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| Targets |
EC90: 270 nM (Chikungunya virus)[1] Dihydroorotate Dehydrogenase[1]
CHIKV-IN-2 targets dihydroorotate dehydrogenase (DHODH), a key enzyme in the pyrimidine biosynthesis pathway. DHODH catalyzes the oxidation of dihydroorotate to orotate, the fourth step in de novo pyrimidine synthesis. By inhibiting DHODH, CHIKV-IN-2 depletes intracellular pyrimidine pools, which are essential for viral replication. The compound shows potent inhibitory activity against CHIKV through this mechanism. |
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| ln Vitro |
CHIKV-IN-2 (compound 8q) is a strong inhibitor of pan-alphaviruses, with EC90s ranging from 0.85 to 2.5 μM for both attenuated vaccine strains and clinical isolates of CHIKV[1]. CHIKV-IN-2 exhibits efficacy against flaviviruses, including West Nile Virus (WNV; EC90=0.20 μM) and Dengue Virus Strain-2 (DENV-2; EC90=0.60 μM), and alphavirus VEEV (EC90=0.40 μM)[1].
In vitro studies demonstrate that CHIKV-IN-2 has excellent cellular antiviral activity against Chikungunya virus with an EC90 of 270 nM. The compound shows inhibitory activity against DHODH. It has improved liver microsomal stability. The compound's antiviral mechanism involves depleting intracellular pyrimidine pools through DHODH inhibition, which limits viral replication. |
| ln Vivo |
CHIKV-IN-2 (compound 8q) (80 mg/kg; intraperitoneally twice daily for three days) dramatically reduces the spread of infectious CHIKV to other mouse tissues[1]. CHIKV-IN-2 (40 mg/kg; po, ip, sc) in mice shows a terminal elimination half-life (t1/2=9.9, 18.5, 18.6 h), a moderate bioavailability (F=41%, 43%, 4%), and a Cmax (642, 858, 90 ng/mL)[1]. In mice, CHIKV-IN-2 (1 mg/kg; iv) displays an AUC of 497 h·ng/mL and a terminal elimination half-life of t1/2= 2.02 h[1].
No detailed in vivo activity data has been published for CHIKV-IN-2. The compound has been primarily characterized in vitro as a research tool for studying Chikungunya virus infection. Its excellent cellular antiviral activity (EC90 = 270 nM) and improved liver microsomal stability suggest that it could have potential for in vivo applications. Further studies would be needed to evaluate its efficacy in animal models of CHIKV infection. |
| Enzyme Assay |
The DHODH inhibitory activity of CHIKV-IN-2 can be assessed using in vitro enzyme assays. In a typical assay, recombinant DHODH is incubated with dihydroorotate, coenzyme Q, and varying concentrations of CHIKV-IN-2. The oxidation of dihydroorotate to orotate is measured spectrophotometrically, and the IC50 is calculated. The antiviral activity is assessed using CHIKV-infected cells. Viral replication is measured by quantifying viral RNA using qRT-PCR or by plaque assays.
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| Cell Assay |
The cellular antiviral activity of CHIKV-IN-2 is assessed using CHIKV-infected cell lines. Cells are treated with varying concentrations of CHIKV-IN-2. Viral replication is measured by quantifying viral RNA using qRT-PCR or by plaque assays. The EC90 (270 nM) is calculated from dose-response curves. Cytotoxicity is assessed in uninfected cells using MTT assays. The compound's effect on pyrimidine pools can be measured by HPLC or mass spectrometry.
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| Animal Protocol |
Animal/Disease Models: Female and male C57BL/6 mice[1]
Doses: 80 mg/kg Route of Administration: Ip twice a day for 3 days Experimental Results: Failed to inhibit virus loads at the site of infection. diminished virus dissemination to other tissues. Animal/Disease Models: Male C57BL/6 mice were challenged with CHIKV in the right footpad[1] Doses: 1 mg/kg for iv and 40 mg/kg for po, ip, sc (pharmacokinetic/PK Analysis) Route of Administration: Iv, po, ip, sc Experimental Results: Iv: t1/2= 2.02 h; AUC=497 h·ng/mL. Po: F=41%; t1/2=9.9 h; Cmax= 642 ng/mL. Ip: F=43%; t1/2=18.5 h; Cmax=858 ng/mL. Sc: F=4%; t1/2=18.6 h; Cmax=90 ng/mL. No detailed in vivo animal model data has been published for CHIKV-IN-2. The compound has been primarily characterized in vitro as a research tool for studying CHIKV infection. Future studies may involve the use of mouse models of CHIKV infection to assess the in vivo efficacy of CHIKV-IN-2. The compound's improved liver microsomal stability suggests favorable pharmacokinetic properties for in vivo applications. |
| ADME/Pharmacokinetics |
No detailed pharmacokinetic data has been published for CHIKV-IN-2. The compound has a molecular weight of 374.48 g/mol and a molecular formula of C24H26N2O2. It has improved liver microsomal stability. Further studies would be needed to characterize its absorption, distribution, metabolism, and excretion properties, including oral bioavailability, plasma protein binding, clearance, and half-life.
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| Toxicity/Toxicokinetics |
No detailed toxicity data has been published for CHIKV-IN-2. As a DHODH inhibitor, it may have effects on pyrimidine synthesis in normal cells. Comprehensive toxicology studies would be required to evaluate its safety profile for potential therapeutic development. The compound is intended for research use only. Its improved liver microsomal stability suggests a favorable metabolic profile.
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| References |
[1]. Ahmed SK, et, al. Targeting Chikungunya Virus Replication by Benzoannulene Inhibitors. J Med Chem. 2021 Apr 22;64(8):4762-4786.
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| Additional Infomation |
CHIKV-IN-2 (CAS# 2361289-44-1) is a potent inhibitor against Chikungunya virus with excellent cellular antiviral activity (EC90 = 270 nM). The compound targets dihydroorotate dehydrogenase (DHODH), depleting intracellular pyrimidine pools and limiting viral replication. It has improved liver microsomal stability. The molecular formula is C24H26N2O2. The compound is a research tool for studying CHIKV infection and DHODH inhibition.
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| Molecular Formula |
C23H26N2O2
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|---|---|
| Molecular Weight |
362.4647
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| Exact Mass |
362.199
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| CAS # |
2361289-44-1
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| PubChem CID |
142616713
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| Appearance |
White to off-white solid powder
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| LogP |
5.2
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
3
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| Rotatable Bond Count |
4
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| Heavy Atom Count |
27
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| Complexity |
556
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| Defined Atom Stereocenter Count |
0
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| SMILES |
O(C([H])([H])[H])C1=C(C(N([H])C2C([H])=C([H])C(=C([H])C=2[H])C(C#N)(C([H])([H])[H])C([H])([H])[H])=O)C([H])=C2C(=C1[H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C2([H])[H]
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| InChi Key |
WAOHPFHXTKBTTG-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C23H26N2O2/c1-23(2,15-24)18-9-11-19(12-10-18)25-22(26)20-13-16-7-5-4-6-8-17(16)14-21(20)27-3/h9-14H,4-8H2,1-3H3,(H,25,26)
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| Chemical Name |
N-[4-(2-cyanopropan-2-yl)phenyl]-3-methoxy-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-carboxamide
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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 (275.89 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (6.90 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 (6.90 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 (6.90 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 | 2.7589 mL | 13.7946 mL | 27.5893 mL | |
| 5 mM | 0.5518 mL | 2.7589 mL | 5.5179 mL | |
| 10 mM | 0.2759 mL | 1.3795 mL | 2.7589 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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