Prodrugs prontosil

In this context, phenacetin can be thought of as a prodrug, that is, an inactive or less active precursor of a more active drug form. The classic example of a prodrug is prontosil, which was the first antibacterial sulfonamide, introduced in 1935 by Gerhard Domagk. However, within a year it was discovered that prontosil itself was inactive. The actual active substance was found to be sulfanilamide, which was formed from prontosil by bacterially mediated fission of the parent compound in the gut (see Chapter 10 for additional coverage). 

Amines have occasionally been incorporated into an azo linkage to produce a prodrug. In fact, it was an azo dye. prontosil. (hat led to the discovery of the sulfonamides as the first antibacterials to be used to treat. systemic infections.--Although prontosil itself was inactive in vitro, it was active... 

Azo Prodrugs Amines have been incorporated into an azo linkage to form prodrugs that can be activated through azo reduction. In fact, sulfa dmgs were discovered because of prontosil (93), an inactive azo dye that was converted in vivo to the active sulfanilamide (95) (Scheme 15). Clinically useful balsalazide (23), olsalazine (25), and sulfasalazine (26) are azo prodrugs of mesalazine (27). They are converted in vivo by bacterial azo reductases in the gut to the active 5-aminosalicylic acid (5-ASA or mesalazine, 27), which is responsible for their anti-inflammatory activity in the treatment of ulcerative colitis, as discussed earlier. 

As shown in Scheme 19.5, however, prontosil is itself an inactive prodrug that, upon oral administration, requires metabolic reduction by the gut microflora to become sulfanilamide, 6. The latter is an active antimicrobial that is very effective against streptococcal infections upon its absorption into the body. Once this was understood, the birth of the sulfonamide antibiotics can be said to have occurred and both Domagk and his daughter lived happily-ever-after. It was later shown that the structure of 6 resembles that of para-aminobenzoic acid (PABA) because... 

Reduction. Reduction, for example azo- and nitro-reduc-tion, is a less common pathway of drug metabolism. Reductase activity is found in the microsomal fraction and in the cytosol of the hepatocyte. Anaerobic intestinal bacteria in the lower gastrointestinal tract are also rich in these reductive enzymes. A historical example concerns Prontosil, a sulfonamide prodrug. It is metabolized by azo-reduction to form the active metabolite, sulfanilamide. Sulfasalazine is also cleaved by azoreduction by intestinal bacteria to form aminosalicylate, the active component, and sulfapyridine. Chloramphenicol is metabolized by... 

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