Proguanil

Katalognummer: B194036

CAS-Nummer: 500-92-5

Molekulargewicht: 259.77 g/mol

InChI-Schlüssel: SSOLNOMRVKKSON-WFGJKAKNSA-N

Achtung: Nur für Forschungszwecke. Nicht für den menschlichen oder tierärztlichen Gebrauch.

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Übersicht

1. Beschreibung

7. Vergleich mit ähnlichen Verbindungen

2. Wirkmechanismus

8. Eigenschaften

3. Biochemische Analyse

9. Retrosynthesis analysis

4. Vorbereitungsmethoden

10. Q & A

5. Analyse chemischer Reaktionen

11. Haftungsausschluss

6. Wissenschaftliche Forschungsanwendungen

Beschreibung

Proguanil D6: is a deuterium-labeled derivative of this compound, an antimalarial agent. This compound is widely used for the prophylaxis and treatment of malaria caused by Plasmodium falciparum and Plasmodium vivax . The deuterium labeling in this compound D6 enhances its stability and allows for more precise pharmacokinetic studies .

Wirkmechanismus

Result of Action

The result of this compound’s action is the prevention and suppression of malaria caused by susceptible strains of P. falciparum and other species of Plasmodium found in some geographical areas of the world . It has causal prophylactic and suppressive activity against P. falciparum and cures the acute infection .

Action Environment

The action, efficacy, and stability of this compound can be influenced by various environmental factors. For instance, dietary fat increases the rate and extent of atovaquone absorption, a drug often used in combination with this compound . Furthermore, this compound is rapidly and extensively absorbed regardless of food intake . .

Biochemische Analyse

Biochemical Properties

Proguanil is a biguanide derivative that is converted to an active metabolite called cycloguanil . It exerts its antimalarial action by inhibiting the enzyme, dihydrofolate reductase, which is involved in the reproduction of the malaria parasite, Plasmodium falciparum and Plasmodium vivax . This inhibition blocks the biosynthesis of purines and pyrimidines, which are essential for DNA synthesis and cell multiplication .

Cellular Effects

This compound works by stopping the malaria parasite, Plasmodium falciparum and Plasmodium vivax, from reproducing once it is in the red blood cells . It does this by inhibiting the enzyme, dihydrofolate reductase, which is involved in the reproduction of the parasite . This leads to failure of nuclear division at the time of schizont formation in erythrocytes and liver .

Molecular Mechanism

The molecular mechanism of this compound involves the inhibition of the enzyme dihydrofolate reductase of plasmodia . This inhibition blocks the biosynthesis of purines and pyrimidines, which are essential for DNA synthesis and cell multiplication . This leads to failure of nuclear division at the time of schizont formation in erythrocytes and liver .

Temporal Effects in Laboratory Settings

This compound has been shown to have potent, but slow-acting, in vitro anti-plasmodial activity . The potent fast-acting activity of this compound is attributed to the dihydrofolate reductase inhibitor cycloguanil .

Dosage Effects in Animal Models

While specific dosage effects of this compound in animal models were not found in the search results, it is known that this compound is extensively absorbed in rats . In both species, toxicity was related to this compound exposure, the principal manifestations being salivation, emesis, and loss of body weight .

Metabolic Pathways

This compound is variably metabolized in the liver by cytochrome P450 isoenzymes to the active triazine metabolite, cycloguanil . This variable metabolism of this compound may have profound clinical importance in poor metabolizers such as the Asian and African populations at risk for malaria infection .

Transport and Distribution

This compound and its metabolite cycloguanil were found to be substrates of organic cation transporter 1 (OCT1), organic cation transporter 2 (OCT2), multidrug and toxin extrusion 1 (MATE1) and multidrug and toxin extrusion 2-K (MATE2-K). These transporters play a crucial role in the distribution and excretion of this compound .

Subcellular Localization

The specific subcellular localization of this compound was not found in the search results. Given its mechanism of action, it can be inferred that this compound likely localizes to the site of the enzyme dihydrofolate reductase, which is involved in the reproduction of the malaria parasite .

Vorbereitungsmethoden

Synthetic Routes and Reaction Conditions: : The synthesis of Proguanil D6 involves the incorporation of deuterium atoms into the this compound molecule. This can be achieved through various methods, including the use of deuterated reagents or solvents during the synthesis process . The reaction conditions typically involve the use of deuterated solvents such as deuterated dimethyl sulfoxide (DMSO) or deuterated ethanol, and the reactions are carried out under controlled temperatures and pressures to ensure the incorporation of deuterium atoms .

Industrial Production Methods: : Industrial production of this compound D6 follows similar synthetic routes but on a larger scale. The process involves the use of automated reactors and precise control of reaction conditions to ensure high yield and purity of the final product .

Analyse Chemischer Reaktionen

Arten von Reaktionen: : Proguanil-D₆ unterliegt verschiedenen chemischen Reaktionen, darunter:

Oxidation: This compound-D₆ kann oxidiert werden, um seinen aktiven Metaboliten, Cycloguanil, zu bilden.

