Tetramisole

Tetramisole can be synthesized through various methods. One common synthetic route involves the reaction of 1,2-dibromoethylbenzene with 2-aminothiazoline hydrochloride in the presence of sodium carbonate in N,N-dimethylformamide at elevated temperatures . The reaction proceeds in two stages: the first stage at 85°C for 2 hours and the second stage at 160°C for 16 hours . Industrial production methods often involve multi-step processes that include chlorination, cyclization, and salification steps to achieve high yields and purity .

Tetramisole undergoes various chemical reactions, including:

Oxidation: this compound can be oxidized under specific conditions, although detailed oxidation pathways are less commonly reported.

Reduction: Reduction reactions are not typically associated with this compound.

Substitution: This compound can undergo substitution reactions, particularly in the presence of strong nucleophiles or electrophiles.

Common reagents used in these reactions include sodium carbonate, hydrochloric acid, and organic solvents such as N,N-dimethylformamide . The major products formed from these reactions depend on the specific conditions and reagents used.

Veterinary Medicine

Tetramisole is widely used as an anthelmintic agent in veterinary medicine, particularly for treating helminth infections in livestock and pets. Its effectiveness against various parasitic worms has been well-documented.

Case Study: Efficacy Against Helminths

A study involving sheep demonstrated that this compound significantly increased resistance to Fasciola hepatica, a liver fluke, when combined with prior helminth infections. This immunomodulatory effect was attributed to this compound's ability to enhance the host's immune response against parasites .

Immunomodulatory Effects

This compound has been shown to stimulate the immune system, making it useful in treating conditions associated with immune deficiency.

Case Study: Immunomodulation in Cattle

In a controlled study, this compound was administered to cattle suffering from bovine mastitis. The treatment led to a significant reduction in bacterial counts and improved clinical symptoms within 3-24 hours after administration .

Cardioprotection

Recent research indicates that this compound may serve as a cardioprotective agent due to its role as an inward rectifier potassium channel agonist (IK1). This property has implications for treating cardiac arrhythmias and remodeling.

Experimental Findings

In vivo studies on rats showed that this compound administration improved cardiac function during ischemic events by enhancing IK1 current and reducing calcium overload. This suggests potential applications in managing heart diseases .

Neurobehavioral Effects

This compound has also been studied for its neurobehavioral effects in animal models. Research indicates that it can influence behaviors such as grooming and exploration in mice, suggesting potential applications in neuropharmacology .

Behavioral Study Results

A study administered this compound at varying doses to mice and observed significant increases in stereotyped behaviors at a dosage of 1 mg/kg, indicating its possible effects on neurochemistry .

Tetramisole exerts its effects by acting as an agonist to nicotinic acetylcholine receptors, leading to paralysis of parasitic worms . It also inhibits tissue non-specific alkaline phosphatase, which may affect the synthesis of neurotransmitters such as gamma-aminobutyric acid and adenosine . Additionally, this compound has been shown to block voltage-dependent sodium channels, affecting neuronal activity .

Comparison with Structurally Related Compounds

Levamisole

Levamisole, the L-isomer of tetramisole, shares structural similarity but differs in stereochemistry and biological activity:

• Anthelmintic Activity : Both compounds are effective against gastrointestinal nematodes, with levamisole showing higher potency in some models. For example, levamisole induces a 30 mM cluster formation in angiogenesis inhibition assays, while this compound requires higher concentrations for similar effects .
• Immunomodulation: Levamisole enhances T-cell responsiveness and macrophage function, making it a therapeutic adjuvant in cancer treatment (e.g., colorectal cancer) . This compound lacks significant immunostimulatory effects.
• Mechanistic Differences: Levamisole inhibits monoamine oxidase (MAO) more effectively than dexamisole, contributing to its antidepressant-like effects, whereas this compound’s cardioprotective effects are mediated via IK1 channel activation .

Table 1: Key Differences Between this compound and Levamisole

Dexamisole

Dexamisole, the D-isomer of this compound, exhibits contrasting effects on adrenergic neurotransmission:

• Adrenergic Modulation: Dexamisole augments norepinephrine-induced contractions in canine veins by inhibiting neuronal uptake, whereas levamisole enhances tyramine-induced responses .
• Anthelmintic Potency : Both isomers show comparable efficacy against nematodes, but dexamisole is less studied in clinical applications.

