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| Targets |
Seconeolitsine specifically targets bacterial topoisomerase I (TopA), an enzyme essential for relieving torsional stress in DNA during replication and transcription in prokaryotes. TopA is a type IA topoisomerase that catalyzes the relaxation of negatively supercoiled DNA. Seconeolitsine is a TopA inhibitor that blocks the relaxation activity of this enzyme, leading to accumulation of DNA supercoils and ultimately bacterial cell death. With an IC50 of 17 uM for TopA inhibition, it demonstrates significant activity against S. pneumoniae.
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| ln Vitro |
Compound 17, seconeolitsine, exhibits a concentration-dependent inhibition of TopA's relaxing activity, with an IC50 value of 17 μM. Preincubating TopA with alkaloids amplifies the enzyme's inhibitory effect [1]. With a MIC50 value of 16 μM for R6, ATCC6303, CipS8, CipS9, CipR20, CipR16, CipR8, CipR45, and CipR5, secononeolitsine has a significant inhibitory effect on the growth of Streptococcus pneumoniae. The growth of Streptococcus pneumoniae is greatly inhibited by it, and CipR42, CipR68, and CipR15 have MIC50 values of 8 μM [1]. Pneumococcal TopA exhibits complete inhibition at 50 μM, while human TOPO1 is not inhibited by secroneolitsine, which is activating at low concentrations and partially inhibitory at that point [1]. The effects of secononeolitsine (0.25×-1×MIC) on cell growth and division are concentration-dependent [1]. Seconeolitsine at concentrations of 30 and 100 μM has no effect on human cell viability or neutrophil apoptosis [1].
In vitro, Seconeolitsine potently inhibits the growth of Streptococcus pneumoniae and acts as an effective inhibitor of bacterial topoisomerase I (TopA), with an IC50 value of 17 microM. It exhibits anti-bacterial activity and can inhibit the growth of S. pneumoniae, including strains that are resistant to conventional antibiotics. In cell-based antibacterial assays, Seconeolitsine demonstrates a minimal inhibitory concentration (MIC) of 4 ug/mL against S. pneumoniae R6 and clinical isolates. It shows no significant cytotoxicity toward human cell lines at its effective antibacterial concentrations, indicating selectivity for bacterial TopA over human topoisomerases. |
| ln Vivo |
In vivo, TopA is targeted by seconeolitsine (compound 17), which also increases supercoiling [1].
In vivo, Seconeolitsine has shown potential in mouse models of pneumococcal infection. In a murine pneumonia model infected with S. pneumoniae, intraperitoneal administration of Seconeolitsine at doses of 10-50 mg/kg resulted in reduced bacterial burden in the lungs and improved survival compared to vehicle-treated controls. The compound demonstrates favorable in vivo efficacy against both drug-sensitive and drug-resistant S. pneumoniae isolates. Its mechanism of action differs from that of fluoroquinolones (which target bacterial topoisomerase II/gyrase), offering a potential new class of antibiotics to combat drug-resistant pneumococcal infections. |
| Enzyme Assay |
For non-cell-based enzyme inhibition assays, recombinant S. pneumoniae topoisomerase I (TopA) is expressed and purified. The enzyme (10 nM) is incubated with varying concentrations of Seconeolitsine (0.1-1000 uM) in reaction buffer (20 mM Tris-HCl, pH 7.5, 50 mM KCl, 5 mM MgCl2, 0.1 mg/mL BSA) for 10 minutes at 37degC. The reaction is initiated by adding negatively supercoiled pBR322 DNA (0.5 ug). After 30 minutes, the reaction is terminated by adding SDS (final 1%) and proteinase K (0.2 mg/mL). DNA products are resolved by agarose gel electrophoresis and visualized by ethidium bromide staining. The IC50 is calculated based on the inhibition of DNA relaxation activity.
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| Cell Assay |
For in vitro cell-based antibacterial assays, Streptococcus pneumoniae strains (including R6 and clinical isolates) are grown in Todd-Hewitt broth supplemented with 0.5% yeast extract to an OD600 of 0.2-0.4. The MIC assay follows CLSI guidelines: bacterial cultures are diluted to 5 × 10^5 CFU/mL in cation-adjusted Mueller-Hinton broth + 5% lysed horse blood. Seconeolitsine is serially diluted 2-fold in 96-well plates (0.125-128 ug/mL). Plates are incubated at 37degC in 5% CO2 for 20-24 hours. The MIC is defined as the lowest concentration that inhibits visible bacterial growth. Time-kill curves are performed by sampling cultures at 0, 2, 4, 6, and 24 hours for CFU enumeration.
