Trimethoprim
Overview
Description
Trimethoprim is an antibiotic primarily used to treat bacterial infections, particularly urinary tract infections. It is also effective against middle ear infections and traveler’s diarrhea. This compound works by inhibiting the bacterial enzyme dihydrofolate reductase, which is essential for the production of tetrahydrofolic acid, a precursor in the synthesis of bacterial DNA .
Scientific Research Applications
Trimethoprim has a wide range of applications in scientific research:
Chemistry: Used as a template for synthesizing new antibacterial agents and studying enzyme inhibition.
Biology: Employed in studies of bacterial resistance mechanisms and metabolic pathways.
Medicine: Widely used in clinical trials for treating bacterial infections and as a prophylactic agent in immunocompromised patients.
Industry: Utilized in the formulation of combination drugs with other antibiotics like sulfamethoxazole
Mechanism of Action
Target of Action
Trimethoprim primarily targets the bacterial enzyme dihydrofolate reductase (DHFR) . DHFR plays a crucial role in the synthesis of purine and pyrimidine nucleotides, which are essential for bacterial DNA synthesis .
Mode of Action
This compound acts as a selective inhibitor of bacterial DHFR . By inhibiting DHFR, it prevents the conversion of dihydrofolate to tetrahydrofolate . This disruption in the conversion process leads to a halt in the synthesis of purine and pyrimidine nucleotides, thereby disrupting bacterial DNA synthesis and leading to cell death .
Biochemical Pathways
The primary biochemical pathway affected by this compound is the dihydrofolate pathway . By inhibiting DHFR, this compound prevents the formation of tetrahydrofolic acid (THF) from dihydrofolic acid (DHF) . THF is necessary for the biosynthesis of bacterial nucleic acids and proteins . The inhibition of this pathway disrupts bacterial DNA synthesis, ultimately preventing bacterial survival .
Pharmacokinetics
This compound is rapidly absorbed, with steady-state concentrations achieved after approximately 3 days of repeat administration . Peak serum concentrations are reached within 1 to 4 hours following the administration of a single dose . The elimination half-life of this compound ranges between 6 and 17 hours . These pharmacokinetic properties impact the bioavailability of this compound, influencing its effectiveness in treating infections.
Result of Action
The molecular and cellular effects of this compound’s action primarily involve the disruption of bacterial DNA synthesis . By inhibiting the formation of THF, an essential precursor in the thymidine synthesis pathway, this compound prevents the synthesis of bacterial DNA . This disruption in DNA synthesis leads to bacterial cell death .
Action Environment
Environmental factors can influence the action, efficacy, and stability of this compound. For instance, the pH of the environment can impact the ionization state of this compound, which in turn affects its adsorption and overall effectiveness . Additionally, the presence of microplastics in the environment can enhance the adsorption of this compound in soil environments . These factors need to be considered when assessing the fate and transport of this compound in various environments .
Safety and Hazards
Trimethoprim can cause serious side effects. It can decrease renal tubular potassium excretion, leading to potentially life-threatening hyperkalemia . Rarely, severe hepatic necrosis occurs . The drug may also cause a syndrome resembling aseptic meningitis . It is also considered a moderate to severe irritant to the skin and eyes .
Future Directions
Due to the spread of community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA), the demand for trimethoprim/sulfamethoxazole (SXT) is increasing in the world . It is not clear whether the resistant strain emerges by overuse of SXT . Therefore, intense searching of new leading structures and active substances, which may be used as new drugs, especially against strain resistant to all available therapeutics, is very important .
Biochemical Analysis
Biochemical Properties
Trimethoprim plays a crucial role in biochemical reactions by inhibiting the enzyme dihydrofolate reductase. This enzyme is responsible for the reduction of dihydrofolic acid to tetrahydrofolic acid, a precursor necessary for the synthesis of thymidine, purines, and certain amino acids. By blocking this enzyme, this compound prevents the formation of tetrahydrofolic acid, thereby inhibiting bacterial DNA synthesis and cell division . This compound interacts specifically with bacterial dihydrofolate reductase, binding to it more strongly than to the mammalian counterpart, which accounts for its selective toxicity towards bacteria .