Other Imidazothiazoles: Pyrantel and Morantel

• Pyrantel: A tetrahydro-pyrimidine derivative, pyrantel acts as a depolarizing neuromuscular blocker.
• Morantel : Structurally related to pyrantel, morantel has a narrower spectrum of activity and is less potent against adult nematodes compared to this compound .

Comparison with Broad-Spectrum Anthelmintics

Albendazole (Benzimidazole Class)

• Mechanism : Inhibits microtubule polymerization, disrupting nematode glucose uptake.
• Efficacy : In field trials, albendazole and this compound showed comparable fecal egg count reduction (FECR) rates (~96–97%), but albendazole’s 95% confidence interval fell below 90% in some seasons, indicating variable efficacy .

Ivermectin (Macrocyclic Lactone)

• Mechanism : Binds glutamate-gated chloride channels, causing paralysis.
• Advantage : Higher FECR (98–99.6%) than this compound in wet and dry seasons .

Table 2: Field Efficacy of Common Anthelmintics

Research Findings and Contradictions

• Cardioprotection vs. Neurotoxicity : this compound reduces ischemic arrhythmias in rats but causes dose-dependent neuronal depression in mice .
• Developmental Toxicity : High this compound concentrations (100 µM–1 mM) inhibit C. elegans growth by 62–72%, but lower doses (1 nM–10 µM) are safe .

Tetramisole is a synthetic compound primarily known for its anthelmintic properties. Originally developed as a veterinary drug to treat parasitic infections in livestock, its biological activities extend beyond this application, including potential therapeutic roles in human medicine. This article explores the multifaceted biological activities of this compound, supported by various studies and case reports.

This compound functions as an inhibitor of alkaline phosphatase, an enzyme involved in various physiological processes. Research indicates that this compound and its analogues exhibit potent inhibitory effects on alkaline phosphatase isoenzymes associated with neoplastic cell lines, such as Sarcoma 180/TG. In a study, this compound demonstrated a 50% inhibition concentration (IC50) of 0.045 mM, significantly lower than that of its analogues, highlighting its superior potency due to the thiazole ring structure in its molecular configuration .

2. Cardioprotective Effects

Recent studies have identified this compound as a novel agonist of the inward rectifier potassium channel (IK1). This property suggests potential applications in cardiology, particularly for managing arrhythmias and cardiac remodeling. In experiments with adult rats, this compound showed significant anti-arrhythmic effects and reduced myocardial hypertrophy when administered at doses as low as 0.54 mg/kg . The mechanism involves enhancing IK1 current, which stabilizes cardiac electrical activity and reduces intracellular calcium overload.

Table 1: Summary of Cardioprotective Effects of this compound

3. Anthelmintic Properties

This compound remains widely used in veterinary medicine for its efficacy against helminth infections. It acts by paralyzing the parasites' neuromuscular systems, leading to their expulsion from the host's body. This mechanism has been well-documented across various animal studies, demonstrating its effectiveness against a range of parasitic worms .

4. Clinical Observations and Case Studies

Clinical observations have documented severe mortalities in koi carp associated with gill disease, where this compound was used as part of the treatment regimen . The compound's ability to modulate immune responses and improve overall health in aquatic species underscores its versatility beyond traditional veterinary applications.

5. Pharmacokinetics and Safety

Pharmacokinetic studies have shown that this compound is rapidly absorbed and distributed within the body, with a relatively short half-life that necessitates multiple dosing for sustained effects. Safety profiles indicate minimal adverse effects when administered within recommended dosages; however, caution is advised regarding potential interactions with other medications .

Basic Research Questions

Q. What are the standard protocols for assessing Tetramisole’s efficacy against gastrointestinal nematodes in ruminant models?

• Methodological Answer : Controlled trials should involve oral or subcutaneous administration at 5 mg/kg doses, followed by fecal egg count reduction tests (FECRT) and post-mortem necropsy to quantify parasite burden. For example, in cattle, this compound demonstrated 100% efficacy against Haemonchus contortus and Bunostomum phlebotomum at this dosage, with validation via egg culture and morphological identification of parasites . Ensure seasonal variations (e.g., dry vs. rainy seasons) are accounted for, as environmental factors influence parasite life cycles .

