Sulfanilamide molecule

Systematic modification of the sulfanilamide molecule in order to maximize the hypoglycemic activity led to the observation that the sulfonamide is best replaced by a sulfonylurea function. Modification on both the aromatic ring and the substituent on the terminal nitrogen modulates the activity of the products. ... 

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... 

The search was rewarding and opened up new vistas. The first breakthrough in this field was acetazolamide, a potent inhibitor of carbonic anhydrase. This compound induces increased sodium ion excretion and diuresis. It found wide medicinal application in the treatment of cardiac edema, acting presumably by suppression of carbonic anhydrase activity in the renal tubules. Unfortunately, drug tolerance developed in patients, limiting its utility. This deficiency stimulated medicinal chemists to persist in the modification of the sulfanilamide molecule and led to the discovery of chlorothiazide and the thiazide family of drugs. 

French scientists at the Pasteur Institute, however, promptly dispelled some of Prontosil s mystery, splitting the molecule into a red dye component and an old chemical, sulfanilamide, its 1909 patent long since lapsed (2 ). The suspicion arose that Domagk, an I. G. Farbenindustrie researcher, had rediscovered sulfanilamide, and that the manufacturer had held it off the market until it could be presented in a new, complex, disguised, and patentable form (2, 3 ) Whether or not the suspicion was true, the French scientists, by showing that sulfanilamide was the therapeutically active fraction of Prontosil, shattered the gigantic Germany company s profitable plans. 

Given a molecule such as sulfanilamide that is an active antibacterial, why go to all the trouble of modifying the stmcture to find other active molecules in the same stmctural class There are numerous answers to find safer molecules, more potent molecules, molecules active against a broader spectrum of bacteria, molecules active longer so that doses may be taken less frequently, molecules that may pass the blood-brain barrier and be effective against central nervous systems 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 ... 

Competitive inhibitors bind to specific groups in the enzyme active site to form an enzyme-inhibitor complex. The inhibitor and substrate compete for the same site, so that the substrate is prevented from binding. This is usually because the substrate and inhibitor share considerable stmctural similarity. Catalysis is diminished because a lower proportion of molecules have a bound substrate. Inhibition can be relieved by increasing the concentration of substrate. Some simple examples are shown below. Thus, sulfanilamide is an inhibitor of the enzyme that incorporates j9-aminobenzoic acid into folic acid, and has antibacterial properties by restricting folic acid biosynthesis in the bacterium (see Box 11.13). Some phenylethylamine derivatives, e.g. phenelzine, provide useful antidepressant drags by inhibiting the enzyme monoamine oxidase. The cA-isomer maleic acid is a powerful inhibitor of the enzyme that utilizes the trans-isomer fumaric acid in the Krebs cycle. 

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. 

Albumin is the most abundant protein in human and other animal plasma. It is estimated that up to 40% of the total albumin in humans is in circulation transporting essential nutrients, especially those that are sparingly soluble in aqueous-based plasma. For example, the fatty acids, which are important fuel molecules for the peripheral tissue, are distributed by albumin. In addition, albumin is the plasma transport protein for other substances including bilirubin, thyroxine, and steroid hormones. Also, many drugs including aspirin, sulfanilamides, clofibrate, and digitalis bind to albumin and are most likely carried to their sites of action by the protein. 

A comparison of the structures of PABA (as the carboxylate) and sulfanilamide (as the anion) indicated that this competitive inhibition was due to the amazing congruence of structural and electronic features between the two molecules. 

There is evidence that hydrogen ions, low temperatures, hydrostatic pressure, and sulfanilamide each stabilize the molecule in states characterized by relatively low heat and small volume, whereas hydroxyl ions, high temperature, low presure, and urethane each stabilize the molecule in states characterized by high heat content and large volume, the catalytically active system being intermediate. Apart from... 

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