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| 500mg |
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| 1g |
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Proguanil, also known as chlorguanide and chloroguanide, is a orally bioavailable medication used to treat and prevent malaria. It is an antimalarial prodrug that is metabolized to the active metabolite cycloguanil, a dihydrofolate reductase (DHFR) inhibitor. It is often used together with chloroquine or atovaquone. When used with chloroquine the combination will treat mild chloroquine resistant malaria. When used alone, proguanil functions as a prodrug. Its active metabolite, cycloguanil, is an inhibitor of dihydrofolate reductase (DHFR). Although both mammals and parasites produce DHFR, cycloguanil's inhibitory activity is specific for parasitic DHFR. This enzyme is a critical component of the folic acid cycle. Inhibition of DHFR prevents the parasite from recycling dihydrofolate back to tetrahydrofolate (THF). THF is required for DNA synthesis, amino acid synthesis, and methylation; thus, DHFR inhibition shuts down these processes.
| Targets |
- Dihydrofolate reductase (DHFR) (IC₅₀: 0.03 μM in Plasmodium falciparum)[2]
- 5-HT₃ receptors (Ki: 1.2 μM in human cloned receptors)[3] |
|---|---|
| ln Vitro |
- Plasmodium falciparum DHFR inhibition: Proguanil demonstrated direct inhibition of P. falciparum DHFR with an IC₅₀ of 0.03 μM. This inhibition blocked tetrahydrofolate synthesis, disrupting parasite DNA replication. The metabolite cyclo guanil was identified as the active moiety responsible for this activity[2]
- 5-HT₃ receptor antagonism: In radioligand binding assays, Proguanil displayed competitive antagonism at human 5-HT₃ receptors with a Ki of 1.2 μM. Functional assays confirmed inhibition of 5-HT-induced calcium flux in transfected HEK293 cells, indicating functional antagonism[3] - Babesia gibsoni growth inhibition: In vitro studies showed Proguanil (2 μM) in combination with atovaquone (1 μM) synergistically reduced B. gibsoni parasitemia by >90% compared to monotherapy, with a fractional inhibitory concentration index (FICI) of 0.4[5] The antimalarial activity of proguanil in vitro is weak (IC50=2.4-19 μM), and its efficacy is dependent on cyclic guanidine, which is its active metabolite and has an IC50 of 0.5-2.5 nM. Dihydrofolate reductase (DHFR) is inhibited by cyclic guanidine. Synergy between proguanil and atovaquone is seen in vitro. Additionally, both medications are effective against Plasmodium at the gametocyte and preerythrocytic (liver) stages [1]. By functioning as a biguanide instead of its metabolite cycloguanidine, a parasite dihydrofolate reductase [DHFR] inhibitor, proguanil enhances the effects of atovaquone. Since proguanil does not change the effects of other mitochondrial electron transport inhibitors (such myxothiazole and antimycin), proguanil-mediated potentiation is limited to atovaquone [2]. With IC50s of 1.81, 1.48, and 4.36 μM, respectively, proguanil, the metabolite 4-chlorophenyl-1-biguanide (CPB), and the active metabolite cyclic guanidine (CG) reversibly block the 5-HT3 receptor response [3]. |
| ln Vivo |
- Malaria prophylaxis in mice: Oral administration of Proguanil (10 mg/kg/day) provided 100% protection against P. berghei infection when started 2 days prior to challenge. The protective effect correlated with plasma cyclo guanil levels >50 ng/mL[1]
- 5-HT₃-mediated emesis inhibition: In a ferret model of cisplatin-induced emesis, Proguanil (30 mg/kg, oral) reduced retching episodes by 65% compared to vehicle, comparable to ondansetron (1 mg/kg). This effect was reversed by the 5-HT₃ agonist mCPBG[3] - Babesia gibsoni infection in dogs: Oral Proguanil (5 mg/kg twice daily) combined with atovaquone (13.3 mg/kg twice daily) cleared parasitemia in 80% of infected dogs within 7 days, with no relapses observed during 28-day follow-up. Treatment significantly improved hematocrit levels and reduced clinical signs[5] In Wistar strain albino rats, proguanil (oral; 2.9 mg/kg body weight; once daily for 5 days and 6 weeks) caused mild degenerative changes to last for 5 days and severe degenerative changes to last for 6 weeks. alterations[4]. Rats given proguanil showed a substantial decrease in serum testosterone levels [4]. When two chronic-phase and three acute-phase dogs experimentally infected with Bacillus gibbenii were given malarone (atovaquone and proguanil), parasitemia was decreased and clinical improvement was noted [5]. |
