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| Targets |
PfDHODH-IN-1 targets Plasmodium falciparum dihydroorotate dehydrogenase (PfDHODH), a flavin-dependent mitochondrial enzyme that catalyzes the fourth and rate-limiting step of de novo pyrimidine biosynthesis. The malaria parasite relies exclusively on de novo pyrimidine synthesis for DNA and RNA production during rapid replication within the host, as it lacks pyrimidine salvage pathways. Inhibition of PfDHODH effectively halts pyrimidine biosynthesis, leading to parasite death. The significant structural differences between parasite and human DHODH enzymes allow for the development of highly selective inhibitors. PfDHODH-IN-1 is an analog of Leflunomide's active metabolite and shares this mechanism of action.
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| ln Vitro |
In vitro, PfDHODH-IN-1 exhibits antimalarial activity by inhibiting PfDHODH. As an analog of the DHODH inhibitor A-771726, it demonstrates IC₅₀ values of 190 nM for human DHODH, 47 nM for mouse DHODH, and 21 nM for rat DHODH. The compound's selectivity for the parasite enzyme over the human enzyme is a key feature that minimizes host toxicity. The inhibitory activity is typically quantified through enzymatic assays measuring the conversion of dihydroorotate to orotate. In cell-based assays, the compound's ability to inhibit parasite growth is assessed in P. falciparum cultures. The compound's potency and selectivity make it a valuable tool for studying pyrimidine metabolism and developing antimalarial therapies.
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| ln Vivo |
In vivo, PfDHODH-IN-1 is expected to exhibit antimalarial activity based on its mechanism of action. By targeting PfDHODH, it disrupts DNA and RNA synthesis in the malaria-causing parasite, leading to parasite death. As an analog of leflunomide's active metabolite, it offers a promising avenue for developing new antimalarial therapies, especially against drug-resistant strains. Detailed in vivo efficacy, pharmacokinetic, and toxicological data for PfDHODH-IN-1 require further investigation from primary research publications. The compound's chemical formula is C₁₄H₁₁F₃N₂O₂, and it is available as a research chemical for antimalarial drug discovery studies.
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| Enzyme Assay |
In vitro enzyme/receptor binding (non-cellular) assays for PfDHODH-IN-1 involve measuring inhibition of recombinant P. falciparum DHODH enzymatic activity. The assay typically uses a colorimetric method detecting the conversion of dihydroorotate to orotate coupled with the reduction of the electron acceptor (e.g., 2,6-dichloroindophenol, DCIP). The enzyme is incubated with varying concentrations of the compound, substrate (dihydroorotate), and coenzyme (ubiquinone or decylubiquinone) in assay buffer (typically 50 mM Tris-HCl, pH 8.0, with 0.1% Triton X-100). The reaction is monitored spectrophotometrically by following the decrease in absorbance at 600 nm (DCIP reduction). IC₅₀ values are calculated from concentration-response curves. Selectivity against human DHODH is assessed using the same assay format with the human enzyme.
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| Cell Assay |
In vitro cellular experiments with PfDHODH-IN-1 are performed using P. falciparum cultures to assess antimalarial activity. Parasites are cultured in human erythrocytes in RPMI 1640 medium supplemented with Albumax or human serum. Cultures are maintained at 37°C in a gas mixture of 5% O₂, 5% CO₂, and 90% N₂. For drug susceptibility testing, synchronized ring-stage parasites are treated with varying concentrations of the compound for 48-72 hours. Parasite growth inhibition is assessed by measuring [³H]hypoxanthine incorporation, by fluorescence-based methods using SYBR Green I, or by microscopic examination of Giemsa-stained blood smears. IC₅₀ values are calculated from concentration-response curves. Cytotoxicity against mammalian cells (e.g., HepG2 or Vero cells) is assessed in parallel to determine the selectivity index.
