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| Targets |
DNA polymerase IIIC (pol IIIC), a replicative DNA polymerase essential for chromosomal DNA replication in low-G+C Gram-positive bacteria. ACX-362E binds to and inhibits the activity of pol IIIC, thereby blocking bacterial DNA synthesis. This inhibition is specific to bacterial polymerases and does not affect mammalian DNA polymerases, providing a basis for its selective antibacterial activity. By targeting pol IIIC, ACX-362E effectively halts bacterial cell division and growth, leading to a bactericidal effect. The compound's potency is demonstrated by its low MIC₅₀ value of 2 μg/mL against C. difficile. Its unique mechanism of action makes it a valuable tool for studying bacterial DNA replication and a potential therapeutic agent for treating C. difficile infections.
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| ln Vitro |
Ibezapolstat binds to and inhibits DNA pol IIIC of aerobic and low-G+C Gram-positive bacteria[1]. Ibezapolstat exhibits broad-spectrum antibacterial action against C. difficile pathogens, with in vitro MICs ranging from 1-8 μg/mL against 104 C. difficile clinical isolates [1].
ACX-362E exhibits potent in vitro antibacterial activity against C. difficile. In a study of 104 clinical isolates of C. difficile, the compound demonstrated in vitro MICs ranging from 1 to 8 μg/mL. This broad-spectrum activity against diverse clinical strains highlights its potential as a therapeutic agent. Its mechanism of action involves binding to and inhibiting DNA polymerase IIIC, which is essential for bacterial DNA replication. The compound's activity is specific to Gram-positive bacteria, as pol IIIC is not found in Gram-negative bacteria or in mammalian cells. Its physicochemical properties, including a LogP of 1.6 and a molecular weight of 423.3 g/mol, are consistent with a drug-like molecule. The compound is orally bioavailable, a critical property for an antimicrobial agent intended for outpatient use. |
| ln Vivo |
In a hamster model of Clostridium difficile-associated disease (CDAD), ibezapolstat is poorly absorbed and appears harmless (with the potential to achieve high local concentrations at sites of C. difficile infection in the colon) [3]. Ibezabolostat (oral; 50 mg/kg; twice daily; for 3 days) exhibits strong anti-C properties. difficult characteristics in a CDAD model of hamsters [3].
In vivo, ACX-362E has demonstrated significant efficacy in a hamster model of Clostridium difficile-associated disease (CDAD). When administered orally at a dose of 50 mg/kg twice daily for three days, the compound provided complete protection to C. difficile-infected animals, with survival sustained for up to five days. The compound is poorly absorbed from the gastrointestinal tract, which allows it to achieve high local concentrations at the site of C. difficile infection in the colon while minimizing systemic exposure and potential side effects. This favorable pharmacokinetic profile, combined with its potent antibacterial activity, makes ACX-362E a promising candidate for the treatment of CDI. |
| Enzyme Assay |
In vitro antibacterial susceptibility testing is the primary method for evaluating ACX-362E's activity. The minimum inhibitory concentration (MIC) is determined using broth microdilution or agar dilution methods according to CLSI guidelines. A range of C. difficile clinical isolates are tested. The compound is dissolved in a suitable solvent, typically DMSO, and then serially diluted in growth medium. The bacterial inoculum is added, and the plates are incubated anaerobically at 37°C for 48 hours. The MIC is the lowest concentration of the compound that inhibits visible bacterial growth. The compound's activity against a panel of C. difficile strains is assessed, and the MIC₅₀ (the concentration required to inhibit 50% of the strains) is calculated.
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| Cell Assay |
In vitro cell-based assays for ACX-362E are not typically performed, as the compound's target is bacterial, not mammalian, cells. However, cytotoxicity assays can be performed to evaluate its safety profile. Mammalian cell lines (e.g., HEK293 or HepG2 cells) are treated with varying concentrations of ACX-362E for 24-72 hours. Cell viability is then measured using a colorimetric assay such as MTT or CCK-8. The concentration that reduces cell viability by 50% (IC50) is calculated. These assays help to determine the compound's selectivity and potential for toxicity. The compound's effects on mammalian cell function, such as mitochondrial activity or membrane integrity, can also be studied.
