Antibacterials sulphonamides

During a clinical trial in 1954 of the sulphonylurea antibacterial sulphonamide known as carbutamide (Fig. 8.49), patients experienced severe side effects. A physician in charge tested the dmg on himself and realised it produced hypoglycaemia. After further clinical investigations, carbutamide was marketed in Europe as an oral hypoglycaemic in patients with mild diabetes, even though it had many side effects. 

In a great many cases the level of free drug in the tissue fluids eventually becomes the same as that in the plasma. This relationship is convenient because the plasma is more accessible for analysis. Among examples investigated are the antibacterial sulphonamide sulfadoxine (TanasiP)... 

Outstanding among drugs which inhibit the production of DNA from several stages back in the biosynthetic pathway are the sulphonamides and the 2,4-diaminopyrimidines used so much as antibacterials and anti-malarials. All of the chemotherapeutic sulphonamides, whether simple sulphanilamide (4.5a) or its more complex heterocyclic derivatives 4.5b) including sulphadiazine, competitively inhibit the enzymes dihydrofolate synthetase which produces dihydrofolic acid 2.14) (see p. 28). The basis of this inhibition, as outlined in Section 2.1 (p. 28), is the similarity in the steric and electronic properties of p-aminobenzoic acid 2,13) (which the enzyme is ready to build into new molecules of dihydrofolic acid) and the sulphonamides (4.5) which, when taken up by the enzyme, merely block it. The basis of the selectivity of these antibacterial sulphonamides depends on two factors, which reinforce one another (i) mammals lack the enzymes necessary for the synthesis of dihydrofolic acid, and hence they tolerate these sulphonamides very well (ii) pathogenic bacteria lack the permease with the aid of which mammals absorb dihydrofolic acid from the diet. Further relevant data will be foimd in Section 9.3. Dihydrofolic acid is only two steps away from the coenzyme required for biosynthesis of thymine and all the purine bases. Deprived of the substrates, especially thymine, bacteria soon die because they can make no new DNA. 

The most cautionary examples of selective metabolisms are those in which man behaves differently from most other mammals, for herein lies one of the dangers in transferring results from laboratory animals to man. Here are some examples. The only animals that dehydrogenate quinic acid to benzoic acid are man and the Old World primates, for not even the New World primates do so. The antibacterial sulphonamide sulpha-dimethoxine is excreted by man and the primates as the N -glucuronide, whereas the common laboratory animals excrete it as the AT-acetyl-derivative (Adamson, Bridges and Williams, 1966). Other aromatic amines such as aniline and sulphanilamide are acetylated in man, and many other mammals, as well as in most species of birds, amphibia, reptiles, and fish nevertheless dogs, frogs and turtles do not perform acetylation. Further examples of different metabolic paths followed by man on the one hand and mammals on the other have been traced for amphetamine, phenylacetic acid, and 6-propylthiopurine in Section 3.4 (p. 82). 

The year 1935 forms a natural division in the history of chemotherapy because of Domagk s discovery of the chemotherapeutic properties of Trontosir, the first of the antibacterial sulphonamides. This discovery refuted a prejudice that chemotherapy applied mainly to protozoal diseases, and it opened a new era in medical and surgical treatment. Wood s later discovery (1940), that sulphonamides blocked the use by bacteria of one of their essential constituents (p-aminobenzoic acid), gave detailed support to Ehrlich s postulate that drugs combined with receptors in such a way as to prevent normal nutrients from reaching them (see Section 9.3a). 

Antibacterial sulphonamides. The discovery of sulphachrysoidine, (i./6, p. 87) ( Prontosil ), followed a strange course. Gerhard Domagk (1895-1964), who later received a Nobel prize for this work, was a pathologist, studying the phagocytosis of streptococci by the Kupffer cells of the... 

There are antagonists of the biosynthesis of dihydrofolic acid, and antagonists of its utilization. The history of the discovery of the antibacterial sulphonamides, typical antagonists of biosynthesis, was given in Section 6.3a. In 1940, Woods showed that the antibacterial action of sulphanilamide depended on its competition with p-aminobenzoic acid (2.15), which is a natural metabolite (Woods, 1940). Later this competition was shown to take place at the site on the enzyme dihydrofolate synthetase, which... 

