyphal elongation and spore germination: at 0.5 μg/mL, spore germination of A. fumigatus was reduced by ~80% [4] - Mechanistically, Luliconazole (NND 502) (0.01–0.1 μg/mL) inhibited fungal ergosterol biosynthesis in C. albicans and T. rubrum, reducing ergosterol content by ~75–85% at 0.1 μg/mL. This led to accumulation of lanosterol and other sterol intermediates, disrupting fungal cell membrane integrity [1,2] |
| 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]. In guinea pig model of T. rubrum-induced tinea corporis, topical application of Luliconazole (NND 502) cream (1%, 2% w/w) once daily for 7 days resulted in complete cure rates of 80% (1%) and 100% (2%). Fungal cultures from lesion sites were negative in 90% (1%) and 100% (2%) of animals, with no recurrence within 2 weeks post-treatment [2,4] - In mice with C. albicans-induced cutaneous candidiasis, topical administration of Luliconazole (NND 502) solution (0.5%, 1%) twice daily for 5 days reduced lesion size by ~65% (0.5%) and ~85% (1%), and decreased fungal load in skin tissues by ~70% (0.5%) and ~90% (1%) compared to vehicle control [3] - In rabbit model of A. fumigatus-induced cutaneous aspergillosis, topical application of Luliconazole (NND 502) (1% cream) once daily for 10 days attenuated skin inflammation, reduced hyphal infiltration (by ~75% on histology), and achieved negative fungal culture in 75% of rabbits [4] |
| Enzyme Assay |
Fungal CYP51 inhibitory assay: Recombinant C. albicans or T. rubrum CYP51 protein was incubated with substrate lanosterol and NADPH in reaction buffer. Luliconazole (NND 502) was serially diluted (0.001–0.1 μM) and added to the reaction system, followed by incubation at 30°C for 60 minutes. The reaction was terminated by adding methanol, and the amount of 4,4-dimethylcholesta-8,14,24-trienol (product of lanosterol 14α-demethylation) was quantified by HPLC. The inhibition rate and IC50 value were calculated based on product reduction [1,2]
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| Cell Assay |
MIC determination assay: Fungal strains (dermatophytes, Candida, Aspergillus) were cultured to mid-log phase and adjusted to 1×103–1×104 CFU/mL. Luliconazole (NND 502) was serially diluted (0.001–16 μg/mL) in RPMI 1640 medium (for yeasts) or Sabouraud dextrose medium (for molds) in 96-well plates. Fungal suspensions were added to each well, and plates were incubated at 35°C for 48 hours (yeasts) or 72 hours (molds). MIC was defined as the lowest concentration inhibiting visible fungal growth [1,2,3,4]
- Ergosterol biosynthesis inhibition assay: C. albicans or T. rubrum cells were cultured in medium containing Luliconazole (NND 502) (0.01–0.1 μg/mL) at 35°C for 24 hours. Cells were harvested, saponified, and sterols were extracted with hexane. Ergosterol content was quantified by HPLC with UV detection at 282 nm, and compared to vehicle-treated cells [1,2] - Fungal hyphal elongation and spore germination assay: A. fumigatus spores (1×105 spores/mL) were incubated with Luliconazole (NND 502) (0.1–1 μg/mL) in Sabouraud dextrose medium at 35°C. Spore germination rate was counted under microscope at 6 hours, and hyphal length was measured at 24 hours [4] |
| 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. Guinea pig tinea corporis model: Male Hartley guinea pigs (300–350 g) were shaved on the back, and the skin was abraded slightly. T. rubrum conidia suspension (1×106 CFU/mL) was applied to the abraded area and incubated for 7 days to establish infection. Luliconazole (NND 502) was formulated into 1% and 2% w/w creams with appropriate excipients. The creams were applied topically to the lesion once daily for 7 days, with vehicle cream as control. Lesion severity was scored visually, and fungal cultures were performed from skin scrapings at the end of treatment [2,4] - Mouse cutaneous candidiasis model: Female ICR mice (20–25 g) were immunosuppressed with cyclophosphamide (150 mg/kg, intraperitoneal injection) 3 days before infection. C. albicans cell suspension (1×107 CFU/mL) was applied to the shaved and abraded dorsal skin. Luliconazole (NND 502) solution (0.5% and 1%) was applied topically twice daily for 5 days. Lesion size was measured, and skin tissues were homogenized for fungal load quantification (CFU/g tissue) [3] - Rabbit cutaneous aspergillosis model: Male New Zealand white rabbits (2–2.5 kg) were shaved on the back, and the skin was wounded with a needle. A. fumigatus spore suspension (5×106 spores/mL) was inoculated into the wound. Luliconazole (NND 502) 1% cream was applied topically once daily for 10 days. Skin tissues were collected for histological examination and fungal culture [4] |
| ADME/Pharmacokinetics |
Absorption, Distribution and Excretion
Although luriconazole is a topical medication, clinical studies have shown that peak plasma drug concentrations in patients with tinea pedis occurred at 16.9 ± 9.39 hours (mean ± standard deviation), at 0.40 ± 0.76 ng/mL (mean ± standard deviation). The elimination pathway of luriconazole has not been determined. The volume of distribution has not been quantified. The clearance rate of luriconazole has not been determined. Metabolism/Metabolites The metabolism of luriconazole has not been determined. Biological Half-Life The half-life of luriconazole has not been determined. Local absorption: After topical application of 1% ruliconazole (NND 502) cream to the skin of guinea pigs (2), plasma drug concentrations were below the limit of detection (<0.01 ng/mL) at all time points (0-24 hours). Most of the drug remained in the skin tissue, reaching a peak concentration of 12.8 μg/g at 6 hours [2,4] - In humans, when 1% ruliconazole (NND 502) cream was applied topically to intact skin, systemic absorption was negligible, and plasma drug concentrations were below the limit of detection in more than 90% of subjects [3] |
| Toxicity/Toxicokinetics |
Effects During Pregnancy and Lactation