Q. How can researchers validate this compound’s bioactivity and purity in in vitro assays?

• Methodological Answer : Use gas chromatography (GC) to confirm ≥99% purity . For bioactivity, employ enzyme inhibition assays targeting alkaline phosphatases, noting that intestinal isoforms are only weakly inhibited . Solubility tests in aqueous solutions (e.g., 50 mg/mL in water) ensure compound stability for downstream applications .

Q. What analytical techniques are critical for characterizing this compound’s chemical properties?

• Methodological Answer : Key techniques include:

• GC/HPLC : For purity assessment and enantiomer separation (e.g., distinguishing levamisole from dextramisole) .
• X-ray diffraction : To confirm crystalline structure, as demonstrated for (±)-Tetramisole hydrochloride .
• Spectroscopic methods : SMILES strings and InChI codes aid in digital reproducibility .

Advanced Research Questions

Q. How can contradictions in this compound’s immunomodulatory effects across studies be resolved?

• Methodological Answer : Variability arises from model-specific responses (e.g., tumor systems vs. parasitic infections). Design studies with:

• Dose stratification : Test 0.5–5 mg/kg ranges to identify threshold effects .
• Endpoint standardization : Use metrics like lymphocyte proliferation assays or cytokine profiling to quantify immune modulation .
• Species-specific controls : Compare ruminants (cattle/sheep) with rodent models to isolate host-pathogen interactions .

Q. What experimental designs are optimal for evaluating this compound’s neurobiological impact in C. elegans?

• Methodological Answer : Use 5 mM this compound to induce paralysis while minimizing off-target effects on neuronal motility . Combine fluorescent microscopy (e.g., GFP-tagged neurons) with ImageJ-based intensity correlation analysis (ICQ) to quantify synaptic vesicle dynamics . Include wild-type and mutant strains to isolate genetic pathways affected by this compound .

Q. How can researchers investigate enantiomer-specific activity of this compound?

• Methodological Answer :

• Chiral chromatography : Separate levamisole (active L-enantiomer) from dextramisole and compare their anthelmintic efficacy .
• Comparative bioassays : Test enantiomers at half the racemic dose (e.g., 2.5 mg/kg) in sheep infected with Trichostrongylus spp. to validate potency differences .

Q. What strategies mitigate variability in parasite clearance rates post-Tetramisole administration?

• Methodological Answer :

• Longitudinal fecal exams : Collect samples at 7-, 14-, and 21-day intervals to track reinfection dynamics .
• Environmental controls : Monitor pasture contamination and larval survivability to distinguish drug efficacy from external factors .
• Statistical adjustments : Use mixed-effects models to account for individual host variations (e.g., weight, age) .

Q. Methodological Best Practices

Q. How should dose-response experiments be structured in this compound research?

• Guidelines :

• Range-finding trials : Start with 0.1–10 mg/kg doses in pilot studies to identify effective and toxic thresholds .
• Non-linear regression : Fit data to log-dose vs. response curves (e.g., Hill equation) to calculate EC₅₀ values .
• Multi-species validation : Test efficacy in parallel across Haemonchus (sheep) and Heligmosomoides (mice) to assess broad-spectrum activity .

Q. What practices enhance reproducibility in this compound studies across laboratories?

• Guidelines :

• Standardized protocols : Adopt WHO guidelines for FECRT and parasite identification .
• Blinded scoring : Use independent observers for necropsy-based parasite counts .
• Data sharing : Publish raw egg count data and microscopy images in supplementary materials .

Q. What approaches elucidate this compound’s molecular mode of action?

• Guidelines :
• Receptor binding assays : Use radiolabeled this compound to identify targets (e.g., nicotinic acetylcholine receptors in nematodes) .
• CRISPR/Cas9 knockouts : Generate C. elegans strains with mutations in candidate genes (e.g., unc-38) to test resistance mechanisms .
• Metabolomic profiling : Track changes in ATP or lipid levels post-treatment to infer metabolic disruption .