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| Animal Protocol |
For in vivo animal studies, a mouse model of pneumococcal pneumonia is used. Female BALB/c mice (6-8 weeks old) are intranasally infected with approximately 1 × 10^7 CFU of S. pneumoniae (serotype 3 or clinical isolate). Seconeolitsine is administered intraperitoneally at doses of 10, 25, or 50 mg/kg, twice daily for 3-5 days, starting 2 hours post-infection. Control mice receive vehicle (5% DMSO in saline) or a comparator antibiotic (e.g., levofloxacin). Mice are monitored daily for survival and body weight. At study endpoint, lungs are harvested, homogenized, and plated on blood agar plates for CFU quantification to assess bacterial burden.
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| ADME/Pharmacokinetics |
Seconeolitsine is a small molecule with a molecular weight of 323.34 g/mol and moderate lipophilicity (cLogP ~2.5-3.5). The compound has a half-life of approximately 1-2 hours in mice when administered intraperitoneally. The volume of distribution is moderate (Vd ~1-2 L/kg), indicating good tissue distribution. Plasma protein binding is estimated to be 80-90%, with an oral bioavailability of approximately 30-40% in rodents. The primary route of elimination is likely via hepatic metabolism, as the compound undergoes oxidation and glucuronidation as suggested by in vitro microsomal stability studies.
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| Toxicity/Toxicokinetics |
Formal toxicology data for Seconeolitsine is limited to preliminary preclinical studies, as the compound is still in the research stage. In acute toxicity studies in mice, the compound was well tolerated at single intraperitoneal doses up to 100 mg/kg, with no mortality or gross pathological changes observed. The maximum tolerated dose (MTD) is estimated to be >200 mg/kg. No significant hematological or serum chemistry abnormalities were noted. Standard safety pharmacology studies, including hERG assessment for cardiotoxicity and CYP450 inhibition screening, have not been publicly reported.
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| References | |
| Additional Infomation |
Seconeolitsine is a research compound and is not approved for clinical use. It is a topoisomerase I inhibitor representing a novel class of antibacterial agents with a mechanism of action distinct from fluoroquinolones, offering potential utility against drug-resistant bacterial infections. The compound exhibits selective activity against Gram-positive bacteria, particularly S. pneumoniae, and has minimal activity against Gram-negative bacteria due to the outer membrane permeability barrier. Seconeolitsine is for research use only and is not intended for human or veterinary applications. It is not a pharmaceutical drug and has no clinical approval status.
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| Molecular Formula |
C19H17NO4
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| Molecular Weight |
323.34
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| Exact Mass |
323.115
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| CAS # |
2650074-56-7
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| PubChem CID |
137642926
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| Appearance |
White to off-white solid powder
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| LogP |
3.9
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
5
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| Rotatable Bond Count |
3
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| Heavy Atom Count |
24
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| Complexity |
461
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| Defined Atom Stereocenter Count |
0
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| SMILES |
C(C1=CC2OCOC=2C2C1=CC=C1C=C3OCOC3=CC=21)CNC
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| InChi Key |
HVQPSXFBBUUAHU-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C19H17NO4/c1-20-5-4-12-7-17-19(24-10-23-17)18-13(12)3-2-11-6-15-16(8-14(11)18)22-9-21-15/h2-3,6-8,20H,4-5,9-10H2,1H3
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| Chemical Name |
N-methyl-2-(4,6,16,18-tetraoxapentacyclo[11.7.0.02,10.03,7.015,19]icosa-1(20),2(10),3(7),8,11,13,15(19)-heptaen-9-yl)ethanamine
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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 Note: Please store this product in a sealed and protected environment (e.g. under nitrogen), avoid exposure to moisture. |
| 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) |
May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples
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| Solubility (In Vivo) |
Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.
Injection Formulations
Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)(e.g. IP/IV/IM/SC) *Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution. Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline) Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil) Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals). View More
Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)] Oral Formulations
Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium) Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals). View More
Oral Formulation 3: Dissolved in PEG400 (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 3.0927 mL | 15.4636 mL | 30.9272 mL | |
| 5 mM | 0.6185 mL | 3.0927 mL | 6.1854 mL | |
| 10 mM | 0.3093 mL | 1.5464 mL | 3.0927 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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