Reduktion: Reduktionsreaktionen können this compound-D₆ zurück in seine Stammverbindung, this compound, umwandeln.

Substitution: Substitutionsreaktionen können an der Chlorgruppe auftreten und zur Bildung verschiedener Derivate führen.

Häufige Reagenzien und Bedingungen

Oxidation: Häufige Oxidationsmittel sind Wasserstoffperoxid und Kaliumpermanganat, typischerweise unter sauren Bedingungen.

Reduktion: Reduktionsmittel wie Natriumborhydrid oder Lithiumaluminiumhydrid werden unter kontrollierten Bedingungen verwendet.

Substitution: Substitutionsreaktionen beinhalten häufig Nukleophile wie Amine oder Thiole unter basischen Bedingungen.

Wichtige Produkte

Cycloguanil: Das Hauptprodukt, das durch die Oxidation von this compound-D₆ gebildet wird.

Verschiedene Derivate: Geformt durch Substitutionsreaktionen.

Wissenschaftliche Forschungsanwendungen

This compound-D₆ hat eine breite Palette wissenschaftlicher Forschungsanwendungen, darunter:

Chemie: Als Referenzverbindung in der analytischen Chemie verwendet, um die Pharmakokinetik und den Metabolismus von this compound zu untersuchen.

Biologie: In biologischen Studien eingesetzt, um den Wirkmechanismus von Antimalariamitteln zu verstehen.

Medizin: Untersucht auf seine potenziellen Antikrebswirkungen, insbesondere bei Brust- und Blasenkrebs

Industrie: In der Entwicklung neuer Antimalariaformulierungen und Arzneimittelverabreichungssysteme eingesetzt.

Wirkmechanismus

This compound-D₆ übt seine Wirkung aus, indem es das Enzym Dihydrofolat-Reduktase hemmt, das für die Reproduktion des Malariaparasiten essentiell ist . Diese Hemmung verhindert, dass der Parasit DNA synthetisiert und sich repliziert, wodurch die Infektion gestoppt wird . Die Deuterierung in this compound-D₆ ermöglicht eine genauere Verfolgung der Verteilung und des Metabolismus des Arzneimittels im Körper .

Wissenschaftliche Forschungsanwendungen

Proguanil D6 has a wide range of scientific research applications, including:

Chemistry: Used as a reference compound in analytical chemistry to study the pharmacokinetics and metabolism of this compound.

Biology: Employed in biological studies to understand the mechanism of action of antimalarial drugs.

Medicine: Investigated for its potential anticancer properties, particularly in breast and bladder cancer

Industry: Utilized in the development of new antimalarial formulations and drug delivery systems.

Vergleich Mit ähnlichen Verbindungen

Eigenschaften

	Proguanil inhibits the dihydrofolate reductase of plasmodia and thereby blocks the biosynthesis of purines and pyrimidines, which are essential for DNA synthesis and cell multiplication. This leads to failure of nuclear division at the time of schizont formation in erythrocytes and liver.
CAS-Nummer	500-92-5
Molekularformel	C11H16ClN5
Molekulargewicht	259.77 g/mol
IUPAC-Name	1-[amino-(4-chloroanilino)methylidene]-2-(1,1,1,3,3,3-hexadeuteriopropan-2-yl)guanidine
InChI	InChI=1S/C11H16ClN5/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)/i1D3,2D3
InChI-Schlüssel	SSOLNOMRVKKSON-WFGJKAKNSA-N
SMILES	CC(C)N=C(N)N=C(N)NC1=CC=C(C=C1)Cl
Isomerische SMILES	[2H]C([2H])([2H])C(C([2H])([2H])[2H])N=C(N)N=C(N)NC1=CC=C(C=C1)Cl
Kanonische SMILES	CC(C)N=C(N)N=C(N)NC1=CC=C(C=C1)Cl
melting_point	129 °C
	500-92-5
Physikalische Beschreibung	Solid
Reinheit	> 95%
Menge	Milligrams-Grams
Verwandte CAS-Nummern	637-32-1 (hydrochloride)
Löslichkeit	2.86e-01 g/L
Synonyme	Bigumal Chlorguanid Chloriguane Chloroguanide Chloroguanide Hydrochloride Hydrochloride, Chloroguanide Hydrochloride, Proguanil Paludrin Paludrine Proguanil Proguanil Hydrochloride
Herkunft des Produkts	United States

Retrosynthesis Analysis

AI-Powered Synthesis Planning: Our tool employs the Template_relevance Pistachio, Template_relevance Bkms_metabolic, Template_relevance Pistachio_ringbreaker, Template_relevance Reaxys, Template_relevance Reaxys_biocatalysis model, leveraging a vast database of chemical reactions to predict feasible synthetic routes.

One-Step Synthesis Focus: Specifically designed for one-step synthesis, it provides concise and direct routes for your target compounds, streamlining the synthesis process.