Cellular Effects
This compound affects various types of cells and cellular processes. In bacterial cells, it disrupts DNA synthesis by inhibiting the production of tetrahydrofolic acid. This inhibition leads to a halt in cell division and ultimately results in bacterial cell death . This compound also impacts cell signaling pathways and gene expression by interfering with the folate metabolism pathway, which is crucial for the synthesis of nucleotides and amino acids . In mammalian cells, this compound can cause side effects such as nausea, vomiting, and rash, which are related to its impact on folate metabolism .
Molecular Mechanism
The molecular mechanism of this compound involves its binding to the active site of dihydrofolate reductase, thereby inhibiting the enzyme’s activity. This binding is highly specific and much stronger for the bacterial enzyme compared to the mammalian enzyme . By inhibiting dihydrofolate reductase, this compound prevents the conversion of dihydrofolic acid to tetrahydrofolic acid, leading to a depletion of tetrahydrofolic acid and subsequent inhibition of DNA synthesis . This mechanism of action is the basis for its antibacterial properties.
Temporal Effects in Laboratory Settings
In laboratory settings, the effects of this compound can change over time. Studies have shown that this compound remains stable under various conditions, but its efficacy can decrease due to bacterial resistance mechanisms . Long-term exposure to this compound can lead to the development of resistance in bacterial populations, which is a significant concern in clinical settings . Additionally, this compound can cause adverse effects such as acute kidney injury and hyperkalemia in patients, particularly in older adults .
Dosage Effects in Animal Models
The effects of this compound vary with different dosages in animal models. At therapeutic doses, this compound effectively treats bacterial infections without causing significant adverse effects . At higher doses, this compound can cause toxic effects such as bone marrow suppression and changes in the hematopoietic system . In animal studies, this compound has been shown to cause teratogenic effects at doses higher than those recommended for therapeutic use .
Metabolic Pathways
This compound is involved in the metabolic pathway of folate synthesis. It inhibits dihydrofolate reductase, preventing the formation of tetrahydrofolic acid from dihydrofolic acid . This inhibition disrupts the synthesis of nucleotides and amino acids, which are essential for DNA and RNA synthesis . This compound’s action on the folate pathway also affects the levels of various metabolites, leading to a decrease in nucleotide synthesis and an increase in stress-related metabolites .
Transport and Distribution
This compound is rapidly absorbed following oral administration and has a high bioavailability . It is distributed widely in the body, with approximately 44% bound to plasma proteins . This compound achieves high concentrations in tissues such as the kidneys and prostate, which is beneficial for treating urinary tract infections . It is also excreted primarily through the kidneys, with a significant portion of the drug being eliminated unchanged in the urine .
Subcellular Localization
This compound’s subcellular localization is primarily within the cytoplasm, where it exerts its inhibitory effects on dihydrofolate reductase . The drug does not require specific targeting signals or post-translational modifications to reach its site of action. Its activity is dependent on its ability to diffuse into bacterial cells and bind to the enzyme . This localization is crucial for its effectiveness in inhibiting bacterial DNA synthesis and preventing cell division .
Preparation Methods
Synthetic Routes and Reaction Conditions: Trimethoprim is synthesized through a multi-step process involving the condensation of 3,4,5-trimethoxybenzaldehyde with guanidine to form 2,4-diamino-5-(3,4,5-trimethoxybenzyl)pyrimidine. The reaction typically occurs under basic conditions with the use of a strong base such as sodium hydroxide .
Industrial Production Methods: In industrial settings, the synthesis of this compound involves large-scale batch processes. The key steps include the preparation of intermediates, followed by their condensation and purification. The final product is obtained through crystallization and drying .
Types of Reactions:
Oxidation: this compound can undergo oxidation reactions, particularly at the methoxy groups, leading to the formation of quinone derivatives.
Reduction: The nitro group in this compound can be reduced to an amine under specific conditions.