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| Animal Protocol |
In vivo animal studies with PfDHODH-IN-1 are not extensively reported in the available literature. For antimalarial compounds, standard in vivo efficacy studies are performed in mouse models of P. berghei or P. falciparum (using SCID mice with human erythrocytes). Mice are infected with the parasite and treated with the compound via oral, intraperitoneal, or intravenous administration at various doses and schedules. Efficacy is assessed by measuring parasitemia in blood smears, survival rates, and recrudescence following treatment. Pharmacokinetic studies in rodents assess absorption, distribution, metabolism, and excretion. The compound's selectivity for PfDHODH over human DHODH is critical for minimizing host toxicity.
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| ADME/Pharmacokinetics |
Comprehensive pharmacokinetic data for PfDHODH-IN-1 are not extensively reported. The compound has a molecular weight of 296.25 and molecular formula C₁₄H₁₁F₃N₂O₂. As an analog of leflunomide's active metabolite, it may share similar pharmacokinetic properties, including good oral bioavailability, extensive plasma protein binding, and a long half-life. Leflunomide is metabolized to the active metabolite A-771726, which has a half-life of approximately 2 weeks in humans. PfDHODH-IN-1 would be expected to have improved physicochemical properties for antimalarial application. The compound is supplied as a research chemical with purity specifications for laboratory use.
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| Toxicity/Toxicokinetics |
Toxicological information for PfDHODH-IN-1 is not extensively detailed in the available literature. As a research compound with antimalarial activity, it should be handled with appropriate safety precautions. Standard safety guidelines for handling potent pharmaceutical compounds apply, including use of personal protective equipment (gloves, safety goggles, lab coat), working in a well-ventilated area, and proper chemical waste disposal. The compound is intended for research use only and is not approved for human therapeutic use. The compound's selectivity for PfDHODH over human DHODH (IC₅₀ 190 nM for human enzyme) suggests a potential therapeutic window, but detailed toxicological studies are needed to fully establish its safety profile.
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| References |
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| Additional Infomation |
PfDHODH-IN-1 (CAS 183945-55-3) is an analog of the bioactive metabolite of Leflunomide (A-771726) and functions as a potent inhibitor of Plasmodium falciparum dihydroorotate dehydrogenase (PfDHODH). The compound has molecular formula C₁₄H₁₁F₃N₂O₂ and molecular weight 296.25. By targeting PfDHODH, the compound disrupts de novo pyrimidine biosynthesis in the malaria parasite, which is essential for DNA and RNA synthesis. PfDHODH-IN-1 exhibits antimalarial activity and offers a promising avenue for developing new antimalarial therapies, especially against drug-resistant strains. As a derivative of A-771726, it shows differential potency across species: IC₅₀ values of 190 nM, 47 nM, and 21 nM for human, mouse, and rat enzymes, respectively. The compound is for research use only and is not approved for clinical use.
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| Molecular Formula |
C14H11N2O2F3
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| Molecular Weight |
296.24454
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| Exact Mass |
296.077
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| CAS # |
183945-55-3
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| PubChem CID |
54684419
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| Appearance |
Off-white to light yellow solid powder
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| LogP |
3.4
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
6
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| Rotatable Bond Count |
3
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| Heavy Atom Count |
21
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| Complexity |
492
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| Defined Atom Stereocenter Count |
0
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| SMILES |
C1CC1C(=C(C#N)C(=O)NC2=CC=C(C=C2)C(F)(F)F)O
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| InChi Key |
IKNOIAXAHSRIGK-QXMHVHEDSA-N
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| InChi Code |
InChI=1S/C14H11F3N2O2/c15-14(16,17)9-3-5-10(6-4-9)19-13(21)11(7-18)12(20)8-1-2-8/h3-6,8,20H,1-2H2,(H,19,21)/b12-11-
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| Chemical Name |
(Z)-2-cyano-3-cyclopropyl-3-hydroxy-N-[4-(trifluoromethyl)phenyl]prop-2-enamide
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| Synonyms |
PfDHODHIN1; PfDHODH 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 Note: This product requires protection from light (avoid light exposure) during transportation and storage. |
| 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 : ~50 mg/mL (~168.78 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (8.44 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 (8.44 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 25.0 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 | 3.3756 mL | 16.8782 mL | 33.7564 mL | |
| 5 mM | 0.6751 mL | 3.3756 mL | 6.7513 mL | |
| 10 mM | 0.3376 mL | 1.6878 mL | 3.3756 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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