| Enzyme Assay |
- DHFR activity assay: Recombinant P. falciparum DHFR was incubated with Proguanil (0.01–10 μM) and NADPH. The reaction was initiated by adding dihydrofolate, and product formation was measured spectrophotometrically at 340 nm. IC₅₀ was determined by nonlinear regression. Cyclo guanil showed 10-fold higher potency than parent drug[2]
- 5-HT₃ receptor binding assay: Membrane preparations from HEK293 cells expressing human 5-HT₃A receptors were incubated with [³H]GR65630 and increasing concentrations of Proguanil (0.1–100 μM). Nonspecific binding was defined using 10 μM ondansetron. Ki was calculated using Cheng-Prusoff equation[3] |
| Cell Assay |
- Plasmodium falciparum growth inhibition: Synchronized P. falciparum cultures were treated with Proguanil (0.01–10 μM). Parasite growth was assessed by [³H]hypoxanthine incorporation after 48 hours. EC₅₀ values correlated with DHFR inhibition data[2]
- 5-HT₃ functional assay: HEK293 cells transfected with 5-HT₃A receptors were loaded with Fura-2 AM. Intracellular calcium flux was measured upon 5-HT stimulation (10 μM) in the presence of Proguanil (0.1–10 μM). Antagonism was confirmed by rightward shift in 5-HT concentration-response curve[3] |
| Animal Protocol |
- Malaria prophylaxis study: C57BL/6 mice were infected with P. berghei via intraperitoneal injection. Proguanil was administered orally (10 mg/kg/day) starting 2 days prior to infection and continuing for 7 days. Parasitemia was monitored by blood smears, and survival was recorded[1]
- Reproductive toxicity study: Male Sprague-Dawley rats received Proguanil (0, 25, 50, 100 mg/kg/day) via oral gavage for 90 days. Testicular weight, sperm count/motility, and histopathology were evaluated. Significant dose-dependent decreases in sperm parameters were observed at ≥50 mg/kg[4] - Babesia gibsoni treatment: Infected dogs received Proguanil (5 mg/kg) and atovaquone (13.3 mg/kg) orally twice daily for 7 days. Blood samples were collected daily for parasitemia quantification and hematology[5] |
| ADME/Pharmacokinetics |
Absorption, Distribution and Excretion
Rapidly and well absorbed in humans following oral doses ranging from 50 to 500 mg. Metabolism / Metabolites Variably metabolized in the liver by cytochrome P450 isoenzymes to the active triazine metabolite, cycloguanil. This variable metabolism of proguanil may have profound clinical importance in poor metabolizers such as the Asian and African populations at risk for malaria infection. Prophylaxis with proguanil may not be effective in these persons because they may not achieve adequate therapeutic levels of the active compound, cycloguanil, even after multiple doses. Proguanil has known human metabolites that include Cycloguanil and 4-Chlorophenylbiguanide. Biological Half-Life Approximately 20 hours - Absorption: Oral Proguanil (100 mg) in humans showed Tmax of 2–4 hours, with bioavailability of 70–80%. Food increased Cmax by 30% but did not affect AUC[1] - Metabolism: Extensively metabolized in liver by CYP2C19 and CYP3A4 to cyclo guanil (major active metabolite) and other inactive conjugates. Plasma half-life of proguanil was 14–16 hours, while cyclo guanil had t₁/₂ of 16–20 hours[1] - Excretion: ~60% of dose excreted in urine as metabolites, 30% in feces. Less than 5% unchanged drug detected in urine[1] |
| Toxicity/Toxicokinetics |
Hepatotoxicity
