Proguanil

合成路线和反应条件: : 盐酸氯胍 D6 的合成涉及将氘原子掺入盐酸氯胍分子中。 这可以通过多种方法实现，包括在合成过程中使用氘代试剂或溶剂 . 反应条件通常涉及使用氘代溶剂，如氘代二甲基亚砜 (DMSO) 或氘代乙醇，反应在受控的温度和压力下进行，以确保氘原子的掺入 .

工业生产方法: : 盐酸氯胍 D6 的工业生产遵循类似的合成路线，但规模更大。 该工艺涉及使用自动化反应器并精确控制反应条件，以确保最终产品的高收率和纯度 .

反应类型: : 盐酸氯胍 D6 会经历各种化学反应，包括：

氧化: 盐酸氯胍 D6 可以被氧化形成其活性代谢物环氯胍.

还原: 还原反应可以将盐酸氯胍 D6 还原回其母体化合物盐酸氯胍.

取代: 取代反应可以在氯基团处发生，导致形成不同的衍生物.

常用试剂和条件

氧化: 常用的氧化剂包括过氧化氢和高锰酸钾，通常在酸性条件下进行.

还原: 在受控条件下使用硼氢化钠或氢化铝锂等还原剂.

取代: 取代反应通常涉及胺或硫醇等亲核试剂，在碱性条件下进行.

主要产品

环氯胍: 盐酸氯胍 D6 氧化形成的主要产物.

各种衍生物: 通过取代反应形成.

Clinical Efficacy

Proguanil is most commonly administered in combination with atovaquone, marketed as Malarone. This combination has demonstrated high efficacy rates in preventing and treating malaria. For instance, a randomized placebo-controlled study showed that this combination was 100% effective in preventing malaria among children living in endemic areas . Another study highlighted that this compound effectively sensitizes malaria parasites to atovaquone, thereby enhancing treatment outcomes even in cases where resistance to other antimalarials is present .

Table 1: Efficacy Data from Clinical Studies

Case Studies

• Atovaquone/Proguanil-Induced Esophageal Ulcers : A case report documented a healthy medical student who developed esophageal ulcers after taking atovaquone/proguanil without water. This incident underscores the importance of proper administration methods for medications .
• Treatment of Imported Malaria : In a study involving travelers returning from endemic regions, atovaquone/proguanil was successfully used to treat multiple cases of P. falciparum and P. vivax malaria. The treatment was effective even in patients who had previously failed other treatments .
• Resistance Cases : A cluster of malaria cases treated with atovaquone/proguanil revealed resistance mutations in the P. falciparum genome. This highlights the ongoing challenge of drug resistance and the need for continuous monitoring and development of new treatment strategies .

Future Applications

Research is ongoing to explore additional applications of this compound beyond malaria treatment. Its potential as an antifungal agent is being investigated, particularly for use in immunocompromised patients at risk for fungal infections . Furthermore, this compound's role in combination therapies with other antimalarials continues to be a focus area due to its ability to enhance the efficacy of existing drugs.

盐酸氯胍 D6 通过抑制二氢叶酸还原酶发挥作用，二氢叶酸还原酶是疟原虫繁殖所必需的酶 . 这种抑制阻止了寄生虫合成 DNA 和复制，从而阻止了感染 . 盐酸氯胍 D6 中的氘标记可以更精确地追踪药物在体内的分布和代谢 .

Antimalarial Agents Targeting DHFR

Cycloguanil (Active Metabolite of Proguanil)

• Structure: Diaminotriazine core with a chlorophenyl group .
• Mechanism : Inhibits plasmodial DHFR with IC₅₀ values comparable to pyrimethamine in biochemical assays (~10–50 nM) .
• Limitations : Rapid resistance due to Pfdhfr mutations (e.g., S108N), which also confer cross-resistance to pyrimethamine .
• Pharmacokinetics : Constitutes ~30% of total plasma drug concentration post-Proguanil administration; shorter half-life (~12–20 hours) compared to this compound (20 hours) .

Pyrimethamine

• Structure: Diaminopyrimidine core, structurally analogous to cycloguanil .
• Efficacy : Higher potency against DHFR (IC₅₀ < 10 nM) but rapid resistance development due to overlapping Pfdhfr mutations .
• Clinical Use : Often combined with sulfadoxine (as Fansidar®), unlike this compound, which is paired with atovaquone (Malarone®) for synergistic action .

Chlorthis compound

• Structure : Chlorophenylbiguanide derivative, similar to this compound.
• Outcome : Withdrawn due to hemolysis in G6PD-deficient patients, despite comparable DHFR inhibition .

