Trimethoprim-d9 (Major)
Overview
Description
Trimethoprim-d9 (Major) is an antibacterial deuterated Trimethoprim . It is used for research purposes and is not intended for diagnostic or therapeutic use .
Synthesis Analysis
A new series of trimethoprim analogs containing amide bonds have been synthesized . The addition of amide bonds into the analogs of Trimethoprim increases their affinity towards dihydrofolate reductase (DHFR) .Molecular Structure Analysis
The molecular formula of Trimethoprim-d9 (Major) is C14H9D9N4O3 and it has a molecular weight of 299.37 .Chemical Reactions Analysis
Trimethoprim has been found to inhibit the growth of a wide range of bacteria in generally much lower concentrations than sulphonamides . Its action with a sulphonamide is strongly synergic and bactericidal .Physical and Chemical Properties Analysis
Trimethoprim-d9 (Major) is a solid substance . It is soluble in DMF, DMSO, and hot methanol . It has a melting point of 207-212°C .Scientific Research Applications
Pharmacokinetic and Environmental Studies
High-performance liquid chromatography (HPLC) methods utilizing solid-phase column extraction have been developed for the analysis of trimethoprim in serum and peritoneal dialysate fluid. This technique, efficient in recovery and sensitive, is crucial for following the pharmacokinetics of trimethoprim, offering a tool for the study of its behavior in biological systems without interference from metabolites or commonly administered drugs (Svirbely & Pesce, 1987). This method is applicable for clinical assays of trimethoprim when high levels of the antibiotic are necessary, especially in combating resistant organisms and serious infections by opportunistic organisms like Pneumocystis carinii, highlighting its importance in medical research and treatment efficacy studies.
Antibiotic Resistance and Molecular Epidemiology
The evolving patterns of trimethoprim resistance, particularly in clinical isolates of Enterobacteriaceae, underscore the importance of continuous surveillance and molecular epidemiological studies. Research spanning over a decade in Paris revealed an increase in trimethoprim resistance, mainly due to strains with high-level resistance. Genetic studies focusing on transferability, plasmid types, and resistance mechanisms contribute to a deeper understanding of antibiotic resistance development and dissemination. Such studies are vital for informing clinical practice and guiding antibiotic stewardship efforts (Goldstein, Papadopoulou, & Acar, 1986).
Advanced Treatment Techniques for Water Purification
The presence of trimethoprim in aquatic environments has raised concerns due to its persistent behavior and potential hazardous effects on both the environment and human health. Advanced oxidation processes (AOPs) have been extensively applied for the elimination of trimethoprim from water systems, demonstrating significant effectiveness. Such studies are crucial for developing and optimizing water treatment technologies to ensure the safety of drinking water and mitigate the environmental impact of pharmaceuticals (Mpatani et al., 2021).
Mechanism of Action
Target of Action
Trimethoprim-d9, also known as Trimethoprim-d9 (Major), primarily targets the bacterial enzyme dihydrofolate reductase (DHFR) . DHFR is a critical enzyme that catalyzes the formation of tetrahydrofolic acid (THF), an essential precursor in the biosynthesis of nucleic acids .
Mode of Action
Trimethoprim-d9 inhibits DHFR, thereby preventing the synthesis of bacterial DNA and ultimately leading to bacterial death . It binds with a much stronger affinity to bacterial DHFR compared to its mammalian counterpart, allowing Trimethoprim-d9 to selectively interfere with bacterial biosynthetic processes .
Biochemical Pathways
The inhibition of DHFR by Trimethoprim-d9 disrupts the biosynthesis pathways of thymidylate and purines, as well as several other amino acids like glycine, methionine, serine, and N-formyl-methionyl tRNA . This leads to an imbalance in the pathways involved in active synthesizing thymidylate, disrupts DNA replication, and eventually causes cell death .
Pharmacokinetics
Trimethoprim-d9 is a potent inhibitor of multidrug and toxin extrusion protein (MATE) and a weak inhibitor of cytochrome P450 (CYP) 2C8 . These properties can influence the absorption, distribution, metabolism, and excretion (ADME) of the compound, impacting its bioavailability .
