Trimethoprim Classification: Synthetic antibacterial drug. Source: As described in US Patent 3,341,541.

Accordingly, 3,4,5-trimethoxybenzaldehyde 1 was treated with Beta-methoxypropionitrile in presence of sodium methoxide (freshly prepared) using methanol as solvent at reflux temperature to give 2-(methoxymethyl)-3-(3,4,5-trimethoxyphenyl)prop-2-enenitrile 2. The nitrile compound 2 was then heated with sodium methoxide (freshly prepared) using methanol as solvent at reflux temperature resulting in to 2-(dimethoxymethyl)-3-(3,4,5-trimethoxyphenyl)prop-2-enenitrile 3. The final step involves condensation of 3 with guanidine using methanol as solvent at reflux temperature to afford 5-[(3,4,5-trimethoxyphenyl)methyl]pyrimidine-2,4-diamine also called Trimethoprim 4. Mechanism of Action: Trimethoprim blocks the production of tetrahydrofolic acid from dihydrofolic acid by binding to and reversibly inhibiting the required enzyme, dihydrofolate reductase. This binding is much stronger for the bacterial enzyme than for the corresponding mammalian enzyme. Thus, trimethoprim selectively interferes with bacterial biosynthesis of nucleic acids and proteins. THF is an essential precursor in the thymidine synthesis pathway and interference with this pathway inhibits bacterial DNA synthesis. Uses & Treatments: For the treatment of urinary tract infections, uncomplicated pyelonephritis (with sulfamethoxazole) and mild acute prostatitis. May be used as pericoital (with sulfamethoxazole) or continuous prophylaxis in females with recurrent cystitis. May be used as an alternative to treat asymptomatic bacteriuria during pregnancy (only before the last 6 weeks of pregnancy). Other uses include: alternative agent in respiratory tract infections (otitis, sinusitus, bronchitis and pneumonia), treatment of Pneumocystis jirovecii pneumonia (acute or prophylaxis), Nocardia infections, and traveller's diarrhea. Spectrum: Broad spectrum. Trimethoprim is said to affect both gram positive and gram negative bacteria. Resistance: Resistance was reported in 2.5%, 2.9%, 3.2% and 4.3% of coliform bacilli according to surveys conducted between the years 1971 to 1979. Trimethoprim resistance in urinary isolates rose from 9.5% in 1975 to 12.9% in 1977. A notable feature is the high proportion of Klebsiella and Enterobacter species among resistant isolates. Of gram-positive bacteria which may be implicated in urinary tract infections, 30% of Staphylococcus epidermidis and 1.6% to 4.1% of Staphylococcus aureus in Britain are currently resistant to trimethoprim. Alternatives: These antibiotics include quinilones (ciprofloxacin, ofloxacin, norfloxacin), amoxicillin (a type of penicillin) and nitrofurantoin. The best choice of antibiotic depends on the bacterial resistance in an area and factors such as previous responses to treatments.