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| Targets |
LolCDE-IN-1 targets the LolCDE complex, an ATP-binding cassette (ABC) transporter that is essential for the localization of lipoproteins to the outer membrane of Gram-negative bacteria. This complex consists of three proteins: LolC, LolD, and LolE. By inhibiting the ATPase activity or the substrate binding of this complex, LolCDE-IN-1 prevents the release of lipoproteins from the inner membrane and their subsequent transport to the outer membrane. This disruption of lipoprotein localization leads to the accumulation of lipoproteins in the inner membrane and ultimately results in bacterial cell death.
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| ln Vitro |
LolCDE-IN-1 (compound 2) impedes the activity of the LolCDE complex, which is necessary for lipoprotein transportation to the external membrane [1]. LolCDE-IN-1 suppresses E. bacteria ATCC 25922 and E. Coli ATCC 25922 ΔtolC, whose respective MICs were 8 μg/ml and 0.125 μg/ml[1]. By focusing on LolCDE and preventing lipoprotein transport to the outer membrane, LolCDE-IN-1 suppresses the development of bacteria [1].
In vitro, LolCDE-IN-1 demonstrates significant antibacterial activity against both tolC-deficient and wild-type Escherichia coli strains. The minimum inhibitory concentration (MIC) of LolCDE-IN-1 against E. coli ATCC 25922 is 8 μg/mL, while its activity is significantly enhanced against the tolC-deficient strain, with an MIC of 0.125 μg/mL. This increased activity against the tolC-deficient strain suggests that the compound may be a substrate of the TolC efflux pump. The antibacterial activity of LolCDE-IN-1 is specific to the LolCDE complex, as it does not show significant activity against other bacterial targets. |
| ln Vivo |
In vivo, the efficacy of LolCDE-IN-1 has not been extensively reported in the literature. However, its potent in vitro activity against E. coli suggests that it has the potential to be developed into an in vivo antibacterial agent. The compound's mechanism of action, which targets a conserved and essential pathway in Gram-negative bacteria, makes it an attractive candidate for further preclinical development. Studies to evaluate its pharmacokinetic properties and efficacy in animal models of infection would be necessary to advance its development.
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| Enzyme Assay |
In vitro enzyme/receptor binding assays for LolCDE-IN-1 involve measuring its inhibition of the LolCDE complex activity. The assay is typically performed using membrane preparations containing the LolCDE complex or using purified recombinant proteins. The ATPase activity of the LolCDE complex is measured in the presence of varying concentrations of the compound, and the IC50 value is calculated. Alternatively, the binding of the compound to the LolCDE complex can be assessed using surface plasmon resonance (SPR) or isothermal titration calorimetry (ITC). These assays are essential for characterizing the compound's mechanism of action and potency.
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| Cell Assay |
In vitro cellular experiments for LolCDE-IN-1 are performed using bacterial cultures to assess its antibacterial activity. The minimum inhibitory concentration (MIC) is determined by the broth microdilution method according to Clinical and Laboratory Standards Institute (CLSI) guidelines. Bacteria are grown in Mueller-Hinton broth and incubated with serial dilutions of the compound. The MIC is defined as the lowest concentration of the compound that inhibits visible bacterial growth after 18-24 hours of incubation. Time-kill assays can also be performed to assess the bactericidal or bacteriostatic nature of the compound.
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| Animal Protocol |
In vivo animal studies for LolCDE-IN-1 have not been extensively reported in the literature. However, if developed, such studies would typically involve mouse models of bacterial infection. Mice would be infected with a pathogenic strain of E. coli, and the compound would be administered via intravenous, intraperitoneal, or oral routes. The efficacy of the treatment would be evaluated by monitoring survival, bacterial burden in tissues, and clinical signs of infection. Pharmacokinetic parameters would also be assessed from plasma samples.
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| ADME/Pharmacokinetics |
The pharmacokinetic properties of LolCDE-IN-1 have not been extensively characterized in the literature. As a small molecule with a molecular weight of 345.37 g/mol, it is expected to have reasonable oral bioavailability if formulated appropriately. The compound's lipophilicity and plasma protein binding would influence its distribution and half-life. Metabolism would likely occur in the liver via cytochrome P450 enzymes. Future studies to characterize its pharmacokinetic profile would be essential for its development as an antibacterial agent.
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| Toxicity/Toxicokinetics |
The toxicity profile of LolCDE-IN-1 has not been extensively reported in the literature. As a compound targeting a bacterial-specific pathway, it is expected to have a low potential for off-target toxicity in mammalian cells. However, standard toxicology studies would be required to assess its safety profile. These studies would include assessments of acute and sub-chronic toxicity, genotoxicity, and cardiovascular safety. The compound's selectivity for the bacterial LolCDE complex over mammalian targets would be a key factor in its safety profile.
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| References |
[1]. Nayar AS, et al. Novel antibacterial targets and compounds revealed by a high-throughput cell wall reporter assay. J Bacteriol. 2015 May;197(10):1726-34.
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| Additional Infomation |
LolCDE-IN-1 is a novel antibacterial compound that targets the LolCDE complex, a key component of the lipoprotein transport system in Gram-negative bacteria. By inhibiting this essential pathway, the compound disrupts the localization of lipoproteins to the outer membrane, leading to bacterial cell death. It demonstrates potent activity against E. coli, with enhanced activity against tolC-deficient strains. LolCDE-IN-1 represents a promising lead compound for the development of new antibiotics targeting Gram-negative pathogens, addressing the growing threat of antibiotic resistance.
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| Molecular Formula |
C₂₁H₁₆FN₃O
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|---|---|
| Molecular Weight |
345.37
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| Exact Mass |
345.127
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| CAS # |
1639933-78-0
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| PubChem CID |
118720981
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| Appearance |
Typically exists as solid at room temperature
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| LogP |
4
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
4
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| Rotatable Bond Count |
5
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| Heavy Atom Count |
26
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| Complexity |
424
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| Defined Atom Stereocenter Count |
0
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| SMILES |
C1=CC(=CC(=C1)OCC2=CC=C(C=C2)F)C3=C(C=NN3)C4=CC=NC=C4
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| InChi Key |
DNZHPYAAJMOOPF-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C21H16FN3O/c22-18-6-4-15(5-7-18)14-26-19-3-1-2-17(12-19)21-20(13-24-25-21)16-8-10-23-11-9-16/h1-13H,14H2,(H,24,25)
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| Chemical Name |
4-[5-[3-[(4-fluorophenyl)methoxy]phenyl]-1H-pyrazol-4-yl]pyridine
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| Synonyms |
LolCDEIN1; LolCDE IN 1
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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 : ~41.67 mg/mL (~120.65 mM)
H2O : < 0.1 mg/mL |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.08 mg/mL (6.02 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 20.8 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: ≥ 2.08 mg/mL (6.02 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 20.8 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.8954 mL | 14.4772 mL | 28.9545 mL | |
| 5 mM | 0.5791 mL | 2.8954 mL | 5.7909 mL | |
| 10 mM | 0.2895 mL | 1.4477 mL | 2.8954 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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