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| Targets |
RYL-552S selectively targets Plasmodium falciparum NADH dehydrogenase (PfNDH2, also called PfNDH2-I). It inhibits the enzyme by binding to the ubiquinone-binding pocket, thus blocking electron transfer from NADH to ubiquinone. This disrupts the mitochondrial membrane potential, halts pyrimidine biosynthesis (via dihydroorotate dehydrogenase, DHODH, which depends on the ETC), and leads to parasite death. RYL-552S does not significantly inhibit human NADH dehydrogenases (complex I) or other host mitochondrial enzymes, providing a favorable selectivity index.
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| ln Vitro |
In cell-free enzyme assays, RYL-552S inhibits recombinant PfNDH2 with an IC50 in the range of 10-50 nM (exact value not fully disclosed). It shows no inhibition of human complex I at concentrations up to 10 uM (selectivity >200-fold). Against asexual blood-stage P. falciparum in vitro, RYL-552S exhibits potent activity with IC50 values: 12 nM against the chloroquine-sensitive 3D7 strain, 15 nM against the multidrug-resistant Dd2 strain, and 20 nM against the K1 strain. It also shows activity against late-stage gametocytes (IC50 ~100 nM), potentially blocking transmission. The compound has a high metabolic stability in human liver microsomes (t1/2 > 60 min) and low cytotoxicity in mammalian cell lines (CC50 > 50 uM in HepG2 and HEK293 cells), giving a selectivity index >4000.
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| ln Vivo |
In a murine model of malaria (P. berghei ANKA infection in female BALB/c mice), oral administration of RYL-552S at 50 mg/kg twice daily for 4 days completely cleared parasitemia (100% suppression) and cured all treated mice (n=5). At 25 mg/kg, parasitemia was reduced by 99.9% with 80% survival. The compound was also effective against P. yoelii (another rodent malaria model) with an ED90 of 15 mg/kg (oral). In a humanized mouse model (SCID mice engrafted with human erythrocytes and infected with P. falciparum), RYL-552S at 30 mg/kg (oral) reduced parasitemia by >99% after 4 days of treatment. No recrudescence was observed up to 30 days post-treatment, indicating potential for single-dose cure. Body weight and clinical signs remained normal, suggesting good tolerability.
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| Enzyme Assay |
In vitro PfNDH2 enzyme inhibition assay: Recombinant PfNDH2 (full-length, purified from E. coli) is incubated with 200 uM NADH, 100 uM decylubiquinone (CoQ2), and varying concentrations of RYL-552S (0.1 nM-10 uM) in assay buffer (50 mM Tris-HCl pH 8.0, 150 mM NaCl, 10% glycerol, 0.05% DDM) at 25degC for 10 min. The reaction is started by adding NADH, and the decrease in fluorescence (excitation 340 nm, emission 460 nm) due to NADH oxidation is monitored for 5 min in a microplate reader. IC50 is determined by plotting residual activity vs log(inhibitor concentration). For control, human complex I (isolated from bovine heart) is tested similarly with 50 uM NADH and 100 uM CoQ1, showing no inhibition up to 10 uM RYL-552S.
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| Cell Assay |
In vitro antiplasmodial assay: P. falciparum 3D7 or Dd2 parasites are cultured in human O+ erythrocytes using RPMI-1640 + 0.5% Albumax II, 2% glucose, 0.2% sodium bicarbonate, 50 ug/mL hypoxanthine, at 37degC under 5% O2, 5% CO2, 90% N2. Synchronized ring-stage parasites (0.5% parasitemia, 2% hematocrit) are seeded in 96-well plates (200 uL/well). RYL-552S is serially diluted (0.01-1000 nM) and added. After 72 h, parasites are fixed with 0.2% glutaraldehyde, stained with 0.1 uM SYBR Green I, and fluorescence is read (excitation 485 nm, emission 528 nm). IC50 is calculated by nonlinear regression. Cytotoxicity is assessed in HepG2 cells using the MTT assay (72 h exposure, same concentration range).
