Sulfanilamides, synthesis

Show how you would use the same sulfonyl chloride as used in the sulfanilamide synthesis to make sulfathiazole and sulfapyridine. 

Some related antibacteiials are also included with the sulfonamides. The azo dye, Piontosil (3) is metabolized to sulfanilamide in and was the piogenitoi of the sulfa dmgs. Also, the antibacteiial sulfones, eg, dapsone (4), are believed to act in a similai fashion on enzymes involved with synthesis of fohc acid, leading to bacterial growth inhibition. 

In a few cases, A/ -heterocycHc sulfanilamides have been prepared by the condensation of an active heterocycHc haHde with the sulfonamide nitrogen of sulfanilamide or its A/-acetyl derivative in the presence of an acid-binding agent. Sulfapyridine, sulfadiazine, and sulfapyrazine have been made by this method (1), but the most important appHcation is probably for the synthesis of sulfachlorapyridazine (9) and sulfamethoxypyridazine (10) (45). 

A sulfanilamide drug of prolonged action, 2-p-aminobenzenesulfamido-4-methylpyiimidine (sulfomerazine 162), first prepared by Japanese chemists from acetacetic aldehyde in 82% yield (49JPJ447), ranks among practically valuable 2-amino-4-methylpyrimidine derivatives. Later, a synthesis of this product directly from l-methoxybut-l-en-3-yne (100°C, AcONa, AcOH, 3 h) in 64% yield has been developed (76MI1). 

Possibly the most significant discovery in the metabolism of aromatic azo compounds had implications that heralded the age of modem chemotherapy. It was shown that the bactericidal effect of the azo dye Prontosil in vivo was in fact due to the action of its transformation product, sulfanilamide, which is an antagonist of 4-aminobenzoate that is required for the synthesis of the vitamin folic acid. Indeed, this reduction is the typical reaction involved in the first stage of the biodegradation of aromatic azo compounds. 

Another observation on oxalate formation is that other a-keto acids, such as oxalosuccinic acid (74) and a-ketoglutaric acid (106) do not seem to yield oxalate directly but indirectly (123). This appears to be due to the fact that only oxaloacetic acid can function as an acetate donor. In this connection the intervention of Coenzyme A may be considered, since it is reported to function in the acetylation of sulfanilamide and choline (73) and recently was shown to take part in the enzymatic synthesis of citric acid. This concept may be illustrated as follows ... 

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... 

Similar success was achieved in the synthesis of analogs of prontosil and sulfanilamide. A number of these analogs were prepared and tested and found to he effective against a variety of infectious diseases. 

The formation of sulfa drugs is another excimple of a multistep synthesis. The sulfa drugs cire bactericides, effective c ainst a wide variety of bacteria because they mimic p-aminobenzoic acid (Figure 13-48). Many bacteria require p-aminobenzoic acid, which they cire unable to synthesize, and need to synthesize folic acid. Many types of sulfa drugs exist, and most of them involve the substitution of one of the hydrogen atoms on the -SO2-NH2. Prontosil (Figure 13-49) was the first commercially available sulfa drug. The metabolism of prontosil produced sulfanilamide. 

Sulfanilamide and its derivatives competitively inhibit the synthesis of folic acid in micro-orgenisms and, thereby, decrease the synthesis of nucleotides needed for the replication. 

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. 

Animals are unable to synthesize folic acid (6.62) and must consume adequate quantities in their diets. Plants and bacteria, however, are able to make folic acid. The first step of this synthesis is catalyzed by dihydropteroate synthetase and reacts dihydroptero-ate diphosphate (6.69) and para-aminobenzoic acid (PABA, 6.70) (Figure 6.25). Because this pathway is not found in humans, inhibition of the reaction is a method to ultimately stop TMP synthesis in an invading bacterium while not impacting the infected host. The sulfonamides, often called sulfa drugs, are a class of antibiotic that exploits the folic acid pathway and inhibits dihydropteroate synthetase. Sulfa drugs bind in the same fashion as PABA and act as competitive inhibitors. The active form of the first sulfa drug is sulfanilamide (6.71). Sulfamethoxazole (6.72) is a sulfa drug that is widely prescribed today.26... 

The sulfonamides, or sulfa drugs, date back to the early 1900s but were not systematically studied until the 1930s. Sulfanilamide (A.17), a key reagent in the synthesis of certain dyes, was the first widely marketed sulfonamide (Figure A.5). Sulfonamides are antimetabolites and competitively inhibit a bacterial enzyme, dihydropteroate synthetase (DHPS) (see Chapter 1 and Chapter 6). DHPS plays a role in the synthesis of tetrahydrofolic acid (THF), an important compound in the preparation of thymidine. Because they limit the... 

What would happen in the synthesis of sulfanilamide if the amino group were not protected as an amide in the chlorosulfonation step ... 

Figure 1.12. Stractures of the sulfonamide drag prontosil rubrum , its antibacterially active metabolite sulfanilamide, and the bacterial metabolite p-Aminobenzoic acid. Sulfanilamide acts as an antimetabolite (i.e., competitive inhibitor) in the synthesis of folic acid, of which aminobenzoic acid is a component...

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