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Purity: ≥98%
SC75741 (SC-75741; SC 75741) is a novel, selective and potent NF-κB inhibitor with potential antiviral and anti-inflammatory activity. With an EC50 of 200 nM, it blocks NF-κB. In non-toxic concentrations, SC75741 prevents influenza viruses (IV) from replicating. Reduced expression of cytokines, chemokines, and pro-apoptotic factors is the result of SC75741's impairment of NF-κB subunit p65's DNA binding. Following this, SC75741 prevents caspase activation and obstructs the nuclear export of viral ribonucleoproteins caused by caspase. The inhibitory potential of 5 uM SC75741 on virus replication in MDCK cells is greatest later in infection. SC75741 caused an effective, dose-dependent decline in viral titers in the human alveolar type II epithelial cell line A549 that was infected with the H5N1 and H7N7 viruses.
| Targets |
NF-κB (EC50 = 200 nM)
Nuclear Factor-κB (NF-κB) p65 Subunit: SC75741 selectively inhibits the nuclear translocation and DNA-binding activity of the NF-κB p65 subunit. It inhibits NF-κB-driven reporter gene activity in HEK293T cells with an IC50 of 0.8 ± 0.1 μM, and suppresses influenza A virus (IAV)-induced p65 nuclear translocation in A549 cells with an EC50 of 1.1 ± 0.2 μM [2] - Influenza A Virus (IAV) Replication: SC75741 indirectly inhibits IAV replication by targeting the NF-κB pathway (not direct viral proteins), with EC50 values of 1.2 ± 0.3 μM (H5N1), 1.5 ± 0.2 μM (H1N1), and 1.4 ± 0.3 μM (H3N2) in MDCK cells (determined by viral titer measurement) [2] |
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| ln Vitro |
SC75741 exhibits immunosuppressive activity by limiting the proliferation of human PBMCs with IC50 of 2.2 μM.[1] SC75741 inhibits transcriptional levels of NF-κB mediated signaling, which prevents the replication of influenza A and B viruses. Additionally, SC75741 exhibits a high barrier to the emergence of virus variants with resistance.[2]
Inhibition of IAV Replication (Multiple Strains): MDCK cells (canine kidney epithelial cells) were infected with IAV strains (H5N1, H1N1, H3N2) at a multiplicity of infection (MOI) of 0.01, then treated with SC75741 (0.1–20 μM) for 48 hours. Viral titers (measured by TCID50 assay) showed concentration-dependent inhibition: at 1 μM, titers of H5N1, H1N1, and H3N2 were reduced by 68%, 62%, and 65% respectively; at 5 μM, titers were reduced by >90% for all strains. No significant inhibition of viral entry (measured by viral nucleoprotein (NP) internalization at 1 hour post-infection) or early replication (viral RNA synthesis at 6 hours post-infection) was observed, indicating SC75741 acts at the late stage of IAV replication [2] - Suppression of NF-κB Activation in IAV-Infected Cells: A549 cells (human alveolar epithelial cells) were infected with H5N1 (MOI=0.1) and treated with SC75741 (0.5–5 μM) for 24 hours. Western blot analysis showed that SC75741 dose-dependently reduced IAV-induced p65 nuclear translocation (by 45% at 1 μM, 72% at 3 μM, 90% at 5 μM) without affecting IκBα phosphorylation or degradation (upstream of p65). RT-PCR and ELISA confirmed that SC75741 also decreased IAV-induced mRNA and protein levels of pro-inflammatory cytokines: TNF-α (reduced by 70% at 5 μM), IL-6 (reduced by 65% at 5 μM), and IFN-β (reduced by 60% at 5 μM) [1,2] |
| ln Vivo |
SC75741 (15 mg/kg i.p.) reduces virus replication and cytokine expression in mice lungs after H5N1 influenza virus infection. Mice that have been exposed to SC75741 (intraperitoneal injection; 15 mg/kg; for 2 days) have 90% less H5N1 virus mRNA spread throughout their lungs.
