General Description
Odorless white powder. Bitter taste.
Reactivity Profile
This compound readily forms salts with acids. .
Air & Water Reactions
Insoluble in water.
Fire Hazard
Flash point data for this chemical are not available. TRIMETHOPRIM is probably combustible.
Description
Trimethoprim selectivity between bacterial and mammalian
dihydrofolate reductases results from the subtle but significant architectural differences between these
enzyme systems. Whereas the bacterial enzyme and the mammalian enzyme both efficiently catalyze the
conversion of dihydrofolic acid to tetrahydrofolic acid, the bacterial enzyme is sensitive to inhibition by
trimethoprim by up to 40,000-fold lower concentrations than the mouse enzyme is. This difference explains
the useful selective toxicity of trimethoprim.
Originator
Eusaprim,Wellcome,Italy,1970
Definition
ChEBI: Trimethoprim is an aminopyrimidine antibiotic whose structure consists of pyrimidine 2,4-diamine and 1,2,3-trimethoxybenzene moieties linked by a methylene bridge. It has a role as an EC 1.5.1.3 (dihydrofolate reductase) inhibitor, a xenobiotic, an environmental contaminant, a drug allergen, an antibacterial drug and a diuretic. It is a member of methoxybenzenes and an aminopyrimidine.
Manufacturing Process
6 grams (0.26 mol) sodium was dissolved in 300 ml methanol under stirring
and refluxing. 47.5 grams (0.55 mol) β-methoxypropionitrile and 98 grams
(0.5 mol) 3,4,5-trimethoxybenzaldehyde were added and the mixture refluxed
gently for 4 hours. The mixture was then chilled and 150 ml of water was
added. The product crystallized rapidly. Crystallization was allowed to proceed
at 5° to 10°C under stirring for 1 hour. The product was filtered by suction
and washed on the filter with 200 ml of 60% ice cold methanol. The crude
material was air-dried and used for further steps without purification. It
melted at 78° to 80°C. A pure sample, recrystallized from methanol, melted
at 82°C. The yield of 3,4,5-trimethoxy-2'-methoxymethylcinnamonitrile was
92 grams, corresponding to 70% of the theory.
19 grams (0.83 mol) sodium was dissolved in 300 ml methanol, 106 grams of
3,4,5-trimethoxy-2'-methoxymethylcinnamonitrile was added and the mixture
gently refluxed for 24 hours. The solution, which had turned brown, was
poured into 1 liter of water and the precipitated oil extracted repeatedly with
benzene. The combined benzene layers (500 to 700 ml) were washed 3 times
with 500 ml of water, the benzene removed by evaporation in a vacuum from
a water bath, and the brown residual oil distilled in vacuo, boiling point 215°
to 225°C/11 mm. The clear, viscous oil, 3,4,5-trimethoxy-2'-cyano_x0002_dihydrocinnamaldehyde dimethyl acetal, weighed 83 grams (71% of the
theory), and showed a nD23 = 1.5230. It solidified upon standing. A sample
recrystallized from methanol melted at 69° to 70°C and showed a strong
melting point depression with the starting material; nD25 = 1.5190.
31.5 grams (0.107 mol) 3,4,5-trimethoxy-2'-cyano-dihydrocinnamaldehyde
dimethyl acetal was refluxed with methanolic guanidine solution (200 ml
containing 0.25 mol of guanidine) for 2 hours. The methanol completely
distilled off under stirring, finally from a bath of 110° to 120°C until the
residue solidified completely to a yellowish crystalline mass. After allowing to
cool, it was slurried with 100 ml of water and collected by vacuum filtration
and dried. The yield of 2,4-diamino-5-(3,4,5-trimethoxybenzyl)pyrimidine
amounted to 28 grams (91% of the theory). The material showed the correct
melting point of 199° to 200°C and was, however, yellowish discolored.
20 grams of the above product was added to 30 ml of 3 N aqueous sulfuric
acid at 60°C under stirring. The solution was chilled under stirring to 5° to
10°C. The crystalline sulfate was collected by vacuum filtration and washed on the filter twice with 10 ml of cold 3 N aqueous sulfuric acid each time. From
the filtrate there was recovered 1.3 grams (6.5%) of discolored material
melting at 195° to 196°C and which can be added to subsequent purification
batches.
The sulfate on the filter was dissolved in 200 ml of hot water, the solution
charcoaled hot, and the product precipitated from the clear colorless filtrate
by the gradual addition of a solution of 20 grams of sodium hydroxide in 40
ml of water under chilling. The precipitate was filtered by suction and washed
thoroughly with water on the filter. The white material, 17.5 grams (88%)
showed the correct melting point of 200° to 201°C, according to US Patent
3,341,541.
Brand name
Proloprim (Monarch); Trimpex
(Roche).
Therapeutic Function
Antibacterial (urinary)
Antimicrobial activity
Trimethoprim has a broad spectrum of antimicrobial activity. It is 20–100 times more
active than sulfamethoxazole with respect to most bacterial forms. Trimethoprim is active
with respect to Gram-positive, aerobic bacteria such as Staphylococcus aureus,
Staphylococcus epidermidis, and various types of Streptococcus and Listeria monocytogenes. Trimethoprim is inferior to sulfonamides against forms of Nocardia. It is active with respect to Gram-negative, aerobic bacteria such as most E. coli, Enterobacter,
Proteus, Klebsiella, Providencia, Morganella, Serratia marcescens, Citrobacter,
Salmonella, Shigella, Yersinia enterocolitica that are sensitive to trimethoprim.