Substitution: this compound can participate in nucleophilic substitution reactions, especially at the aromatic ring positions.
Common Reagents and Conditions:
Oxidation: Reagents such as potassium permanganate or chromium trioxide are commonly used.
Reduction: Catalytic hydrogenation or the use of reducing agents like sodium borohydride.
Substitution: Halogenating agents or nucleophiles like amines and thiols.
Major Products:
Oxidation: Quinone derivatives.
Reduction: Amino derivatives.
Substitution: Various substituted aromatic compounds.
Comparison with Similar Compounds
Pyrimethamine: Used primarily as an antimalarial agent.
Methotrexate: Used in cancer therapy and autoimmune diseases.
Sulfamethoxazole: Often combined with trimethoprim for synergistic effects
Uniqueness: this compound is unique in its selective inhibition of bacterial dihydrofolate reductase, making it highly effective against a broad spectrum of bacterial infections. Its combination with sulfamethoxazole enhances its antibacterial efficacy and reduces the likelihood of resistance development .
Properties
IUPAC Name |
5-[(3,4,5-trimethoxyphenyl)methyl]pyrimidine-2,4-diamine |
Source
|
|---|---|---|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
InChI |
InChI=1S/C14H18N4O3/c1-19-10-5-8(6-11(20-2)12(10)21-3)4-9-7-17-14(16)18-13(9)15/h5-7H,4H2,1-3H3,(H4,15,16,17,18) |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
InChI Key |
IEDVJHCEMCRBQM-UHFFFAOYSA-N |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
Canonical SMILES |
COC1=CC(=CC(=C1OC)OC)CC2=CN=C(N=C2N)N |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
Molecular Formula |
C14H18N4O3 |
Source
|
| Record name | TRIMETHOPRIM | |
| Source | CAMEO Chemicals | |
| URL | https://cameochemicals.noaa.gov/chemical/21180 | |
| Description | CAMEO Chemicals is a chemical database designed for people who are involved in hazardous material incident response and planning. CAMEO Chemicals contains a library with thousands of datasheets containing response-related information and recommendations for hazardous materials that are commonly transported, used, or stored in the United States. CAMEO Chemicals was developed by the National Oceanic and Atmospheric Administration's Office of Response and Restoration in partnership with the Environmental Protection Agency's Office of Emergency Management. | |
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| Record name | trimethoprim | |
| Source | Wikipedia | |
| URL | https://en.wikipedia.org/wiki/Trimethoprim | |
| Description | Chemical information link to Wikipedia. | |
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
DSSTOX Substance ID |
DTXSID3023712 |
Source
|
| Record name | Trimethoprim | |
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Molecular Weight |
290.32 g/mol |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
Physical Description |
Trimethoprim is an odorless white powder. Bitter taste. (NTP, 1992), Solid |
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|
| Record name | TRIMETHOPRIM | |
| Source | CAMEO Chemicals | |
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| Record name | Trimethoprim | |
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Solubility |
less than 1 mg/mL at 75 °F (NTP, 1992), ... Very slightly soluble in water and slightly soluble in alcohol., Soluble in N,N-dimethylacetamide (DMAC) at 13.86; benzyl alcohol at 7.29; propylene glycol at 2.57; chloroform at 1.82; methanol at 1.21; ether at 0.003; benzene at 0.002 g/100 ml at 25 °C., In water, 400 mg/l @ 25 °C, 6.15e-01 g/L |
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| Record name | TRIMETHOPRIM | |
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Mechanism of Action |