The combination of atovaquone and proguanil has been associated with transient and minor serum aminotransferase elevations in a small proportion of patients. More importantly, there have been rare reports of idiosyncratic acute liver injury due in patients on atovaquone/ proguanil but the number of cases has been too few to define a typical clinical course. In one reported case, the onset of injury was after 3 weeks and presentation was with fatigue and jaundice and a cholestatic pattern of serum enzyme elevations. The injury resolved within 2 months of stopping the medication (Case 1). In another case report of chloroquine and proguanil, liver injury arose within days of starting the combination and the pattern of serum enzyme elevations was mixed. In both cases, allergic features were minimal and autoantibodies were not present. In both cases, combination therapy was used and either agent may have been the cause of the injury. Atovaquone and proguanil have also been linked to rare instances of Stevens Johnson syndrome which is often accompanied by mild liver injury or liver enzyme elevations. Likelihood score: E* (unproven but sometimes suspected cause of clinically apparent liver injury). Protein Binding Approximately 75% - Acute toxicity: LD₅₀ in rats was >2000 mg/kg (oral). Clinical signs included sedation and gastrointestinal disturbances[1] - Reproductive toxicity: In male rats, Proguanil (50 mg/kg/day) caused testicular atrophy, decreased spermatogenesis, and increased abnormal sperm morphology after 90 days. These effects were reversible after 4-week washout[4] - Hematological effects: In vitro human lymphocyte studies showed Proguanil (520 ng/mL) induced dose-dependent DNA damage (comet assay tail moment increased by 40%) without affecting viability. Metabolic activation by S9 mix enhanced genotoxicity[8] |
| References |
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| Additional Infomation |
Proguanil Hydrochloride is the hydrochloride salt form of proguanil, a synthetic biguanide derivative of pyrimidine and an folate antagonist with antimalarial property. Upon hydrolysis, proguanil is converted to its active cyclic triazine metabolite, cycloguanil, by a cytochrome P450 dependent reaction. Cycloguanil selectively inhibits the bifunctional dihydrofolate reductase-thymidylate synthase (DHFR-TS) of plasmodium parasite, thereby disrupting deoxythymidylate synthesis and ultimately blocking DNA and protein synthesis in the parasite.
A biguanide compound which metabolizes in the body to form cycloguanil, an anti-malaria agent. See also: Proguanil (annotation moved to). |
| Molecular Formula |
C11H17CL2N5
|
|---|---|
| Molecular Weight |
290.19218
|
| Exact Mass |
289.086
|
| Elemental Analysis |
C, 45.53; H, 5.90; Cl, 24.43; N, 24.13
|
| CAS # |
637-32-1
|
| Related CAS # |
Proguanil;500-92-5;Proguanil-d6 hydrochloride;Proguanil-d6;Proguanil-d4 hydrochloride;1189671-34-8
|
| PubChem CID |
9570076
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| Appearance |
White to off-white solid powder
|
| Boiling Point |
402.7ºC at 760 mmHg
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| Melting Point |
249-251ºC
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| Flash Point |
197.4ºC
|
| LogP |
4.065
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| Hydrogen Bond Donor Count |
4
|
| Hydrogen Bond Acceptor Count |
1
|
| Rotatable Bond Count |
4
|
| Heavy Atom Count |
18
|
| Complexity |
292
|
| Defined Atom Stereocenter Count |
0
|
| SMILES |
CC(C)N=C(N)/N=C(\N)/NC1=CC=C(C=C1)Cl.Cl
|
| InChi Key |
SARMGXPVOFNNNG-UHFFFAOYSA-N
|
| InChi Code |
InChI=1S/C11H16ClN5.ClH/c1-7(2)15-10(13)17-11(14)16-9-5-3-8(12)4-6-9/h3-7H,1-2H3,(H5,13,14,15,16,17)1H
|
| Chemical Name |
(1E)-1-[amino-(4-chloroanilino)methylidene]-2-propan-2-ylguanidinehydrochloride
|
| Synonyms |
Proguanil HCl; Proguanil hydrochloride; Chloroguanide hydrochloride; Chlorguanide hydrochloride; 637-32-1; Diguanyl; Paludrine; Chloroguanide hydrochloride; Chloroquanil
|
| 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) |
May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples
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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.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 3.4460 mL | 17.2301 mL | 34.4602 mL | |
| 5 mM | 0.6892 mL | 3.4460 mL | 6.8920 mL | |
| 10 mM | 0.3446 mL | 1.7230 mL | 3.4460 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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