The half-life of SC74751 is approximately 40 minutes, and its plasma levels (intravenously administered at 5 mg/kg and intraperitoneally administered at 15 mg/kg; for 3.5 and 6 hours) decrease mono-exponentially after intravenous administration. SC75741 has a half-life of 55 minutes after being administered intravenously, and it appears that this is due to a slow peritoneal uptake of the drug. Protection Against Lethal H5N1 Infection in Mice: Female BALB/c mice (6–8 weeks old) were intranasally infected with a lethal dose (10×50% egg infectious dose, EID50) of H5N1 virus. SC75741 was administered via intraperitoneal injection at a dose of 20 mg/kg/day at 1 hour, 24 hours, and 48 hours post-infection (3 total doses). Compared to the vehicle control group (DMSO + saline), SC75741 treatment significantly improved survival rate (from 0% to 60% at 14 days post-infection) and reduced body weight loss (from 35% to 12% at 7 days post-infection). Lung viral titers (measured by TCID50) in the treatment group were 100-fold lower than controls at 3 days post-infection. Histopathological analysis of lung tissue showed that SC75741 attenuated H5N1-induced pulmonary inflammation: reduced alveolar edema, neutrophil infiltration, and epithelial cell damage (histology score decreased from 8.5 ± 1.2 to 3.2 ± 0.8) [1] - Reduction of Systemic Inflammation in Mice: Serum from H5N1-infected mice treated with SC75741 (20 mg/kg) showed significantly lower levels of TNF-α (from 950 ± 80 pg/mL to 280 ± 40 pg/mL) and IL-6 (from 1200 ± 100 pg/mL to 320 ± 50 pg/mL) at 3 days post-infection (measured by ELISA). Immunohistochemical staining of lung tissue revealed that SC75741 inhibited p65 nuclear accumulation in alveolar epithelial cells and macrophages (positive cell rate decreased from 65% to 20%) [1] |
| Enzyme Assay |
In accordance with the manufacturer's instructions, the A549-NF-κB-SEAP cell line is used to prepare the NF-κB reporter gene assay. In essence, pNF-κB-SEAP reporter gene plasmid-stably transfected A549 cells are plated and given the night to attach. The cells are then stimulated with 10 ng/ml TNF-α for 22 hours after being incubated with the aforementioned compounds at concentrations of 100, 30, 10, 3, 1, 0.3, 0.1, and 0 μM for 5 hours. Using a chemiluminescent SEAP reporter gene assay, the cell's supernatant is examined for SEAP activity.
NF-κB Reporter Gene Assay: HEK293T cells were co-transfected with an NF-κB-luciferase reporter plasmid (pNF-κB-luc) and a Renilla luciferase internal control plasmid (pRL-TK) using a transfection reagent. Twenty-four hours post-transfection, cells were treated with SC75741 (0.1–10 μM) for 2 hours, then stimulated with TNF-α (10 ng/mL) for 6 hours. Cells were lysed with passive lysis buffer, and luciferase activity was measured using a dual-luciferase assay system. The relative luciferase activity (firefly/Renilla) was calculated, and the IC50 was determined as the concentration of SC75741 that inhibited 50% of TNF-α-induced reporter activity [2] - NF-κB p65 DNA-Binding Assay (EMSA): Nuclear extracts were prepared from H5N1-infected A549 cells (MOI=0.1, 24 hours post-infection) treated with SC75741 (0.5–5 μM). Extracts (10 μg protein) were incubated with a 32P-labeled double-stranded oligonucleotide containing the NF-κB consensus binding site (5′-AGTTGAGGGGACTTTCCCAGGC-3′) in binding buffer (20 mM Tris-HCl pH7.5, 50 mM NaCl, 1 mM DTT, 10% glycerol, 0.5 μg poly(dI-dC)) for 20 minutes at room temperature. Samples were separated by 6% non-denaturing polyacrylamide gel electrophoresis, dried, and exposed to X-ray film. Band intensity of the p65-DNA complex was quantified using ImageJ, and inhibition rate was calculated relative to infected, untreated controls [2] |
| Cell Assay |
Cell viability assay is prepared using a CellTiter-BluTM Cell Viability Assay. Four replicates are measured for each compound concentration.
IAV Viral Titer Measurement (TCID50 Assay): MDCK cells were seeded in 96-well plates at 2×10⁴ cells/well and cultured overnight. Cells were infected with IAV (H5N1, H1N1, H3N2) at MOI=0.01 for 1 hour at 37°C, then the inoculum was removed and replaced with medium containing SC75741 (0.1–20 μM). After 48 hours of incubation, culture supernatants were collected and serially diluted (10⁻¹ to 10⁻⁸) in fresh medium. Diluted supernatants were added to new MDCK cell monolayers and incubated for 72 hours. Cytopathic effect (CPE) was observed under a microscope, and the 50% tissue culture infectious dose (TCID50) was calculated using the Reed-Muench method [2] - Western Blot for NF-κB Activation Markers: A549 cells were infected with H5N1 (MOI=0.1) and treated with SC75741 (0.5–5 μM) for 24 hours. Cytoplasmic and nuclear extracts were prepared using a nuclear extraction kit. Equal amounts of protein (30 μg) were separated by 10% SDS-PAGE, transferred to PVDF membranes, and blocked with 5% non-fat milk for 1 hour. Membranes were incubated overnight at 4°C with primary antibodies against p65 (nuclear/cytoplasmic), IκBα, phospho-IκBα (Ser32), or β-actin (cytoplasmic control)/histone H3 (nuclear control). After washing, membranes were incubated with HRP-conjugated secondary antibodies for 1 hour, and bands were visualized with ECL reagent. Band intensity was quantified using ImageJ [1,2] - RT-PCR for Pro-Inflammatory Cytokines: A549 cells were infected with H5N1 (MOI=0.1) and treated with SC75741 (0.5–5 μM) for 24 hours. Total RNA was extracted using TRIzol reagent, and 1 μg RNA was reverse-transcribed to cDNA. RT-PCR was performed with specific primers for TNF-α, IL-6, IFN-β, and GAPDH (internal control). Reaction conditions: 95°C for 5 minutes, 35 cycles of 95°C (30s), 58°C (30s), 72°C (30s), and final extension at 72°C for 10 minutes. PCR products were separated by 1.5% agarose gel electrophoresis, stained with ethidium bromide, and quantified using ImageJ [1] |
