Since some dyestuffs selectively stained micro-organisms, Ehrlich proposed that various pathogenic organisms might be controlled by the selective use of dyestuffs. Over the years, this led to many investigations and to some useful anti-bacterial substances including the acriflavine 6.9 anti-bacterial agents introduced in 1917.
In 1909, the organoarsenic compound, salvarsan 6.11 was found to be active against trypanosomiasis (sleeping sickness) and syphilis. Salvarsan was derived from an earlier (1905) drug, p-aminophenylarsonic acid (atoxyl) and modelled on an azo-dye with the supposition that it would contain an arsenic:arsenic double bond in place of the nitrogen:nitrogen double bond. Formulations such as 6.10 were proposed. Subsequent work has shown that this is incorrect and that salvarsan is a polymer
6.11 in which the singly bonded arsenic atoms may lie in a ring. The current suggestion is that salvarsan is a mixture of cyclic species containing arsenic in three- and five-membered rings.
It was known that the sulfamyl (-NHSO2_) group facilitated the binding of dyestuffs to wool protein. Hence, Domagk (1932) investigated the anti-bacterial activity of some dyestuffs including prontosil red 6.12. Unlike today, the primary bioassay included whole animal tests and he was able to show that the compound was active against a Streptococcus infection in mice and a Staphylococcus infection in rabbits. Again unlike today, the compound was rapidly tested in humans where it was shown to control septicaemia in children including Domagk's daughter. It had a significant effect on infant mortality. It was soon realized (1935) that the active compound was a bio-transformation product, sulfanilamide 6.13. However, although this was used as an anti-bacterial agent, it was accompanied by a side effect. The amino group was acetylated in man and the acetate crystallized out in the kidneys. A series of structural modifications were then made to overcome this problem.
The synthesis of sulfonamides is outlined in 6.14 and 6.15. This synthesis is readily adapted to make a range of derivatives, i.e., it fulfils one of the major criterion of a synthesis in medicinal chemistry, that of flexibility.
One of these, sulfapyridine (M and B 693) 6.16, achieved fame because it was used to treat the wartime Prime Minister, Winston Churchill in 1943 when he had contracted pneumonia. Other sulfonamides that have been used include sulfathiazole 6.17, sulfadiazine 6.18 and sulfamethoxazole 6.19.
Structure:activity relationships showed a structural requirement for the p-aminophenylsulfonamide group in which the sulfonamide group should carry only one substituent. The N-H of the sulfonamide group is quite acidic. All of the heterocyclic rings attached to this grouping have an imino group and are probably hydrolysed enzymatically.
Insight into the mechanism of action of the sulfonamides came from an observation by Woods and Fildes in 1940 of the structural similarity between sulfanilamide 6.13 and p-aminobenzoic acid 6.20.
p-Aminobenzoic acid was a growth factor for bacteria and in 1946 it was found that it was a component of dihydrofolic acid 6.22. Di-hydrofolic acid is biosynthesized by coupling a dihydropteridine 6.21 with p-aminobenzoic acid 6.20 and then adding a glutamic acid unit. This biosynthesis is inhibited by sulfanilamide. Dihydrofolic acid is the precursor of tetrahydrofolic acid, which is the co-enzyme for a number of essential biosynthetic steps including the addition of the C1 unit to uracil to form thymidine, a major component of the nucleic acids. In humans, folic acid is an essential dietary factor which is obtained from food. It is not biosynthesized by man. Consequently, the sulfonamides have no direct effect on folic acid in man but only on the production of folic acid in bacteria.
The conversion of dihydrofolic acid 6.22 to tetrahydrofolic acid 6.24 is inhibited by another anti-bacterial agent, trimethoprim 6.23. A combination therapy of sulfamethoxazole 6.19 and trimethoprim (co-trimazole) has been particularly useful in combating resistance. If a bacterium develops resistance to sulfamethoxazole, it is killed by trimethoprim before it can replicate and so the resistance cannot be passed on. The enzyme dihydrofolate reductase has been crystallized and its X-ray crystal structure has been determined. The structure of the enzyme containing bound trimethoprim has also been determined.
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