	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 编号	500-92-5
分子式	C11H16ClN5
分子量	259.77 g/mol
IUPAC 名称	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 键	SSOLNOMRVKKSON-WFGJKAKNSA-N
SMILES	CC(C)N=C(N)N=C(N)NC1=CC=C(C=C1)Cl
手性 SMILES	[2H]C([2H])([2H])C(C([2H])([2H])[2H])N=C(N)N=C(N)NC1=CC=C(C=C1)Cl
规范 SMILES	CC(C)N=C(N)N=C(N)NC1=CC=C(C=C1)Cl
熔点	129 °C
	500-92-5
物理描述	Solid
纯度	> 95%
数量	Milligrams-Grams
相关CAS编号	637-32-1 (hydrochloride)
溶解度	2.86e-01 g/L
同义词	Bigumal Chlorguanid Chloriguane Chloroguanide Chloroguanide Hydrochloride Hydrochloride, Chloroguanide Hydrochloride, Proguanil Paludrin Paludrine Proguanil Proguanil Hydrochloride
产品来源	United States

Retrosynthesis Analysis

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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: Proguanil 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 Proguanil impacts Plasmodium falciparum?

A2: Research suggests Proguanil, 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 Proguanil affect other stages of the Plasmodium life cycle besides the erythrocytic stage?

A3: Yes, both Proguanil and Atovaquone demonstrate activity against gametocytes and pre-erythrocytic (hepatic) stages of malaria parasites []. This is supported by studies indicating that short-term Proguanil 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 Proguanil metabolized in the human body?

A4: Proguanil 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 Proguanil metabolism among individuals?

A5: Inter-individual variability in Proguanil 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 Proguanil 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 Proguanil metabolism, like CYP3A4 [].

Q6: How is Proguanil eliminated from the body?

A6: Both Proguanil 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 Proguanil?

A7: Yes, Proguanil 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 Proguanil resistance [, ].

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

A8: Yes, cross-resistance has been observed between Proguanil 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 Proguanil interact with other drugs?

A9: Yes, Proguanil'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 Proguanil's area under the curve (AUC) and maximum concentration (Cmax), potentially impacting its efficacy [].

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

A10: Emerging research suggests that Proguanil may have anti-cancer properties, particularly in breast cancer. Studies have shown that Proguanil 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 Proguanil for therapeutic use?

A11: Proguanil 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 Proguanil tablets, potentially altering its bioavailability and warranting further investigation for potential herb-drug interactions [].

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

A12: High-performance liquid chromatography (HPLC) is widely used to measure Proguanil 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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