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| Animal Protocol |
Animal/Disease Models: Female Syrian golden hamster (80-90 g), CDAD model [3]
Doses: 50 mg/kg Route of Administration: Orally, twice (two times) daily for 3 days Experimental Results: Complete protection of C. difficile-infected animals, sustained A period of up to 5 days. In vivo animal studies for ACX-362E are typically conducted in the hamster model of CDAD. Female Syrian golden hamsters (80-90 g) are infected with C. difficile and then treated with the compound. The compound is administered orally at a dose of 50 mg/kg twice daily for three days. The animals are monitored for survival, weight loss, and clinical signs of infection. Fecal samples are collected to measure bacterial counts. At the end of the study, the animals are euthanized, and the cecal tissue is collected for histopathological analysis. These studies provide critical data on the compound's in vivo efficacy and safety. |
| ADME/Pharmacokinetics |
The pharmacokinetic properties of ACX-362E are characterized by its poor oral absorption, which is a desirable feature for a drug targeting C. difficile infection in the colon. This allows the compound to achieve high local concentrations in the gastrointestinal tract while minimizing systemic exposure and potential side effects. The compound is metabolized in the liver and excreted in the feces. Its half-life in the body is relatively short. For research purposes, it is soluble in DMSO and can be formulated for oral administration. The compound should be stored as a powder at -20°C for long-term stability.
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| Toxicity/Toxicokinetics |
The toxicological profile of ACX-362E is not extensively documented in the literature. In the hamster model of CDAD, the compound appeared to be well-tolerated at the tested dose of 50 mg/kg. No significant adverse effects were reported. However, as a novel antibiotic, its safety profile would need to be fully evaluated in preclinical and clinical studies. For laboratory handling, standard safety precautions for research chemicals should be observed, including the use of personal protective equipment (gloves, lab coat, safety goggles). The compound is intended for research use only and is not for human therapeutic or diagnostic use.
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| References |
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| Additional Infomation |
Ibezapolstat is being studied in the clinical trial NCT04247542 (ACX-362E [Ibezapolstat] for oral treatment of Clostridium difficile infection).
ACX-362E is also known as Ibezapolstat. It is an orally bioavailable DNA polymerase IIIC inhibitor being developed for the treatment of Clostridium difficile infection. The compound has been studied in clinical trials, including NCT04247542. It exhibits potent in vitro and in vivo activities against C. difficile. ACX-362E has a molecular formula of C₁₈H₂₀Cl₂N₆O₂ and a molecular weight of 423.30 g/mol. It is supplied as a white to off-white solid powder with a purity of ≥98%. The compound is for research use only. |
| Molecular Formula |
C18H20CL2N6O2
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|---|---|
| Molecular Weight |
423.2964
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| Exact Mass |
422.102
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| CAS # |
1275582-97-2
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| PubChem CID |
136022209
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| Appearance |
White to off-white solid powder
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| LogP |
1.6
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
5
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| Rotatable Bond Count |
6
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| Heavy Atom Count |
28
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| Complexity |
588
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| Defined Atom Stereocenter Count |
0
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| SMILES |
ClC1=C(C=CC(=C1)CNC1=NC2=C(C(N1)=O)N(C=N2)CCN1CCOCC1)Cl
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| InChi Key |
DEGSGBKTODESHH-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C18H20Cl2N6O2/c19-13-2-1-12(9-14(13)20)10-21-18-23-16-15(17(27)24-18)26(11-22-16)4-3-25-5-7-28-8-6-25/h1-2,9,11H,3-8,10H2,(H2,21,23,24,27)
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| Chemical Name |
2-[(3,4-dichlorophenyl)methylamino]-7-(2-morpholin-4-ylethyl)-1H-purin-6-one
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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 : ~62.5 mg/mL (~147.65 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.08 mg/mL (4.91 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 (4.91 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 20.8 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: ≥ 2.08 mg/mL (4.91 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 | 2.3624 mL | 11.8120 mL | 23.6239 mL | |
| 5 mM | 0.4725 mL | 2.3624 mL | 4.7248 mL | |
| 10 mM | 0.2362 mL | 1.1812 mL | 2.3624 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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