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| Targets |
Succinate dehydrogenase (SQR, also known as complex II) in the mitochondrial electron transport chain of dermatophyte species, specifically Trichophyton rubrum and Trichophyton mentagrophytes. ME1111 exerts its antifungal effect by selectively targeting and inhibiting succinate dehydrogenase, disrupting ATP production and leading to fungal cell death. The target was confirmed by whole-genome analysis of laboratory-generated resistant mutants which revealed point mutations in the structural regions of genes encoding subunits of succinate dehydrogenase (SdhB, SdhC, or SdhD). ME1111 shows a selective profile with significantly stronger inhibition of fungal SQR compared to the human equivalent.
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| ln Vitro |
Trichophyton mentagrophytes TIMM 2789 is inhibited by ME1111 with MICs of 0.25 μg/mL and 0.5 μg/mL in SDB and RPMI 1640 medium, respectively [1]. ME1111 primarily modifies cell membrane permeability [1]. ME1111 only exhibits modest inhibition in human cell lines, while it strongly inhibits the succinate-2,6-dichlorophenol reductase process in Trichophyton rubrum and Trichophyton mentagrophytes (IC50: 0.029 μg/mL, 0.025 μg/mL) [2].
ME1111 demonstrates potent antifungal activity against dermatophyte reference strains with an MIC range of 0.12 to 0.5 mg/L and an MIC50 and MIC90 of 0.5 mg/L for both Trichophyton rubrum and Trichophyton mentagrophytes. The MIC90 of ME1111 against dermatophyte strains was 0.25 μg/ml, equivalent to that of the comparators amorolfine and ciclopirox (0.25 and 0.5 μg/ml, respectively). ME1111 is fungicidal at clinically achievable concentrations, with MFC90s against T. rubrum and T. mentagrophytes of 8 μg/ml, comparable to ciclopirox. ME1111 strongly inhibited the succinate-2,6-dichlorophenolindophenol reductase reaction in T. rubrum and T. mentagrophytes with IC50s of 0.029 and 0.025 μg/ml, respectively. |
| ln Vivo |
In vivo, ME1111's excellent nail penetration allows it to reach the site of fungal infection beneath the nail plate, making it effective for onychomycosis treatment. The small molecular weight of ME1111 (202.25 g/mol) is a key attribute that facilitates penetration through the human nail plate. In animal models of onychomycosis, topical application of ME1111 results in effective fungal clearance due to its ability to penetrate the nail barrier and reach the target site of infection. The compound's selective inhibition of fungal succinate dehydrogenase over the human enzyme contributes to its favorable therapeutic index for topical use.
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| Enzyme Assay |
In vitro enzyme assays involve measuring inhibition of succinate dehydrogenase activity from Trichophyton species, typically by monitoring the decrease in enzyme-catalyzed substrate conversion in the presence of various concentrations of ME1111. The inhibitory effect on the candidate target is evaluated by a spectrophotometric enzyme assay using mitochondrial fractions. Specifically, the succinate-2,6-dichlorophenolindophenol reductase reaction is measured in T. rubrum and T. mentagrophytes mitochondrial fractions. IC50 values (0.029 and 0.025 μg/ml respectively) are determined from concentration-response curves. Point mutations are introduced into candidate genes by reverse genetics to confirm target specificity.
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| Cell Assay |
Cell viability assay[1]
Cell Types: T. mentagrophytes TIMM 2789 Tested Concentrations: 0.125 μg/mL, 0.0625 μg/mL Incubation Duration: 4 hrs (hours), 8 hrs (hours), 24 hrs (hours) Experimental Results: Inhibition of mycelial growth in a dose-dependent and time-dependent manner dependent manner and induce various morphological changes. Cellular antifungal activity is assessed using broth microdilution methods in media such as SDB and RPMI 1640, with MIC values determined against dermatophyte strains including T. rubrum and T. mentagrophytes (n=400 for MIC, n=300 for MFC). ME1111's MIC90 against dermatophyte strains was 0.25 μg/ml, equivalent to amorolfine and superior to ciclopirox (0.5 μg/ml). ME1111 was fungicidal at clinically achievable concentrations with MFC90s against T. rubrum and T. mentagrophytes of 8 μg/ml. Resistance development potential was examined in 4 dermatophytes following repeated exposure, and ME1111, like ciclopirox, did not induce resistance. |
| Animal Protocol |
In vivo animal models for onychomycosis typically involve topical application of ME1111 to infected nails in appropriate animal models (such as guinea pigs or other suitable species), followed by assessment of fungal clearance and nail penetration. The compound's small molecular weight (202.25 g/mol) facilitates penetration through the nail plate. Efficacy is evaluated by measuring fungal burden reduction, clinical score improvement, and histopathological examination of nail tissue. Pharmacokinetic studies focus on nail penetration and local tissue distribution following topical application.
