| Size | Price | Stock | Qty |
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| 5mg |
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| 500mg | |||
| Other Sizes |
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
Following oral doses of 50 to 500 mg, guanidine is rapidly and well absorbed in the human body. Metabolism/Metabolites It is metabolized in the liver by cytochrome P450 isoenzymes to the active triazine metabolite cyclic guanidine, but the degree of metabolism varies. This metabolic variation in guanidine may have important clinical significance for populations with slower metabolism (e.g., Asian and African populations susceptible to malaria). For these populations, prophylaxis with guanidine may be ineffective because even with multiple doses, they may not achieve sufficient therapeutic concentrations of the active compound cyclic guanidine. Known metabolites of guanidine include cyclic guanidine and 4-chlorophenylbiguanidine. Biological Half-Life Approximately 20 hours. Absorption: After oral administration of guanidine (100 mg), the time to peak concentration (Tmax) in the human body is 2–4 hours, with a bioavailability of 70–80%. Food can increase Cmax by 30%, but does not affect AUC[1] - Metabolism: In the liver, it is mainly metabolized by CYP2C19 and CYP3A4 to cyclic guanidine (the main active metabolite) and other inactive conjugates. The plasma half-life of guanidine is 14–16 hours, while that of cyclic guanidine is 16–20 hours[1] - Excretion: Approximately 60% of the dose is excreted in the urine as metabolites, and 30% is excreted in the feces. Less than 5% of the original drug is detected in the urine[1] |
| Toxicity/Toxicokinetics |
Hepatotoxicity
Atorvaquinone and guanidine combination therapy has been associated with transient and mild elevations in serum transaminases in a small number of patients. More importantly, there have been a few reports of specific acute liver injury in patients taking atorvaquinone/guanidine, but the number of cases is too small to determine a typical clinical course. In one reported case, the injury occurred 3 weeks after administration, presenting as fatigue, jaundice, and cholestatic elevations in serum enzymes. The injury resolved within 2 months of discontinuation (Case 1). In another case report of chloroquine and guanidine, liver injury occurred within days of initiation of combination therapy, with a mixed pattern of elevated serum enzymes. In both cases, allergic symptoms were mild, and no autoantibodies were detected. Both cases involved combination therapy, and either drug could have been a cause of the injury. Atorvaquinone and guanidine have also been associated with rare cases of Stevens-Johnson syndrome, which is typically accompanied by mild liver injury or elevated liver enzymes. Probability Score: E (Unproven, but sometimes suspected as a cause of clinically apparent liver injury). Protein binding Approximately 75% - Acute toxicity: LD₅₀ >2000 mg/kg (oral) in rats. Clinical symptoms included sedation and gastrointestinal disturbances [1] - Reproductive toxicity: In male rats, guanidine (50 mg/kg/day) caused testicular atrophy, decreased spermatogenesis, and increased abnormal sperm morphology after 90 days. These effects were reversible after 4 weeks of washout [4] - Hematologic effects: In vitro human lymphocyte studies showed that guanidine (520 ng/mL) induced dose-dependent DNA damage (40% increase in comet tail moment) without affecting cell viability. Metabolic activation of the S9 mixture enhanced its genotoxicity [8] |
| References |
|
| Additional Infomation |
Proguanidine hydrochloride is the hydrochloride form of proguanidine, a synthetic pyrimidine biguanide derivative and a folic acid antagonist with antimalarial activity. After hydrolysis, proguanidine is converted to its active cyclic triazine metabolite, cyclic guanidine, via a cytochrome P450-dependent reaction. Cyclic guanidine selectively inhibits the bifunctional dihydrofolate reductase-thymidine synthase (DHFR-TS) of Plasmodium, thereby disrupting deoxythymidine synthesis and ultimately blocking the synthesis of Plasmodium's DNA and proteins.
A biguanide compound that is metabolized in vivo to cyclic guanidine (an antimalarial drug). See also: Proguanidine (note 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
|
| Appearance |
White to off-white solid powder
|
| Boiling Point |
402.7ºC at 760 mmHg
|
| Melting Point |
249-251ºC
|
| Flash Point |
197.4ºC
|
| LogP |
4.065
|
| 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
|
| 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)
|
| 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
|
|---|---|
| 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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