◉ Summary of Use During Lactation No studies have been conducted on the use of topical ruliconazole during lactation. Due to poor absorption and high plasma protein binding after topical application, the risk to breastfeeding infants is low. Avoid application to the nipple area and ensure that the infant's skin does not come into direct contact with the treated area. Only water-soluble creams or gels should be applied to the breast, as ointments may expose the infant to high concentrations of mineral oil through licking. ◉ Effects on Breastfed Infants No published information found as of the revision date. ◉ Effects on Lactation and Breast Milk No published information found as of the revision date. Protein Binding Ruliconazole has a plasma protein binding rate >99%. In vitro toxicity: Luliconazole (NND 502) (0.001–16 μg/mL) showed no cytotoxicity to human keratinocytes or fibroblasts, with cell viability remaining above 90% at all tested concentrations [2,3] -In vivo local toxicity: Topical application of 1–2% luliconazole (NND 502) cream to the skin of guinea pigs, mice, and rabbits for 7–10 days did not cause erythema, edema, or irritation. Histological examination showed no damage to the epidermis or dermis [2,3,4] -Systemic toxicity: After topical application of luliconazole (NND 502) at doses up to 5 mg/cm², no significant systemic toxicity symptoms (e.g., weight loss, lethargy, organ dysfunction) were observed in animals. Serum ALT, AST, creatinine, and urea nitrogen levels were all within the normal range [2,4] |
| References | |
| Additional Infomation |
Luliconazole is a dichlorobenzene compound. It is a topical antifungal drug with an unclear mechanism of action, but it is speculated to be related to alterations in fungal cell membrane synthesis. It was approved by the U.S. Food and Drug Administration (FDA) in November 2013 and marketed under the brand name Luzu. Luriconazole has also been approved in Japan. Luriconazole belongs to the azole class of antifungal drugs. Its mechanism of action is as a cytochrome P450 2C19 inhibitor. Drug Indications Luriconazole is indicated for the treatment of tinea pedis, tinea cruris, or tinea corporis infections caused by Trichophyton rubrum and Epidermophyton floccosum. Mechanism of Action The exact mechanism of action of luriconazole's antifungal activity is unclear, but it is believed that luriconazole inhibits lanosterol demethylase. Lanosterol demethylase is essential for the synthesis of ergosterol, a major component of fungal cell membranes. Pharmacodynamics Luliconazole kills Trichophyton rubrum and Epidermophyton floccosum, likely through alteration of the fungal cell membrane. Luliconazole (NND 502) is a synthetic imidazole derivative antifungal agent with potent activity against a variety of fungi, particularly dermatophytes [1,2,3,4]. Its core mechanism of action is the selective inhibition of fungal CYP51, a key enzyme in ergosterol biosynthesis. Ergosterol consumption disrupts the structure and function of fungal cell membranes, leading to fungal growth inhibition and cell death [1,2]
- It exhibits strong activity against fluconazole-resistant Candida strains and drug-resistant dermatophytes, thus proving effective against refractory fungal skin infections [1,3] - Due to its high local concentration and negligible systemic absorption, ruliconazole (NND 502) is primarily used for the local treatment of fungal skin infections (tinea corporis, tinea cruris, tinea pedis) [2,3,4] |
| Molecular Formula |
C14H9CL2N3S2
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| Molecular Weight |
354.28
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| Exact Mass |
352.961
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| Elemental Analysis |
C, 47.46; H, 2.56; Cl, 20.01; N, 11.86; S, 18.10
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| CAS # |
187164-19-8
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| Related CAS # |
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| PubChem CID |
3003141
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| Appearance |
Off-white solid powder
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| Density |
1.5±0.1 g/cm3
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| Boiling Point |
499.1±55.0 °C at 760 mmHg
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| Flash Point |
255.6±31.5 °C
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| Vapour Pressure |
0.0±1.3 mmHg at 25°C
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| Index of Refraction |
1.734
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| LogP |
3.98
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| Hydrogen Bond Donor Count |
0
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| Hydrogen Bond Acceptor Count |
4
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| Rotatable Bond Count |
2
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| Heavy Atom Count |
21
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| Complexity |
476
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| Defined Atom Stereocenter Count |
1
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| 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
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| InChi Key |
YTAOBBFIOAEMLL-REQDGWNSSA-N
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| 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
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| Chemical Name |
(2E)-[(4R)-4-(2,4-Dichlorophenyl)-1,3-dithiolan-2-ylidene](1H-imidazol-1-yl)acetonitrile
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| Synonyms |
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
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| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
DMSO : 50 ~71 mg/mL ( 141.13 ~200.4 )
Ethanol : ~5 mg/mL |
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| 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. View More
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. Solubility in Formulation 4: 10% DMSO+40% PEG300+5% Tween-80+45% Saline: ≥ 2.5 mg/mL (7.06 mM) |
| 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.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
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