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| ADME/Pharmacokinetics |
Pharmacokinetic studies of ME1111 focus on its penetration into human nails and local tissue distribution following topical application, with minimal systemic absorption expected due to its topical route of administration. The small molecular weight of 202.25 g/mol facilitates penetration through the human nail plate to reach the site of fungal infection. As a topical agent for onychomycosis, ME1111 is designed to achieve high local concentrations in the nail and nail bed while minimizing systemic exposure, reducing the risk of systemic side effects commonly associated with oral antifungal agents like terbinafine and itraconazole.
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| Toxicity/Toxicokinetics |
Preclinical toxicity studies have shown ME1111 exhibits only modest inhibitory effects in human cell lines, indicating a favorable safety profile for topical use. ME1111 demonstrates significantly stronger inhibition of fungal succinate dehydrogenase compared to the human equivalent, contributing to its selective toxicity profile. In human cell lines, ME1111 showed only moderate inhibition of the succinate-2,6-dichlorophenolindophenol reductase reaction. The compound has low potential for the development of resistance in dermatophytes, as demonstrated by repeated exposure studies in 4 dermatophyte strains where ME1111, like ciclopirox, did not induce resistance.
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| References |
[1]. Nishiyama Y, et al. Morphological Effect of the New Antifungal Agent ME1111 on Hyphal Growth of Trichophyton mentagrophytes, Determined by Scanning and Transmission Electron Microscopy. Antimicrob Agents Chemother. 2016 Dec 27;61(1).
[2]. Takahata S, et al. Mechanism of Action of ME1111, a Novel Antifungal Agent for Topical Treatment of Onychomycosis. Antimicrob Agents Chemother. 2015 Nov 23;60(2):873-80. |
| Additional Infomation |
ME-1111 is a succinate dehydrogenase inhibitor of Trichophyton species that has been evaluated in preclinical and clinical trials for onychomycosis. Its mechanism of action indicates a selective profile, targeting the mitochondrial electron transport chain of dermatophytes and disrupting ATP production. The compound is being developed as a topical agent, offering a potential alternative to oral antifungals which suffer from disadvantages including drug interactions and potential liver toxicity. ME1111's small molecular weight enhances its ability to penetrate the nail plate, and studies suggest it has low potential for resistance development.
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| Molecular Formula |
C12H14N2O
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| Molecular Weight |
202.2524
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| Exact Mass |
202.11
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| CAS # |
1391758-52-3
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| PubChem CID |
60143882
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| Appearance |
White to light yellow solid powder
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| LogP |
2.7
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
2
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| Rotatable Bond Count |
1
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| Heavy Atom Count |
15
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| Complexity |
222
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| Defined Atom Stereocenter Count |
0
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| InChi Key |
VQXHPRBERPTLQW-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C12H14N2O/c1-8-4-5-11(12(15)6-8)14-10(3)7-9(2)13-14/h4-7,15H,1-3H3
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| Chemical Name |
2-(3,5-dimethylpyrazol-1-yl)-5-methylphenol
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| Synonyms |
ME1111 ME 1111 ME-1111
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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 |
| 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 : ~100 mg/mL (~494.44 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (12.36 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 (12.36 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 (12.36 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 4.9444 mL | 24.7219 mL | 49.4438 mL | |
| 5 mM | 0.9889 mL | 4.9444 mL | 9.8888 mL | |
| 10 mM | 0.4944 mL | 2.4722 mL | 4.9444 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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