Sulfanilamide, structure

It is noteworthy that sulfanilamide structural modifications have led to other valuable classes of drugs already discussed, including the hypoglycemic sulfonylureas and the diuretic carbonic anhydrase inhibitors. 

Bacteria require p-aminobenzoic acid to biosyn thesize folic acid a growth factor Structurally sul fanilamide resembles p-aminobenzoic acid and is mistaken for it by the bacteria Folic acid biosynthesis IS inhibited and bacterial growth is slowed suffi ciently to allow the body s natural defenses to effect a cure Because animals do not biosynthesize folic acid but obtain it in their food sulfanilamide halts the growth of bacteria without harm to the host... 

Factor b above is discussed in Sections II, B, 1 II, B, 4 and II, C. A hydrogen-bonded structure such as 221 can account for the facile reaction of 5-bromouracil or for the unique, so-called hydrolyzability of carboxymethylthio-azines (237). The latter may also react via the intramolecular mechanism indicated in 136. The hydrogen-bonded transition state 238 seems a reasonable explanation of the fact that 3,4,6- and 3,4,5-trichloropyridazines react with glacial acetic acid selectively to give 3-pyridazinones while other nucleophiles (alkoxides, hydrazine, ammonia, or sulfanilamide anion) react at the 4- and 5-positions. In this connection, 4-amino-3,5-dichloro-pyridazine in liquid hydrazine gives (95°, 3hr, 60%yield)the isomer-... 

Chemotherapy is the control and treatment of disease by synthetic drugs. Most of these are organic compounds, often of remarkably simple structure. Sulfanilamide is one example of an organic compound synthesized by chemists for the treatment of bacterial infections. 

In contrast to humans, bacteria have the biochemical ability to synthesize folic acid from simpler molecules. Here we have a clear biochemical difference between human beings and infectious organisms that we can exploit to our benefit. The reaction catalyzed by an enzyme known as dihydropteroate synthetase, in which a complex heterocycle is linked to p-aminobenzoic acid, is key. Now recognize the structural similarity between sulfanilamide, or other sulfonamides, and p-aminobenzoic acid ... 

Given this structural similarity, it should not be surprising to learn that sulfanilamide competes with p-aminobenzoic acid for a binding site on the surface of dihydropteroate synthetase. Put another way, sulfanilamide binds to the enzyme where p-aminobenzoic acid should bind but no reaction occurs. The consequence is that a step in folic acid biosynthesis is disrupted and the bacterial cell is deprived of adequate folic acid. Nucleic acid synthesis, among other things, is disrupted, leading to a cessation of cell growth and division. The human immune system can mop up what remains. No similar consequences befall the human host since it cannot make folic acid in the first place and must get an adequate supply of this vitamin in the diet. 

The structure of sulfa drug molecules, however, is very similar to that of the PABA molecule. Compare the structure of sulfanilamide, in part 2 of the diagram, with that of PABA. Notice how easily the sulfanilamide molecule can substitute for the PABA molecule in the synthesis of the bacterium s folic acid. The problem for the bacterium, however, is that folic acid produced from a sulfa drug molecule is... 

Mammals must obtain their tetrahydrofolate requirements from their diet, but microorganisms are able to synthesize this material. This offers scope for selective action and led to the use of sulfanilamide and other antibacterial sulfa drugs, compounds that competitively inhibit the biosynthetic enzyme (dihydropteroate synthase) that incorporates p-aminobenzoic acid into the structure (see Box 7.23). 

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. 

Sulfanilamides are antibiotics that serve as structural analogs of para-aminobenzoic acid (PABA), a substrate In the formation of folic acid by many bacteria. Substitution of the sulfanilamide compound In place of PABA In the reaction prevents formation of the critical coenzyme folic acid. 

The oldest example of the use of nonclassical isosteres involves the replacement of the carboxamide in foUc acid by sulfonamide, to give the sulfanilamides. Diaminopyrimidines, as antimalarial agents, are also based on folate isosterism, in addition to the exploitation of auxiliary binding sites on dihydrofolate reductase. This concept of nonclassical isosteres or bioisosteres — that is, moieties that do not have the same nnmber of atoms or identical electron structure — is really the classical structure modification approach. 

The mode of action of sulfanilamides became known around 1947, when the structure and biosynthesis of folic acid were elucidated. This compound is built by bacteria from the heterocyclic pteroyl moiety, p-aminobenzoate, and glutamate. p-Aminobenzene-sulfonamide (9.89, sulfanilamide) is a competitive inhibitor of the synthase enzyme, acting as an antimetabolite of p-aminobenzoate. Occasionally, the sulfanilamide can even be incorporated into the modified folate, resulting in an inactive compound and thus an inactive enzyme. This theory, proposed by Woods and Fildes in 1940, became the first molecular explanation of drug action. 

The structure of sulfonamides is shown for representative purposes. Among the several thousand compounds in existence, about 25-30 have found widespread use. Sulfanilamide itself is, by present-day standards, very inactive. It was the development of heterocyclic derivatives that produced the highly potent sulfathiazole (9.90). When a succinyl or phthalyl group is attached to the aniline nitrogen, the inactive acylanilide derivatives will not be absorbed from the intestinal tract. Slow deacylation by intestinal... 

The compound sulfanilamide exhibits a structural similarity to para-amino benzoic acid (PABA). Woods and Fields proposed the theory that sulfonamides, being structurally similar to PABA, inhibit bacterial folate synthetase so that folic acid is not formed which is needed for a number of metabolic reactions. Folic acid derived from PABA is essential for bacterial metabolism. Sulfonamides inhibit the enzyme folic acid synthetase which is... 

The basic formulas of the sulfonamides and their structural similarity to p-aminobenzoic acid (PABA) are shown in Figure 46-1. Sulfonamides with varying physical, chemical, pharmacologic, and antibacterial properties are produced by attaching substituents to the amido group (-S02-NH-R) or the amino group (-NH2) of the sulfanilamide nucleus. 

Sulfa drugs have a close structural resemblance to PABA. When taken by a person suffering from a bacterial infection, a sulfa drug is transformed by the body to the compound sulfanilamide, which attaches to the bacterial receptor sites designed for PABA, as shown in Figure 14.7, thereby preventing the synthesis of folic acid. Without folic acid, the bacteria soon die. The patient, however, because he or she receives folic acid from the diet, lives on. 

Some 10,000 structurally dilferent sulfonamides have been synthesized as a result of the discovery of the antibacterial properties of sulfanilamide. The practice of synthesizing numerous structurally related compounds in an elfort to find some that are more efficient or have fewer side effects than those already available is very important to the pharmaceutical industry. However, as is usually the case, of the many known sulfonamides only about thirty have the proper balance of qualities to be clinically useful. 

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