Trimethoprim is a reversible inhibitor of dihydrofolate reductase, one of the principal enzymes catalyzing the formation of tetrahydrofolic acid (THF) from dihydrofolic acid (DHF). Tetrahydrofolic acid is necessary for the biosynthesis of bacterial nucleic acids and proteins and ultimately for continued bacterial survival - inhibiting its synthesis, then, results in bactericidal activity. Trimethoprim binds with a much stronger affinity to bacterial dihydrofolate reductase as compared to its mammalian counterpart, allowing trimethoprim to selectively interfere with bacterial biosynthetic processes. Trimethoprim is often given in combination with sulfamethoxazole, which inhibits the preceding step in bacterial protein synthesis - given together, sulfamethoxazole and trimethoprim inhibit two consecutive steps in the biosynthesis of bacterial nucleic acids and proteins. As a monotherapy trimethoprim is considered bacteriostatic, but in combination with sulfamethoxazole is thought to exert bactericidal activity., Trimethoprim is a bacteriostatic lipophilic weak base structurally related to pyrimethamine. It binds to and reversibly inhibits the bacterial enzyme dihydrofolate reductase, selectively blocking conversion of dihydrofolic acid to its functional form, tetrahydrofolic acid. This depletes folate, an essential cofactor in the biosynthesis of nucleic acids, resulting in interference with bacterial nucleic acid and protein production. Bacterial dihydrofolate reductase is approximately 50,000 to 60,000 times more tightly bound by trimethoprim than is the corresponding mammalian enzyme., To determine the incidence & severity of hyperkalemia during trimethoprim therapy, 30 consecutive patients with acquired immunodeficiency syndrome receiving high-dose (20 mg/kg/day) trimethoprim were studied; in addition, the mechanism of trimethoprim-induced hyperkalemia was investigated in rats. Trimethoprim increased serum potassium concn by 0.6 mmol/l despite normal adrenocortical function & glomerular filtration rate. Serum potassium levels >5 mmol/l were observed during trimethoprim treatment in 15 of 30 patients. In rats, iv trimethoprim inhibited renal potassium excretion by 40% & increased sodium excretion by 46%. It was concluded that trimethoprim blocks apical membrane sodium channels in the mammalian distal nephron. As a consequence, the transepithelial voltage is reduced & potassium secretion is inhibited. Decreased renal potassium excretion secondary to these direct effects on kidney tubules leads to hyperkalemia in a substantial number of patients being treated with trimethoprim-containing drugs. |
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Color/Form |
White to cream, crystalline powder | |
CAS No. |
738-70-5 |
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| Record name | TRIMETHOPRIM | |
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Melting Point |
390 to 397 °F (NTP, 1992), 199-203 °C, 199 - 203 °C |
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Synthesis routes and methods I
Procedure details
Synthesis routes and methods II
Procedure details
Retrosynthesis Analysis
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| Precursor scoring | Relevance Heuristic |
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| Model | Template_relevance |
| Template Set | Pistachio/Bkms_metabolic/Pistachio_ringbreaker/Reaxys/Reaxys_biocatalysis |
| Top-N result to add to graph | 6 |
Feasible Synthetic Routes
Q1: How does trimethoprim exert its antibacterial effect?
A1: this compound inhibits bacterial dihydrofolate reductase (DHFR), an enzyme essential for the synthesis of tetrahydrofolic acid. Tetrahydrofolic acid is crucial for the production of purines and pyrimidines, which are the building blocks of DNA and RNA. By inhibiting DHFR, this compound disrupts bacterial DNA and RNA synthesis, ultimately leading to bacterial cell death. [, , , , ]
Q2: What is the significance of dihydrofolate accumulation in this compound's mechanism of action?
A2: While this compound's primary target is DHFR, studies have shown that its antibacterial effect is not solely due to enzyme inhibition. The accumulation of dihydrofolate in bacteria treated with this compound plays a significant role. This accumulation leads to depletion of tetrahydrofolate cofactors, further hindering purine and pyrimidine biosynthesis. This dual mechanism contributes to this compound's effectiveness. []
Q3: What happens to the folate pool in bacteria upon this compound treatment?
A3: Research using radiolabeled precursors indicates that this compound treatment causes a rapid and transient accumulation of dihydrofolate in bacteria. This is followed by a complete conversion of all folate forms into cleaved catabolites, mainly pteridines and para-aminobenzoylglutamate, and the stable, non-reduced form, folic acid. []
Q4: What is the molecular formula and weight of this compound?