Trimethoprim is also active with respect to Legionella, Acinetobacter, Vibrio,
Aeromonas, Pseudomonas maltophila, P. cepacia, although P. aeruginosa is resistant to
trimethoprim.
Biochem/physiol Actions
Inhibits the synthesis of tetrahydrofolate by procaryote specific dihydrofolate reductase (DHFR).
Mechanism of action
Haemophilus influenzae and H. ducreyi are sensitive to trimethoprim. Pathogenic
Neisseria (meningococci and gonococci) and Branhamella catarrhalis are moderately
resistant to trimethoprim, although they are very sensitive to a combination of trimethoprim and sulfamethoxazole. Anaerobic bacteria in general are resistant to trimethoprim,
although a combination of trimethoprim-sulfamethoxazole does have an effect on them.
Pneumocystis carinii is also sensitive to that combination.
Bacterial resistance to trimethoprim can originate because of a number of reasons:
inability of the drug to penetrate through the membrane (P. aeruginosa); the presence of
dihydrofolate reductase that is not sensitive to inhibition by trimethoprim; overproduction
of dihydrofolate reductase and mutation expressed as thyminic dependence, when the
organism requires exogenic thymine for synthesizing DNA, i.e. bypassing metabolic
blockage caused by trimethoprim.
Resistance to a combination of trimethoprim-sulfamethoxazole is always less frequent
than when any of these drugs is used separately. This combination of drugs, which is
known by the commercial names cotrimoxazole, bactrim, biseptol, sulfatrim, and many
others, is used for treating infections of the respiratory tract, infections of the urinary tract,
gastric infections, surgical infections, enteritis, meningitis, and other diseases.
Clinical Use
Trimethoprim (5-[(3,4,5-trimethoxyphenyl)methyl]-2,4-pyrimidinediamine or 2,4-diamino-5-(3,4,5-trimethoxybenzyl)pyrimidine) is closely related to several antimalarialsbut does not have good antimalarial activity by itself; it is,however, a potent antibacterial. Originally introduced incombination with sulfamethoxazole, it is now available as asingle agent.
Approved by the FDA in 1980, trimethoprim as a singleagent is used only for the treatment of uncomplicatedurinary tract infections. The argument for trimethoprim asa single agent was summarized in 1979 by Wormser andDeutsch. They point out that several studies comparingtrimethoprim with TMP–SMX for the treatment ofchronic urinary tract infections found no statistically relevantdifference between the two courses of therapy.The concern is that when used as a single agent, bacterianow susceptible to trimethoprim will rapidly developresistance. In combination with a sulfonamide, however,the bacteria will be less likely to do so. That is, they willnot survive long enough to easily develop resistance toboth drugs.
Synthesis
Trimethoprim, 2,4-diamino-5-(3,4,5-trimethoxybenzyl)pyrimidine (33.1. 51), is synthesized in various ways. The first scheme of synthesis begins with ethyl ester of 3,4,5-trimethoxydehydrocinnamic acid, which is formylated with ethyl formate using sodium as a base to make an enol of the semialdehyde 3,4,5-trimethoxybenzylmalonic ester (33.1.49), which undergoes a heterocyclization reaction with guanidine to make 2-amino- 4-hydroxy-5-(3,4,5-trimethoxybenzyl)pyrimidine (33.1.50). Subsequent replacement of the hydroxyl group in the resulting product with chlorine using phosphorous oxychloride and then with an amino group using ammonia gives the desired trimethoprim.
All of the other syntheses begin with 3,4,5-trimethoxybenzaldehyde. According to one of them, condensation of 3,4,5-trimethoxybenzaldehyde with 3-ethoxy- or 3-anilinopropionitrile gives the corresponding benzylidene derivative (33.1.52), which upon direct reaction with guanidine gives trimethoprim.
Trimethoprim has also been synthesized by condensing 3,4,5-trimethoxybenzaldehyde with malonic acid dinitrile in a Knoevenagel reaction, which forms the derivative (33.1.53), which is partially reduced to the enamine (33.1.54) by hydrogen using a palladium on carbon catalyst, which upon being reacted with guanidine is transformed into trimethoprim.
Finally, trimethoprim can be synthesized in a manner that also uses a Knoevenagel condensation of 3,4,5-trimethoxybenzaldehyde as the first step, but this time with ethyl cyanoacetate, which gives an ylidene derivative (33.1.55). The double bond in this product is reduced by hydrogen over a palladium on carbon catalyst, giving 3,4,5-trimethoxybenzylcyanoacetic ester (33.1.56). Reacting this in a heterocyclization reaction with guanidine gives the desired trimethoprim.
Drug interactions
Potentially hazardous interactions with other drugs
Anti-arrhythmics: increased risk of ventricular
arrhythmias with amiodarone - avoid; concentration
of procainamide increased.
Antiepileptics: antifolate effect and concentration of
fosphenytoin and phenytoin increased.
Antimalarials: increased risk of antifolate effect with
pyrimethamine.
Ciclosporin: increased risk of nephrotoxicity;
concentration of ciclosporin reduced by IV
trimethoprim.
Cytotoxics: increased risk of haematological
toxicity with azathioprine, methotrexate and
mercaptopurine; antifolate effect of methotrexate
increased.
Tacrolimus: possible increased risk of nephrotoxicity.
Metabolism
About 10 to 20
% of trimethoprim is metabolised in the liver and small amounts are excreted in the faeces via the bile, but most, about 40 to 60
% of a dose, is excreted in urine, mainly as unchanged drug.
Trimethoprim is excreted mainly by the kidneys through glomerular filtration and tubular secretion.