Result of Action
The molecular and cellular effects of Trimethoprim-d9’s action include the inhibition of bacterial DNA synthesis, leading to bacterial death . Some of the new analogs of Trimethoprim-d9 inhibited DHFR activity more strongly than Trimethoprim did, indicating that the addition of amide bonds into the analogs of Trimethoprim-d9 increases their affinity towards DHFR .
Action Environment
Environmental factors can influence the action, efficacy, and stability of Trimethoprim-d9. For instance, pH plays a role in the mode of action of Trimethoprim-d9 on Escherichia coli . Moreover, soil-related factors, animal husbandry and waste management, potable and wastewater, and food safety can contribute to antimicrobial resistance . These factors need to be considered in modeling the fate and transport of Trimethoprim-d9 in coastal/estuarine waters .
Safety and Hazards
Future Directions
Biochemical Analysis
Biochemical Properties
Trimethoprim-d9 interacts with the enzyme dihydrofolate reductase (DHFR), which plays a crucial role in the biosynthesis pathways of thymidylate, purines, and several amino acids . The interaction between Trimethoprim-d9 and DHFR inhibits the enzyme’s activity, disrupting DNA replication and eventually leading to cell death .
Cellular Effects
The effects of Trimethoprim-d9 on cells are primarily due to its inhibition of DHFR. This disruption in folate metabolism leads to an imbalance in the pathways involved in synthesizing thymidylate, which is essential for DNA replication . As a result, the function of cells is significantly affected, leading to cell death .
Molecular Mechanism
Trimethoprim-d9 exerts its effects at the molecular level by binding to the DHFR enzyme. This binding inhibits the enzyme’s activity, preventing the reduction of dihydrofolate acid to tetrahydrofolic acid . This disruption in folate metabolism leads to an imbalance in the pathways involved in synthesizing thymidylate, which is essential for DNA replication .
Metabolic Pathways
Trimethoprim-d9 is involved in the folate metabolism pathway. It interacts with the DHFR enzyme, which catalyzes the reduction of dihydrofolate acid to tetrahydrofolic acid . The inhibition of DHFR by Trimethoprim-d9 disrupts this metabolic pathway, leading to an imbalance in the pathways involved in synthesizing thymidylate .
Properties
IUPAC Name |
5-[[3,4,5-tris(trideuteriomethoxy)phenyl]methyl]pyrimidine-2,4-diamine | |
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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)/i1D3,2D3,3D3 | |
Source | PubChem | |
URL | https://pubchem.ncbi.nlm.nih.gov | |
Description | Data deposited in or computed by PubChem | |
InChI Key |
IEDVJHCEMCRBQM-GQALSZNTSA-N | |
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 | PubChem | |
URL | https://pubchem.ncbi.nlm.nih.gov | |
Description | Data deposited in or computed by PubChem | |
Isomeric SMILES |
[2H]C([2H])([2H])OC1=CC(=CC(=C1OC([2H])([2H])[2H])OC([2H])([2H])[2H])CC2=CN=C(N=C2N)N | |
Source | PubChem | |
URL | https://pubchem.ncbi.nlm.nih.gov | |
Description | Data deposited in or computed by PubChem | |
Molecular Formula |
C14H18N4O3 | |
Source | PubChem | |
URL | https://pubchem.ncbi.nlm.nih.gov | |
Description | Data deposited in or computed by PubChem | |
DSSTOX Substance ID |
DTXSID10662219 | |
Record name | Trimethoprim-d9 | |
Source | EPA DSSTox | |
URL | https://comptox.epa.gov/dashboard/DTXSID10662219 | |
Description | DSSTox provides a high quality public chemistry resource for supporting improved predictive toxicology. | |
Molecular Weight |
299.37 g/mol | |
Source | PubChem | |
URL | https://pubchem.ncbi.nlm.nih.gov | |
Description | Data deposited in or computed by PubChem | |
CAS No. |
1189460-62-5 | |
Record name | Trimethoprim-d9 | |
Source | EPA DSSTox | |
URL | https://comptox.epa.gov/dashboard/DTXSID10662219 | |
Description | DSSTox provides a high quality public chemistry resource for supporting improved predictive toxicology. | |
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