Accurate Predictions: Utilizing the extensive PISTACHIO, BKMS_METABOLIC, PISTACHIO_RINGBREAKER, REAXYS, REAXYS_BIOCATALYSIS database, our tool offers high-accuracy predictions, reflecting the latest in chemical research and data.

Strategy Settings

Precursor scoring	Relevance Heuristic
Min. plausibility	0.01
Model	Template_relevance
Template Set	Pistachio/Bkms_metabolic/Pistachio_ringbreaker/Reaxys/Reaxys_biocatalysis
Top-N result to add to graph	6

Feasible Synthetic Routes

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Q & A

Q1: How does Proguanil exert its antimalarial effect?

A1: this compound itself has weak antimalarial activity. Its effectiveness stems from its active metabolite, Cycloguanil, a potent inhibitor of dihydrofolate reductase (DHFR) []. DHFR is a crucial enzyme in the folate metabolic pathway, essential for DNA synthesis and cellular replication in parasites like Plasmodium falciparum []. By inhibiting DHFR, Cycloguanil disrupts DNA synthesis and ultimately kills the parasite [, ].

Q2: Are there other mechanisms by which this compound impacts Plasmodium falciparum?

A2: Research suggests this compound, in combination with Atovaquone, might interfere with mitochondrial electron transport and collapse mitochondrial membrane potential in the parasite, further contributing to its antimalarial activity [].

Q3: Does this compound affect other stages of the Plasmodium life cycle besides the erythrocytic stage?

A3: Yes, both this compound and Atovaquone demonstrate activity against gametocytes and pre-erythrocytic (hepatic) stages of malaria parasites []. This is supported by studies indicating that short-term this compound administration might provide causal prophylaxis for Plasmodium vivax by inhibiting liver-stage schizonts, although it doesn't seem to prevent late attacks related to hypnozoite reactivation [].

Q4: How is this compound metabolized in the human body?

A4: this compound is primarily metabolized in the liver by cytochrome P450 (CYP) enzymes, specifically CYP2C19 and CYP3A4 [, ]. The primary metabolic pathway involves CYP2C19-mediated conversion to its active metabolite, Cycloguanil [, ].

Q5: What factors contribute to the variability in this compound metabolism among individuals?

A5: Inter-individual variability in this compound metabolism is influenced by several factors, primarily genetic polymorphisms in the CYP2C19 gene [, ]. Individuals homozygous for the CYP2C19*2 allele exhibit significantly reduced metabolic capacity, leading to higher this compound and lower Cycloguanil levels []. Other factors include co-administration of drugs that are CYP2C19 inducers or inhibitors [], and variations in the expression and activity of other enzymes involved in this compound metabolism, like CYP3A4 [].

Q6: How is this compound eliminated from the body?

A6: Both this compound and Cycloguanil are predominantly eliminated through the kidneys []. Therefore, dosage adjustments are necessary for patients with renal impairment to prevent drug accumulation [].

Q7: Are there documented cases of resistance to this compound?

A7: Yes, this compound resistance has been observed and is primarily attributed to point mutations in the dihydrofolate reductase (DHFR) gene of Plasmodium falciparum [, ]. The S108N mutation is particularly associated with this compound resistance [, ].

Q8: Is there cross-resistance between this compound and other antimalarial drugs?

A8: Yes, cross-resistance has been observed between this compound and Pyrimethamine, another antifolate drug []. This is attributed to their shared mechanism of action, both targeting the DHFR enzyme in the parasite. The presence of the triple mutant DHFR haplotype (S108N+N51I+C59N) in Plasmodium falciparum has been linked to resistance to both drugs [, ].

Q9: Does this compound interact with other drugs?

A9: Yes, this compound's metabolism can be affected by co-administration with other drugs metabolized by CYP2C19, such as Phenytoin []. Concomitant use of Phenytoin, a CYP2C19 inducer, can decrease this compound's area under the curve (AUC) and maximum concentration (Cmax), potentially impacting its efficacy [].

Q10: Beyond malaria, are there other potential therapeutic applications for this compound?

A10: Emerging research suggests that this compound may have anti-cancer properties, particularly in breast cancer. Studies have shown that this compound inhibits the growth of breast cancer cells in vitro and in vivo, potentially by inducing oxidative stress, disrupting mitochondrial function, and triggering apoptosis [, ].

Q11: What are the key considerations in formulating this compound for therapeutic use?

A11: this compound formulations aim to optimize solubility, bioavailability, and stability []. The choice of excipients and manufacturing processes can significantly influence these factors. For instance, some herbal formulations may significantly impact the dissolution profile of this compound tablets, potentially altering its bioavailability and warranting further investigation for potential herb-drug interactions [].

Q12: What analytical techniques are commonly employed to quantify this compound and its metabolites?

A12: High-performance liquid chromatography (HPLC) is widely used to measure this compound and its metabolites in biological samples like plasma and urine [, , ]. Ultra-performance liquid chromatography (UPLC) offers enhanced speed and sensitivity for pharmacokinetic studies [].

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