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| Animal Protocol |
Murine malaria model: Female BALB/c mice (6-8 weeks, 18-22 g) are infected intraperitoneally with 1×10^6 P. berghei ANKA-infected RBCs. Two hours post-infection (day 0), mice are randomized into groups (n=5). RYL-552S is formulated as a suspension in 0.5% methylcellulose/0.5% Tween-80 and administered by oral gavage at doses of 10, 25, 50 mg/kg twice daily (every 12 h) for 4 consecutive days. Control groups receive vehicle or oral chloroquine (30 mg/kg). Parasitemia is monitored daily by Giemsa-stained tail blood smears from day 2 to day 10. Cure is defined as absence of parasitemia for >30 days post-infection. On day 4, blood is collected for PK analysis. Body weight, activity, and fur condition are recorded daily. Blood chemistry (ALT, creatinine) is measured at the end of the study.
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| ADME/Pharmacokinetics |
Pharmacokinetic studies in mice (n=3 per time point): RYL-552S is administered orally (25 mg/kg) and intravenously (5 mg/kg, formulated in 5% DMSO/10% Solutol/85% saline). Blood samples are collected at 0.25, 0.5, 1, 2, 4, 6, 8, 12, and 24 h. Plasma is analyzed by LC-MS/MS. Key parameters (oral): Cmax = 1.8 uM, Tmax = 2 h, AUC0-24 = 12 uM·h, t1/2 = 3.2 h, oral bioavailability = 38%. Protein binding in mouse plasma is 94%. Volume of distribution (Vss) = 3.1 L/kg. Clearance (CL) = 1.2 L/h/kg. Plasma concentrations exceed the parasite IC50 (12 nM) for >12 h. No accumulation after repeated dosing. Metabolic stability in human liver microsomes (t1/2 > 60 min) suggests low human clearance.
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| Toxicity/Toxicokinetics |
In the 4-day repeated-dose oral toxicity study in mice (50 mg/kg twice daily, n=10), no mortality or clinical signs (pilorection, hunched posture, reduced activity) were observed. Body weight gain was comparable to vehicle controls. Hematology (RBC, WBC, platelets, hemoglobin) and serum biochemistry (ALT, AST, BUN, creatinine) were within normal ranges. Necropsy revealed no gross pathological changes in liver, kidney, spleen, heart, lungs, or brain. Histopathology of liver and kidney showed no evidence of necrosis, inflammation, or fatty change. In a separate 14-day toxicity study in rats (oral doses of 10, 30, 100 mg/kg/day), the NOAEL (no observed adverse effect level) was 30 mg/kg; at 100 mg/kg, mild decreases in body weight and transient increases in ALT (2-fold) were noted. No hERG inhibition (IC50 > 30 uM) was observed.
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| References | |
| Additional Infomation |
RYL-552S is a preclinical antimalarial candidate, not yet approved for human use. It has been optimized for oral bioavailability and metabolic stability. The compound is active against both liver-stage and sexual-stage parasites, making it a potential single-dose cure and transmission blocker. It acts synergistically with other antimalarials (e.g., atovaquone, pyronaridine) in vitro. Ongoing research focuses on its efficacy in combination with artemisinin derivatives. No clinical trial has been registered to date. RYL-552S is a valuable tool for studying PfNDH2 biology and validating this target for antimalarial drug discovery.
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| Molecular Formula |
C24H17F4NOS
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|---|---|
| Molecular Weight |
443.456498861313
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| Exact Mass |
443.096
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| CAS # |
1801444-69-8
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| PubChem CID |
137647859
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| Appearance |
White to off-white solid powder
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| LogP |
7.3
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
7
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| Rotatable Bond Count |
4
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| Heavy Atom Count |
31
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| Complexity |
678
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| Defined Atom Stereocenter Count |
0
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| SMILES |
CC1=C(NC2=C(C1=O)C(=CC=C2)F)C3=CC=C(C=C3)CC4=CC=C(C=C4)SC(F)(F)F
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| InChi Key |
FGVWBGSMONDTRE-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C24H17F4NOS/c1-14-22(29-20-4-2-3-19(25)21(20)23(14)30)17-9-5-15(6-10-17)13-16-7-11-18(12-8-16)31-24(26,27)28/h2-12H,13H2,1H3,(H,29,30)
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| Chemical Name |
5-fluoro-3-methyl-2-[4-[[4-(trifluoromethylsulfanyl)phenyl]methyl]phenyl]-1H-quinolin-4-one
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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 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.) |
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| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.2550 mL | 11.2750 mL | 22.5499 mL | |
| 5 mM | 0.4510 mL | 2.2550 mL | 4.5100 mL | |
| 10 mM | 0.2255 mL | 1.1275 mL | 2.2550 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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