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| Targets |
Plasmodium
DSM502 targets dihydroorotate dehydrogenase (DHODH), a mitochondrial enzyme essential for de novo pyrimidine biosynthesis. DHODH catalyzes the oxidation of dihydroorotate to orotate, the fourth step in the de novo synthesis of pyrimidine nucleotides. Pyrimidines are essential for DNA and RNA synthesis, and their depletion inhibits cell proliferation. DSM502 exhibits nanomolar potency against Plasmodium DHODH, the enzyme from the malaria parasite, with no inhibition of mammalian DHODHs. |
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| ln Vitro |
DSM502 has inhibitory activity with no inhibition of the human enzyme against P. falciparum DHODH (PfDHODH, IC50=20 nM), P. vivax DHODH (PvDHODH, IC50=14 nM), and Pf3D7 cells (EC50=14 nM)[1].
In vitro studies demonstrate that DSM502 exhibits nanomolar potency against Plasmodium DHODH and Plasmodium parasites. The compound has no inhibitory effect on mammalian DHODHs, indicating high selectivity for the parasite enzyme over the host enzyme. DSM502 has antimalarial activity and can be used as a lead for antimalarial compounds. No detailed IC50 or EC50 values have been published in the available literature. |
| ln Vivo |
In contrast to the 85% clearance in the GSK research, DSM502 (10 and 50 mg/kg; po once daily for 4 days) results in 97% parasite clearance in a confirmatory SCID study[1]. Mouse studies with DSM502 (18.3 and 50 mg/kg; a single po) show high oral bioavailability (>100%, >100%), apparent t1/2 (2.6, 3.6 h), and Cmax (8.4, 42.3 μM)[1]. In mice, Vss (1.2 L/kg), plasma clearance (26.1 mL/min/kg), and apparent t1/2 (2.8 h) are all demonstrated by DSM502 (2.8 mg/kg; a single IV)[1].
No detailed in vivo activity data has been published for DSM502. The compound has been characterized as a DHODH inhibitor with antimalarial activity. Its selectivity for Plasmodium DHODH over mammalian DHODH suggests that it could have potential for in vivo applications in treating malaria. Further studies would be needed to evaluate its efficacy in animal models of malaria. |
| Enzyme Assay |
The DHODH inhibitory activity of DSM502 can be assessed using in vitro enzyme assays. In a typical assay, recombinant Plasmodium DHODH or mammalian DHODH is incubated with dihydroorotate, coenzyme Q, and varying concentrations of DSM502. The oxidation of dihydroorotate to orotate is measured spectrophotometrically, and the IC50 is calculated. The selectivity of DSM502 for Plasmodium DHODH over mammalian DHODH is confirmed by comparing IC50 values against both enzymes.
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| Cell Assay |
The antimalarial activity of DSM502 is assessed using Plasmodium parasite cultures. In a typical assay, Plasmodium falciparum parasites are cultured in human red blood cells and treated with varying concentrations of DSM502. Parasite growth is measured by quantifying parasite DNA using SYBR Green or by measuring lactate dehydrogenase activity. The EC50 for inhibition of parasite growth is calculated from dose-response curves. Cytotoxicity against mammalian cells is assessed using MTT assays.
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| Animal Protocol |
Animal/Disease Models: SCID (severe combined immunodeficient) mouse (23-36 g) were inoculated with parasites[1]
Doses: 10 and 50 mg/kg Route of Administration: Po one time/day for 4 days starting on day 3 after mice had been inoculated with parasites Experimental Results: Resulted in 97% parasite clearance compared to 85% clearance in the GSK study. The 10 mg/kg mouse died on day 5. No detailed in vivo animal model data has been published for DSM502. The compound has been primarily characterized in vitro as a DHODH inhibitor with antimalarial activity. Future studies may involve the use of mouse models of malaria to assess the in vivo efficacy of DSM502. The compound's selectivity for Plasmodium DHODH over mammalian DHODH suggests that it may have a favorable safety profile. |
| ADME/Pharmacokinetics |
No detailed pharmacokinetic data has been published for DSM502. The compound has a molecular weight of 323.31 and a molecular formula of C16H16F3N3O. It has a purity of ≥99%. 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 DSM502. The compound has no inhibitory effect on mammalian DHODHs, suggesting that it may have a favorable selectivity profile with minimal off-target effects on host cells. As a DHODH inhibitor, the compound may have effects on pyrimidine synthesis in host cells at high concentrations. Comprehensive toxicology studies would be required to evaluate its safety profile for potential therapeutic development.
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| References |
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| Additional Infomation |
DSM502 (CAS# 2426616-55-7) is a pyrrole-based inhibitor of dihydroorotate dehydrogenase (DHODH) with antimalarial activity. It exhibits nanomolar potency against Plasmodium DHODH and Plasmodium parasites, with no inhibitory effect on mammalian DHODHs. The compound can be used as a lead for antimalarial compounds. The molecular formula is C16H16F3N3O and molecular weight is 323.31. DSM502 is a research tool for studying DHODH inhibition and malaria.
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| Molecular Formula |
C16H16F3N3O
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|---|---|
| Molecular Weight |
323.31
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| Exact Mass |
323.124
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| CAS # |
2426616-55-7
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| PubChem CID |
154699462
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| Appearance |
White to off-white solid powder
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| LogP |
3
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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 |
4
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| Heavy Atom Count |
23
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| Complexity |
439
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| Defined Atom Stereocenter Count |
0
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| SMILES |
N1C=C(CC2=CC=C(C(F)(F)F)N=C2)C(C)=C1C(NC1CC1)=O
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| InChi Key |
AFOVOYRODSYDMK-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C16H16F3N3O/c1-9-11(8-21-14(9)15(23)22-12-3-4-12)6-10-2-5-13(20-7-10)16(17,18)19/h2,5,7-8,12,21H,3-4,6H2,1H3,(H,22,23)
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| Chemical Name |
N-cyclopropyl-3-methyl-4-[[6-(trifluoromethyl)pyridin-3-yl]methyl]-1H-pyrrole-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 : 250 mg/mL (773.25 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.08 mg/mL (6.43 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. Solubility in Formulation 2: ≥ 2.08 mg/mL (6.43 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 20.8 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 | 3.0930 mL | 15.4650 mL | 30.9301 mL | |
| 5 mM | 0.6186 mL | 3.0930 mL | 6.1860 mL | |
| 10 mM | 0.3093 mL | 1.5465 mL | 3.0930 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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