Trimethoprim: Chemical Structure, Mechanism of Action, SAR, Synthesis, Uses & Side effects

Chemical formula:

• C14H18N4O3

Structure of Trimethoprim

Mechanism of action:

• Trimethoprim is a selective inhibitor of bacterial dihydrofolate reductase (DHFR). By inhibiting DHFR, it prevents the conversion of dihydrofolate to tetrahydrofolate, which is essential for the synthesis of purine and pyrimidine nucleotides. This disrupts bacterial DNA synthesis and leads to cell death.

Structure-Activity Relationship (SAR) of Trimethoprim:

1.Pyrimidine Ring:

• The core structure of trimethoprim is a pyrimidine ring, which is crucial for its antibacterial activity. The pyrimidine ring mimics a portion of the folic acid molecule, allowing trimethoprim to inhibit dihydrofolate reductase (DHFR), an enzyme critical for bacterial DNA synthesis.

2.Trimethoxybenzyl Group:

• The 2,4,5-trimethoxybenzyl group at the 5-position of the pyrimidine ring enhances the drug's affinity for bacterial DHFR over human DHFR. This selective inhibition is important for its therapeutic effect with reduced toxicity.

3.Methyl Group:

• The presence of a methyl group at the 4-position on the pyrimidine ring is also essential for the activity of trimethoprim, contributing to its effective binding with the bacterial DHFR.

4.Lipophilicity and Solubility:

• The overall lipophilicity and solubility of trimethoprim, influenced by its functional groups, affect its absorption and distribution in the body, important for its pharmacokinetics

Structure-Activity Relationship (SAR) of Trimethoprim

Synthesis of Trimethoprim:

The synthesis of trimethoprim generally involves the following steps:

1.Synthesis of 3,4,5-Trimethoxybenzaldehyde:

• This can be achieved by the methylation of gallic acid or its derivatives:

• Gallic Acid Derivative + Methylating Agent → 3,4,5-Trimethoxybenzaldehyde

2.Condensation with 2,4-Diaminopyrimidine:

• The 3,4,5-trimethoxybenzaldehyde is then condensed with 2,4-diaminopyrimidine. This step usually involves a reaction under acidic conditions:

• 3,4,5-Trimethoxybenzaldehyde + 2,4-Diaminopyrimidine → Trimetho

Uses:

• Trimethoprim is used primarily for the treatment of urinary tract infections (UTIs) and is sometimes used for the treatment of respiratory infections, such as acute bronchitis and pneumonia. It is often prescribed in combination with sulfamethoxazole (co-trimoxazole) for a synergistic effect.

Side effects:

• Common side effects of trimethoprim include gastrointestinal disturbances (nausea, vomiting, diarrhea), skin rash, and itching. Less common side effects include blood dyscrasias, such as leukopenia, thrombocytopenia, and megaloblastic anemia, as well as hyperkalemia (high potassium levels in the blood).