The selectivity of the antibacterial sulphonamides depends on the nonutilization of p-aminobenzoic acid by mammals, which do not make their own dihydrofolic acid, but obtain it in food. Pathogenic bacteria, on the other hand, cannot absorb preformed dihydrofolic acid (Wood, et aL 1961), and hence are vulnerable to the sulphonamides which prevent them from synthesizing it. 

Sulphonamides were introduced by Domagk in 1935. It had been shown that a red azo dye, prontosil (Fig. 5.16B), had a curative effect on mice infected with /3-haemolytic streptococci it was subsequently found that in vivo, prontosil was converted into sulphanilamide. Chemical modifications of the nucleus of sulphanilamide (see Fig. 5.16A) e compounds with higher antibacterial activity, although this was often accompanied by greater toxicity. In general, it may be stated that the sulphonamides... 

Pyridazine-derived sulphonamide antibacterials, in particular sulphamethoxypyridazine, are still the subject of extensive investigations. Thus, for instance, in volumes 82 to 108 of Chemical Abstracts, there are more than 300 abstracts of papers dealing with compound (95, R1 = MeO R2 = H), which are not included in the present review due to space limitations. Only selected examples are mentioned. 

Therefore, from the late 19th century the whole of medicine was seeking disease-specific treatments, a process that resulted in some very effective disease-specific drugs being developed starting with antibacterials like sulphonamides and hormones including thyroxine and insulin. Thus in developing disease-specific models of treatment,... 

AgSD differs from other silver salts in its physical properties it does not react rapidly with chloride or thiol groups or with protein and thus its antibacterial activity is not reduced. It does not become dark on standing or in contact with body tissues and unlike other sulphonamides its activity is not eliminated in the presence of p-aminobenzoic acid (PABA) (2) [40]. 

BRL 61063 dpamfylline. brocresine [ban, inn. usan) (CL 54998 nsd 1055) is a substituted bromophenol, a HISTIDINE DECARBOXYLASE INHIBITOR and DIAMINE OXIDASE INHIBITOR. It was formerly used in the treatment of gastric ulcers, brodimoprim [inn] is a dihydrofolate reductase INHIBITOR which can be used as an antibacterial and SULPHONAMIDE potentiator. 

It may also have ANTIPSYCHOTIC activity, dapiprazole hydrochloride dapiprazole. dapitant [inn] (RPR 100893) is a substituted isoindole, a TACHYKININ RECEPTOR ANTAGONIST, selective for the NK,-receptor subtype. It has potential as an ANTIMIGRAINE AGENT, dapsone [ban, inn, usan] is a sulphone with actions similar to SULPHONAMIDES and with ANTIBACTERIAL activity. It can be used as an antileprotic and for infective dermatitis herpetiformis. and is being investigated for the treatment and prevention of Pneumocystis carinii pneumonia (e.g. in AIDS), daptomycin [ban, inn, usan] is an (aminoglycoside) antibiotic. It has antibacterial properties. 

Pronestyl " procainamide, pronetalol pronethalol. pronethalol [ban] (pronetalol [inn] Alderlin " Nethalide ") is a p-ADRENOCEPTOR antagonist with antianginal, antiarrhythmic and anthiypertensive properties. It was the first p-blocker used clinically (ICI), though it was withdrawn at an early stage, prontosil (diaminoazobenzenesulfoname) is a red-coloured sulphonamide with antibacterial activity, converted in vivo to sulphanilamide as active metabolite. It is of historical importance as the first agent of this type (Domagk, 1935). It is also a carbonic anhydrase inhibitor, used experimentally. 

Suleo-C carbaryl. suleparoid sodium heparan sulphate, sulfabenz [inn, usan] (sulfanilaniiide) is a sulphonamide with ANTIBACTERIAL activity and was used as a veterinary ANTICOCCIDIAL. 

Sulfamylon mafenide. sulfanilamide [inn] (avC Prontosii album ) is a SULPHONAMIDE with ANTIBACTERIAL activity now chiefly of historical importance (it is the active principle of prontosii, the first sulphonamide used), but still with some uses (e.g. bacterial vaginitis). Numerous derivatives have antibacterial... 

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