A4: this compound is represented by the molecular formula C14H18N4O3 and has a molecular weight of 290.3 g/mol. []
Q5: Are there any spectroscopic data available for this compound and its derivatives?
A5: Yes, various spectral techniques like Fourier-transform infrared spectroscopy (FT-IR), proton nuclear magnetic resonance (1H-NMR), heteronuclear multiple bond correlation (HMBC) spectroscopy, and mass spectrometry have been used to characterize this compound and its novel derivatives. These techniques provide insights into the structural properties and confirm the formation of new compounds. []
Q6: What factors influence the stability of this compound solutions for injection?
A6: The stability of injectable this compound-sulfamethoxazole solutions, particularly after dilution with infusion fluids, is significantly influenced by the formation of a 1:1 molecular compound between this compound and sulfamethoxazole. This compound exhibits low solubility in water. Furthermore, the pH of the medium and the type of infusion fluid used for dilution can also impact stability, potentially leading to the separation of other solid phases such as this compound monohydrate and sulfamethoxazole hemihydrate. []
Q7: What is a significant mechanism of this compound resistance in bacteria like Stenotrophomonas maltophilia?
A8: The presence of class 1 integrons, mobile genetic elements capable of capturing and expressing gene cassettes, is significantly associated with this compound resistance. These integrons often carry genes encoding resistance to this compound and other antibiotics. []
Q8: How does the BpeEF-OprC efflux pump contribute to this compound resistance in Burkholderia pseudomallei?
A9: The BpeEF-OprC efflux pump in B. pseudomallei plays a crucial role in conferring resistance to this compound. Mutations in genes like bpeT and bpeS, which regulate the expression of this efflux pump, can lead to constitutive expression or overexpression of the pump. This increased efflux activity effectively removes this compound from the bacterial cell, reducing its intracellular concentration and leading to resistance. []
Q9: How is this compound typically administered, and what are the implications for its pharmacokinetic profile?
A10: this compound is often administered orally. In healthy volunteers, a single daily dose of 300 mg resulted in serum concentrations exceeding the minimum inhibitory concentration for most urinary pathogens for up to 5 days. Notably, there was individual variation in bioavailability and urinary excretion, indicating the importance of personalized dosing considerations. []
Q10: Does the route of administration affect the pharmacokinetics of this compound and sulfamethoxazole?
A11: Yes, the route of administration significantly influences the pharmacokinetics of this compound and sulfamethoxazole. Studies in horses comparing intravenous and oral administration of this compound/sulfamethoxazole formulations revealed differences in the time to reach peak plasma concentration and bioavailability for both drugs. []
Q11: How does this compound distribute within the body, particularly during pregnancy?
A12: Research in pregnant women indicates that this compound can cross the placenta and enter fetal tissues and fluids. Interestingly, its concentration in fetal fluids and tissues remained relatively consistent. This observation underscores the importance of carefully considering potential risks and benefits when using this compound during pregnancy. []
Q12: What analytical techniques are commonly employed for the detection and quantification of this compound?
A13: Several analytical techniques are used to determine this compound levels, including high-performance liquid chromatography (HPLC), often coupled with UV detection or mass spectrometry, and spectrophotometry. These methods offer varying degrees of sensitivity, selectivity, and applicability depending on the specific matrix and analytical goal. [, , ]
Q13: Can you provide an example of a specific HPLC method for this compound analysis?
A14: An HPLC method utilizing solid-phase column extraction has been developed for this compound analysis in serum, plasma, and dialysate fluid. This method boasts high sensitivity (0.05 mg/mL), excellent reproducibility, and a wide linear range (2-100 mg/mL), making it suitable for pharmacokinetic studies and clinical applications. []
Q14: How can magnetosensing technology be applied to this compound detection?
A15: Innovative approaches employing open droplet microchannel-based magnetosensors have been developed for the immunofluorometric assay of this compound. This method offers a sensitive and specific alternative to traditional ELISA or immunochromatographic assays, demonstrating a wide linear detection range suitable for monitoring this compound levels in food samples. []
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