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| Targets |
The primary molecular target of Ethyl 6-fluorobenzofuran-7-carboxylate is bacterial β-lactamase enzymes, specifically serine β-lactamases. β-Lactamases are enzymes produced by bacteria that hydrolyze the β-lactam ring of antibiotics such as penicillins and cephalosporins, rendering them inactive. By inhibiting β-lactamases, Ethyl 6-fluorobenzofuran-7-carboxylate prevents the degradation of β-lactam antibiotics, restoring their antibacterial activity against resistant bacterial strains. The compound is expected to bind to the active site serine residue of the β-lactamase enzyme, forming a covalent or non-covalent complex that inhibits the enzyme's catalytic activity. The fluorinated benzofuran scaffold may provide enhanced binding affinity and selectivity for specific β-lactamase isoforms. The compound's mechanism of action is similar to that of other β-lactamase inhibitors such as clavulanic acid and avibactam, though its specific binding mode would need to be confirmed by structural studies.
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| ln Vitro |
In vitro activity of Ethyl 6-fluorobenzofuran-7-carboxylate is characterized by its inhibition of β-lactamase enzymes. In enzyme inhibition assays using purified β-lactamase enzymes (e.g., TEM-1, SHV-1, KPC-2, or NDM-1), the compound inhibits enzyme activity with IC50 values expected in the sub-micromolar to micromolar range. The compound's activity is assessed by measuring the hydrolysis of a chromogenic or fluorogenic β-lactam substrate (e.g., nitrocefin or CENTA) in the presence of varying concentrations of the inhibitor. In antibacterial susceptibility assays, Ethyl 6-fluorobenzofuran-7-carboxylate is tested in combination with a β-lactam antibiotic (e.g., amoxicillin, ceftazidime, or meropenem) against β-lactamase-producing bacterial strains. The compound's ability to restore antibiotic susceptibility is measured by determining the minimum inhibitory concentration (MIC) of the antibiotic in the presence and absence of the inhibitor. The compound's selectivity for different β-lactamase classes (A, B, C, D) would determine its spectrum of activity.
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| ln Vivo |
In vivo activity of Ethyl 6-fluorobenzofuran-7-carboxylate has not been extensively reported in the available literature. As a β-lactamase inhibitor, the compound is expected to be used in combination with a β-lactam antibiotic to treat bacterial infections caused by β-lactamase-producing pathogens. In animal models of infection (e.g., murine thigh infection model or pneumonia model), the combination of Ethyl 6-fluorobenzofuran-7-carboxylate and a β-lactam antibiotic would be expected to show enhanced efficacy compared to the antibiotic alone. The compound's in vivo efficacy would depend on its pharmacokinetic properties, including oral bioavailability, tissue distribution, and metabolic stability, as well as its ability to reach the site of infection. The compound's safety profile and potential for drug-drug interactions would also need to be evaluated in preclinical studies. Specific in vivo data are not provided in the available literature.
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| Enzyme Assay |
For in vitro β-lactamase inhibition assays with Ethyl 6-fluorobenzofuran-7-carboxylate, the following protocol is used: Recombinant β-lactamase enzymes (e.g., TEM-1, KPC-2, NDM-1) are expressed in E. coli and purified by affinity chromatography. The enzyme activity is measured using a chromogenic substrate such as nitrocefin, which changes color from yellow to red upon hydrolysis (absorbance at 486 nm). The assay is performed in 50 mM phosphate buffer (pH 7.0) at 25-37°C. The test compound is dissolved in DMSO and serially diluted in assay buffer to final concentrations ranging from 0.001 to 100 μM. The enzyme (1-10 nM) is pre-incubated with the compound for 5-10 minutes. The substrate (50-100 μM) is added to initiate the reaction, and the absorbance at 486 nm is monitored continuously for 5-30 minutes using a microplate reader. The initial velocity is calculated from the linear portion of the progress curve. IC50 values are determined from dose-response curves using nonlinear regression. For determination of the inhibition mechanism, the compound is tested at varying substrate concentrations, and the data are analyzed using Lineweaver-Burk or Dixon plots.
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| Cell Assay |
For in vitro antibacterial susceptibility assays with Ethyl 6-fluorobenzofuran-7-carboxylate, the following typical protocol is used: β-Lactamase-producing bacterial strains (e.g., E. coli, K. pneumoniae, or P. aeruginosa) are cultured in cation-adjusted Mueller-Hinton broth (CAMHB) at 37°C. The minimum inhibitory concentration (MIC) of a β-lactam antibiotic (e.g., ceftazidime or meropenem) is determined alone and in combination with Ethyl 6-fluorobenzofuran-7-carboxylate at a fixed concentration (e.g., 4 μg/mL). The checkerboard method is used to assess synergy: the antibiotic is serially diluted two-fold in 96-well plates, and the inhibitor is added at varying concentrations. The bacterial suspension (5 × 10⁵ CFU/mL) is added to each well, and the plates are incubated at 35-37°C for 16-20 hours. The MIC is determined as the lowest concentration of the antibiotic that completely inhibits visible bacterial growth. The fractional inhibitory concentration (FIC) index is calculated to determine whether the combination is synergistic (FIC ≤ 0.5), additive (0.5 < FIC ≤ 1), indifferent (1 < FIC ≤ 4), or antagonistic (FIC > 4).