This compound Derivatives in Cancer Therapy

4-Trifluoromethoxy this compound Derivatives (5C–8C)

• Structural Modifications : Trifluoromethoxy group and optimized alkyl chain length (n-heptyl in 8C) .
• Efficacy :
  • IC₅₀ : 5C–8C show IC₅₀ values 3–5× lower than this compound in bladder (T24, UMUC3) and ovarian (OVCAR3) cancer cells .
  • Mechanism : Activate AMPK/mTOR pathway (e.g., 8C upregulates p-AMPK and inhibits p-mTOR at 2.0 μM), unlike this compound, which lacks this activity .

Biguanides with Dual Antimalarial and Anticancer Activity

Metformin and Phenformin

• Mitochondrial Uptake : Unlike this compound, phenformin enters mitochondria to inhibit complex I, enhancing ROS production .
• Anticancer Potency : this compound induces apoptosis at higher concentrations (IC₅₀ ~10–20 μM) compared to phenformin (IC₅₀ ~1–5 μM) .

PS-15 (this compound Analog)

• Structure : Cyclopentyl-linked biguanide .
• Activity : 10× greater potency against multidrug-resistant P. falciparum than this compound, with prolonged half-life in vivo .

Drug Combinations and Synergy

Atovaquone/Proguanil (Malarone®)

• Synergy : Atovaquone inhibits mitochondrial cytochrome b, while cycloguanil targets DHFR, reducing resistance risk .
• Prophylaxis Efficacy : 97% protection in malaria-endemic regions vs. 77% for this compound alone .

This compound and Eis Inhibitors

• Repurposing : this compound inhibits acetyltransferase Eis in M. tuberculosis (IC₅₀ ~50 μM). Its analogue, modified with a hydrophobic tail, shows 10× improved potency .

Pharmacokinetic and Pharmacodynamic Considerations

• Metabolism : CYP2C19 poor metabolizers (PMs) exhibit 65% lower cycloguanil levels but retain partial antimalarial efficacy, suggesting this compound’s intrinsic activity .
• Drug Interactions : Omeprazole (CYP2C19 inhibitor) reduces cycloguanil formation by 47% in vitro and 32% in vivo .

Proguanil is an antimalarial compound primarily used in the prevention and treatment of malaria, particularly against Plasmodium falciparum and Plasmodium vivax . Its biological activity is closely linked to its metabolism into the active metabolite cycloguanil, which exerts significant effects on the malaria parasites. This article explores the biological activity of this compound, including its mechanisms of action, pharmacokinetics, clinical efficacy, and safety profile.

This compound functions as a dihydrofolate reductase (DHFR) inhibitor , which is crucial for the biosynthesis of purines and pyrimidines necessary for DNA synthesis in malaria parasites. The inhibition of DHFR leads to a failure in nuclear division during the schizont formation phase within erythrocytes and liver cells .

Key Mechanisms:

• Inhibition of Dihydrofolate Reductase : this compound and its metabolite cycloguanil inhibit DHFR in malaria parasites, disrupting folate metabolism essential for DNA replication .
• Synergistic Action with Atovaquone : When combined with atovaquone (as in Malarone), this compound enhances the efficacy against resistant strains of malaria by targeting different pathways in the parasite's lifecycle .

Pharmacokinetics

This compound is rapidly absorbed following oral administration, with peak plasma concentrations occurring within 1-3 hours. It has a high bioavailability (approximately 75%) and is extensively metabolized in the liver to cycloguanil via cytochrome P450 enzymes (CYP2C19) .

Pharmacokinetic Parameters:

Clinical Efficacy

Numerous studies have demonstrated the high efficacy of this compound, particularly when used in combination with atovaquone. A systematic review indicated that this combination therapy has a prophylactic efficacy of approximately 95.8% against malaria .

Case Studies:

• Study on Children : In a randomized controlled trial involving 320 children in Gabon, none of the children receiving atovaquone-proguanil developed positive blood smears during chemosuppression, compared to 25 cases in the placebo group (p<0.001)【6】【8】.
• Efficacy Against Resistant Strains : this compound has shown effectiveness even in regions where resistance to other antimalarial drugs is prevalent. For example, high antimalarial efficacy was observed in patients with poor metabolizer genotypes for CYP2C19【4】【5】.

Safety Profile

This compound is generally well-tolerated, with a lower incidence of adverse effects compared to alternative treatments. Common side effects include gastrointestinal disturbances such as nausea and vomiting【5】【6】. A meta-analysis reported fewer treatment-related adverse events leading to discontinuation among patients taking atovaquone-proguanil compared to those on other regimens【2】.

Adverse Effects Overview:

Q. Basic: What experimental protocols are recommended for determining Proguanil hydrochloride’s solubility in Biopharmaceutics Classification System (BCS) studies?

