Sulfonamide Drugs And Trimethoprim

Sulfonamide drugs are a group of synthetic antimicrobial drugs that have a broad spectrum of use with respect to Gram-positive as well as Gram-negative microorganisms. They were introduced into medical practice even before the discovery of penicillins. Sulfonamide drugs are derivatives of sulfanilamide (p-aminobenzenesulfonamide), which is a structural analog of p-aminobenzoic acid (component necessary in bacteria for synthesizing folic acid), the precursor of purine, nucleic acids, and especially DNA.

Animal cells are not able to synthesize folic acid by themselves—it must be obtained through the consumption of food.

In addition, most bacteria are not able to utilize folic acid of exogen origin, so they synthesize the folic acid necessary for vital functions by themselves. This is the difference between bacterial and animal cells, and it is the reason behind the selective toxicity of sulfonamides.

Sulfanilamide, whose structure is similar to the structure of p-aminobenzoic acid, competes with p-aminobenzoic acid for inclusion in the folic acid molecule. In short, by taking the place of p-aminobenzoic acid, it "interferes" with the biosynthesis of folic acid. As a result, the "misled" enzymes construct a "false" molecule of folic acid, which is not able to carry out the vital function of true folic acid.

p-aminobenzoic acid sulfanilamide p-aminobenzoic acid sulfanilamide cooh folic acid cooh folic acid cooh

"false folic acid"


"false folic acid"

Thus sulfonamides are bacteriostatic drugs that inhibit bacterial growth by interfering with the microbial synthesis of folic acid. More specifically, sulfonamides block the biosyn-thetic pathway of folic acid synthesis, thus competitively inhibiting the transformation of p-aminobenzoic acid to folic acid (mediated by the enzyme dihydropteroate synthetase), which allows them to be considered as antimetabolites.

Currently, various sulfanilamide drugs are used in medicine, the choice of which depends on various factors, but above all on the type of stimulant, course of the disease, speed in which the drug is absorbed from the gastrointestinal tract, the speed in which it is excreted, and its ability to diffuse into different organs and tissues.

Sulfonamides have a broad spectrum of antimicrobial activity, including Staphylococcus aureus, nonenterococcal types of Streptococcus, Listeria monocytogenes, Nocardia, Neisseria, Haemophilus influenzae, enteric Gram-negative types of E. coli, Proteus mirabilis, and a few forms of anaerobic bacteria. Above all, sulfonamides are used for treating uncomplicated infections of the urinary tract, infections caused by Nocardia asteroids, streptococcal pharyngitis, menigococcal diseases, toxoplasmosis, and others.

Resistance to such drugs does develop during long-term use. Bacterial resistance to sul-fonamides can develop as a result of mutations expressed either in the overproduction of p-aminobenzoic acid, or in changes in dehydroproteorate synthetase itself, which becomes more sensitive to the drugs. Resistance can also be mediated by plasmids that code for dehydroproteorate synthetase, or by reduced diffusion of the drug through bacterial cell membranes.

Sulfanilamide drugs do not currently have a clear classification. However, they are grouped as systemic (absorptive action), and local. They are subdivided into short-lasting (sulfacytine, sulfadiazin, sulfamerazine, sulfametazine, sulfametizole, sulfisoxazole); moderate-lasting (sulfamethoxazole, sulfapyridine); and long-lasting (sulfamethoxypiridazine, sulfamter), which, however, are no longer used as independent drugs because of extremely rare, yet nonetheless occurring, hypersensitivity reactions. Drugs for local use include those for ophthalmological use (sulfacetamide, sulfozoxazol); vaginal use (sulfabenzamide, sul-facetamide, sulfathiazole, sulfizoxazol); and external use (maphenid, silver sulfadiazine). Finally, this group includes sulfasalazine and phthalylsulfathiazole, a drug that acts in the lumen of the intestines, but which is poorly absorbed from the gastrointestinal tract.

In terms of chemistry, sulfanilamide drugs can be represented by the following simple formula (except for rare exceptions, such as phthalazol):

A huge number of compounds of this type have been synthesized, primarily by reacting 4-acetylaminobenzenesulfonyl chloride with various amines (predominantly aromatic and heteroaromatic), followed by a removal of the protective acetyl group from the amine region of the molecule, or by reacting 4-aminobenzenesulfonamide with an appropriate aromatic or heteroaromatic halogen derivative. The first method is predominantly used because it is easy to do. In terms of determining a correlation between structure and activity, it was shown that the free p-amino group in the benzene ring is necessary for the exhibition of antibacterial activity, and it can only be replaced by those groups that permit its transformation to a free amino group. The presence of an additional substituent in the o- and m-positions of the benzene ring reduces the activity of the given series of compounds as antibacterial agents. Replacing one of the hydrogen atoms on the nitrogen atom in the sulfonamide region of the molecule leads to a significant change in the activity and solubility of the compounds. Moreover, the nature of the substituent in the sulfonyl radical determines the antimicrobial activity and the pharmacokinetic features of each of the individual compound. Thus the presence of this easily obtained and high volume product, 4-acetylaminobenzenesulfonyl chloride, which is made by reacting acetylaniline with chlorosulfonic acid, or the presence of 4-aminobenzenesulfonamide, which is made from a further reaction of 4-acetylaminoben-zenesulfonyl chloride with ammonia and subsequent hydrolysis, the task of synthesizing new, potential sulfonamides has practically resorted to making new heteroaromatic amines. The most widely used sulfonamides examined below are made using these methods.

Sulfacytine: Sulfacytine, N1-(1-ethyl-1,2-dihydro-2-oxo-4-pyrimidinyl)-sulfanilamide (33.1.5), is synthesized by reacting 4-acetylaminobenzenesulfonyl chloride with 1-ethyl-cyto-sine (33.1.3) followed by reductive deacylation of the acetanilide part of the molecule (33.1.4) using a system of zinc - sodium hydroxide, which gives the desired sulfacytine. 1-Ethylcytosine (33.1.3) is in turn synthesized from 3-ethylaminopropionitrile, which is reacted with cyanic acid (potassium cyanate-hydrochloric acid) in the first stage of synthesis to give 1-(2-cyanoethyl)-1-ethylurea (33.1.1). This easily cyclizes to 1-ethyl-5,6-dihydrocyto-sine in the presence of sodium methoxide, and is isolated in the form of a hydrobromide (33.1.2) for subsequent oxidation of the ordinary C5-C6 bond. Bromine turns out to be the optimal oxidant for this purpose, and using nitrobenzene as the solvent gives a hetero-aromatic amine, 1-ethylcytosine (33.1.3), which was transformed to the desired sulfacytine in the aforementioned manner— by reacting it with 4-acetylaminobenzenesulfonyl chloride and subsequent removal of the protecting acetyl group from the amine part of the molecule [1-4].

O 1.CH3ONa O

NC-CH2-CH2-NH-C2H5 -► N-C2H5 -» H2N—^ N-C2H5 -»

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