| Animal Protocol |
Inbred female C57BL/6 mice at the age of 6-8 weeks[2]
15 mg/kg Intraperitoneal injection; for 2 days Lethal H5N1 Mouse Infection Model: Female BALB/c mice (6–8 weeks old, n=10 per group) were anesthetized with isoflurane and intranasally infected with 10×EID50 of H5N1 influenza virus (0.05 mL volume). SC75741 was dissolved in DMSO (10% final concentration) and diluted with sterile physiological saline to a concentration of 2 mg/mL. Mice in the treatment group received intraperitoneal injections of SC75741 at 20 mg/kg/day at 1 hour, 24 hours, and 48 hours post-infection. The vehicle control group received an equal volume of 10% DMSO in saline. Mice were monitored daily for survival rate and body weight for 14 days. At 3 days post-infection, 3 mice per group were euthanized by cervical dislocation: lung tissues were collected for viral titer (TCID50) and histopathological analysis, and serum was collected for cytokine (TNF-α, IL-6) measurement by ELISA [1] |
| Toxicity/Toxicokinetics |
In vitro cytotoxicity: The cytotoxicity of MDCK, A549 and HEK293T cells after treatment with SC75741 (0.1–50 μM) for 48 hours was detected by the MTT assay. At concentrations ≤20 μM, cell viability remained above 90%; at a concentration of 50 μM, cell viability decreased by approximately 15% (MDCK), 12% (A549) and 10% (HEK293T) compared to the solvent control group, respectively [1,2]. In vivo safety (mice): BALB/c mice treated with SC75741 (20 mg/kg/day, 3 times) showed no significant changes in body weight (excluding infection-related weight loss) and organ weight (liver, kidney, lung) compared to the solvent control group. Serum biochemical analysis (ALT, AST, BUN, creatinine) was normal 3 days post-infection, indicating no significant hepatotoxicity or nephrotoxicity was observed. Histopathological examination of liver and kidney tissues revealed no signs of damage [1].
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| References |
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| Additional Infomation |
Antiviral mechanism of action: SC75741 does not directly target viral proteins (such as hemagglutinin, neuraminidase, and RNA polymerase), but inhibits IAV replication by blocking the nuclear translocation of NF-κB p65. NF-κB activation is essential for the late stage of IAV replication (virus assembly/release) and excessive pro-inflammatory response; therefore, SC75741 has dual antiviral and anti-inflammatory effects [1,2]
- Broad-spectrum antiviral: SC75741 can inhibit the replication of multiple avian influenza virus subtypes (H5N1, H1N1, H3N2) in vitro, including highly pathogenic avian influenza virus (HPAI) H5N1 and seasonal influenza virus strains, indicating its potential application value in responding to multiple influenza outbreaks [2] - High antiviral resistance: In the drug resistance screening experiment, MDCK cells were infected with H1N1 virus and cultured for 15 generations in suboptimal concentration (0.5×EC50) of SC75741. No significant increase in EC50 values (≤1.2-fold change) was observed, indicating a low tendency for avian influenza viruses to develop resistance to SC75741—this may be because the drug targets the host pathway (NF-κB) rather than viral proteins [2] |
| Molecular Formula |
C29H23N7O2S2
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| Molecular Weight |
565.67
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| Exact Mass |
567.151
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| Elemental Analysis |
C, 61.58; H, 4.10; N, 17.33; O, 5.66; S, 11.34
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| CAS # |
913822-46-5
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| Related CAS # |
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| PubChem CID |
23661638
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| Appearance |
Light yellow to brown solid powder
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| LogP |
5.377
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
9
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| Rotatable Bond Count |
6
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| Heavy Atom Count |
40
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| Complexity |
915
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| Defined Atom Stereocenter Count |
0
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| SMILES |
O=C(C1=CSC(C2CCN(C3C4=C(C=CS4)N=CN=3)CC2)=N1)NC1NC2C(=CC=C(C(C3C=CC=CC=3)=O)C=2)N=1
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| InChi Key |
QNZVBFMXWNWVKG-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C29H23N7O2S2/c37-24(17-4-2-1-3-5-17)19-6-7-20-22(14-19)34-29(33-20)35-27(38)23-15-40-28(32-23)18-8-11-36(12-9-18)26-25-21(10-13-39-25)30-16-31-26/h1-7,10,13-16,18H,8-9,11-12H2,(H2,33,34,35,38)
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| Chemical Name |
N-(6-benzoyl-1H-benzimidazol-2-yl)-2-(1-thieno[3,2-d]pyrimidin-4-ylpiperidin-4-yl)-1,3-thiazole-4-carboxamide
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| Synonyms |
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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 |
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| 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) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.08 mg/mL (3.68 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 (3.68 mM) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), suspension solution; with ultrasonication. 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 (3.68 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 | 1.7678 mL | 8.8391 mL | 17.6782 mL | |
| 5 mM | 0.3536 mL | 1.7678 mL | 3.5356 mL | |
| 10 mM | 0.1768 mL | 0.8839 mL | 1.7678 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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