This compound hydrochloride’s solubility should be assessed using standardized protocols aligned with BCS guidelines. Key steps include:

• pH conditions : Testing at critical pH values (1.2, 4.5, 6.8) to simulate gastrointestinal environments.
• Dose/Solubility (D/S) ratio : Ensuring the maximum D/S ratio remains <250 mL across all pH levels to confirm "high solubility" classification .
• Experimental design : Avoiding conditions that induce physicochemical incompatibilities (e.g., pH 3.3 instability) to prevent false-negative results .
• Validation : Reporting inconclusive results transparently to refine protocol accuracy .

Q. Advanced: How does CYP2C19 genetic polymorphism influence this compound’s pharmacokinetics and therapeutic efficacy?

This compound is a prodrug metabolized by CYP2C19 to its active metabolite, cycloguanil. Genetic variability impacts:

• Metabolic ratios : Poor metabolizers (PMs) with two non-functional CYP2C19 alleles exhibit urinary metabolic ratios >13, compared to <9 in heterozygotes .
• Pharmacokinetic disparities : PMs show 5–10× lower cycloguanil plasma concentrations, reducing antimalarial efficacy. Conversely, PMs have higher this compound and 4-chlorophenylbiguanide (CPB) levels, potentially increasing toxicity risks .
• Clinical implications : In populations with high CYP2C19*2/*3 allele frequencies (e.g., Vanuatu), genotyping is critical for dose optimization .

Q. Basic: What validated analytical methods are used for simultaneous quantification of this compound and its metabolites?

A robust RP-HPLC method employs:

• Column : Kromasil C18 (150 × 4.6 mm, 5 µm).
• Mobile phase : 0.1% OPA:ACN (50:50 v/v) at 1.0 mL/min flow rate.
• Detection : UV at 287 nm, yielding retention times of 2.15 min (this compound) and 2.48 min (Atovaquone).
• Validation : Linearity ranges of 25–150 µg/mL (this compound) and 62.5–375 µg/mL (Atovaquone), with recovery rates >98% . For plasma/urine, LC-MS/MS achieves LLOQs of 1 µg/L (this compound) and 0.5 µg/L (cycloguanil) .

Q. Advanced: How do contradictory efficacy outcomes arise in clinical trials of Atovaquone-Proguanil (AP) combinations?

AP’s efficacy against Plasmodium falciparum varies due to:

• PCR-adjusted endpoints : Trials differentiating recrudescence (treatment failure) from reinfection. For example, a 2014 Cameroon trial reported 9.4% PCR-adjusted failure rates for AP vs. 2.9% for artesunate-amodiaquine, though statistical power was limited .
• Regional resistance patterns : AP maintains >95% efficacy in non-African regions but shows reduced effectiveness in high-transmission areas due to prior exposure and parasite resistance .
• Study design : Small sample sizes (e.g., n=60 in Ethiopia) limit generalizability .

Q. Advanced: What methodological considerations address this compound’s folate antagonism in pregnancy-related research?

This compound inhibits dihydrofolate reductase, necessitating:

• Folic acid supplementation : Co-administration of 5 mg/day folic acid to mitigate teratogenicity risks, despite limited evidence of congenital malformations .
• Pharmacovigilance : Monitoring adverse outcomes (e.g., fetal loss, preterm birth) in trials, as seen in U.S. military data .
• Ethical constraints : Prioritizing alternative antimalarials in first-trimester studies due to residual uncertainties .

Q. Basic: What historical insights inform this compound’s mechanism of action as a causal prophylactic?

This compound’s unique prophylactic activity stems from:

• Prodrug activation : Hepatic conversion to cycloguanil, a dihydrofolate reductase inhibitor that blocks Plasmodium sporozoite development in hepatocytes .
• Mosquito-stage inhibition : Early studies demonstrated suppression of gametocyte maturation in Anopheles vectors, reducing transmission potential .

Q. Advanced: How do alternative metabolic pathways (e.g., CPB formation) impact this compound’s pharmacokinetic modeling?

CPB, a minor metabolite via CYP3A4-mediated N-dealkylation, complicates kinetic analyses by:

• Compartmental modeling : Requiring triexponential fitting to account for parallel elimination pathways (e.g., median AUCs: 3046 ng·h/mL for this compound vs. 257 ng·h/mL for CPB) .
• Tissue distribution : Higher whole-blood concentrations of this compound (5× plasma) and CPB (4× plasma) suggest erythrocyte binding, altering volume of distribution estimates .

Q. Advanced: What strategies optimize this compound dosing in CYP2C19-polymorphic populations?

• Phenotype-genotype correlation : Pre-screening for CYP2C19*2/*3 alleles to identify PMs requiring dose adjustments .
• Therapeutic drug monitoring (TDM) : Targeting cycloguanil plasma levels >40 ng/mL, as subtherapeutic concentrations (<20 ng/mL) correlate with treatment failure .