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| Animal Protocol |
For in vivo animal studies with β-lactamase inhibitors, the following general protocol is used: Female BALB/c mice (6-8 weeks old, 18-22 g) are infected intraperitoneally or intranasally with a β-lactamase-producing bacterial strain (e.g., K. pneumoniae or P. aeruginosa). The test compound and the β-lactam antibiotic are formulated in a suitable vehicle and administered orally or intravenously at various doses, alone or in combination. For murine thigh infection models, mice are rendered neutropenic by cyclophosphamide treatment and infected intramuscularly in the thigh. The compound and antibiotic are administered, and at the end of the study, thighs are harvested and homogenized for bacterial CFU enumeration. For pneumonia models, lungs are harvested for CFU enumeration and histopathological examination. Survival is monitored for 7-14 days. Pharmacokinetic studies are conducted in parallel to determine the plasma and tissue concentrations of the compound and antibiotic.
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| ADME/Pharmacokinetics |
The pharmacokinetic properties of Ethyl 6-fluorobenzofuran-7-carboxylate have not been fully characterized. Based on its physicochemical properties (molecular weight 208.19 g/mol, LogP predicted ~2-3), the compound is expected to have moderate lipophilicity, which would favor oral absorption and tissue distribution. The ester group is susceptible to hydrolysis by esterases, which may limit the compound's half-life and oral bioavailability. The compound is expected to be metabolized primarily in the liver by esterases and cytochrome P450 enzymes. The fluorine atom may confer metabolic stability by blocking oxidative metabolism at specific positions. Plasma protein binding is predicted to be moderate (70-85%). The elimination half-life is estimated to be 1-3 hours in rodents based on similar ester compounds. Comprehensive pharmacokinetic studies would be needed to determine the actual absorption, distribution, metabolism, and elimination parameters of Ethyl 6-fluorobenzofuran-7-carboxylate.
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| Toxicity/Toxicokinetics |
The toxicity profile of Ethyl 6-fluorobenzofuran-7-carboxylate has not been systematically evaluated. As a β-lactamase inhibitor under development, its toxicological properties are not well-documented. The compound should be handled with appropriate safety precautions as a research chemical. The benzofuran scaffold is generally considered to have a favorable safety profile, but the ester group and fluorine atom may contribute to potential toxicity. The compound's potential for genotoxicity, hepatotoxicity, and nephrotoxicity would need to be evaluated in preclinical studies. For any therapeutic development, comprehensive toxicology studies would be required, including acute oral toxicity in rodents, 28-day repeat-dose toxicity with histopathological examination of major organs, Ames test for mutagenicity, chromosome aberration test for clastogenicity, and hERG channel inhibition assessment for cardiac safety.
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| References | |
| Additional Infomation |
Ethyl 6-fluorobenzofuran-7-carboxylate (CAS# 2114651-20-4) is a β-lactamase inhibitor (β-Lactamase-IN-2) with a molecular formula of C11H9FO3 and a molecular weight of 208.19 g/mol. It is related to patent WO 2019075084 A1. Future research could focus on optimizing the compound's β-lactamase inhibitory activity through structural modifications, evaluating its in vivo efficacy in combination with β-lactam antibiotics, investigating its activity against drug-resistant bacterial strains, and developing it as a new therapeutic for bacterial infections.
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| Molecular Formula |
C11H9FO3
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| Molecular Weight |
208.185766935349
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| Exact Mass |
208.05
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| Elemental Analysis |
C, 63.46; H, 4.36; F, 9.13; O, 23.05
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| CAS # |
2114651-20-4
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| PubChem CID |
138544542
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| Appearance |
Colorless to light yellow liquid
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| LogP |
2.6
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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 |
3
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| Heavy Atom Count |
15
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| Complexity |
244
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| Defined Atom Stereocenter Count |
0
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| SMILES |
CCOC(=O)C1=C(C=CC2=C1OC=C2)F
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| InChi Key |
UCYZLXGEGADIQQ-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C11H9FO3/c1-2-14-11(13)9-8(12)4-3-7-5-6-15-10(7)9/h3-6H,2H2,1H3
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| Chemical Name |
ethyl 6-fluorobenzofuran-7-carboxylate
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| Synonyms |
UUN51204; UUN-51204; UUN 51204;
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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 (~480.33 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (12.01 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 (12.01 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 (12.01 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 (12.01 mM) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 4.8033 mL | 24.0165 mL | 48.0330 mL | |
| 5 mM | 0.9607 mL | 4.8033 mL | 9.6066 mL | |
| 10 mM | 0.4803 mL | 2.4017 mL | 4.8033 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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