Following the dramatic success of Protosil, a cascade of sulphanilamide derivatives began to be synthesised and tested, by 1948 more than 4500 existed, but only about two dozen actually have been used in clinical practice. The sulpha drugs have proven to be ineffective against certain infections such as Salmonella (Patrick, 2001). Other problems such as toxicity observed in some patients and the evolution of sulphanilamide-resistant bacterial strains, resulted in them being superseded by penicillin. Only a few sulphonamides are extensively used today, for infections in patient with AIDS, urinary tract infections and burn therapy (Fullerton, 1998).
The role of sulphonamides
The sulphonamides interfere with bacterial folate metabolism. In order for purine synthesis to occur, tetrahydrofolate (THF) is a requirement. It is also a cofactor for the methylation of various amino acids. The formation of dihydrofolate from para aminobenzoic acid (PABA) is catalysed by dihydropteroate synthase. Dihydrofolate is further reduced to THF by dihydrofolate reductase. Microorganisms require extracellular PABA to form folic acid. Sulphonamides are analogues of PABA hence they take the place of PABA. They then competitively inhibit dihydrofolate synthase resulting in an accumulation of PABA and deficient THF formation (van Boxtel, 2001).
The action of sulphonamides is bacteriostatic and is reversible in the presence of an excess of PABA, for example in necrotic tissue and abscesses.
HTS
The purpose of HTS is to identify potential lead candidates as fast as possible, whereas the purpose of combinatorial chemistry (CC) and classical medicinal chemistry (MC) is to improve the activity of chemical leads as fast as possible. If sulphonamide was discovered as a lead by this method it would either require modification by MC, this would be due to it not being amenable to current technologies. The quality of the screening library is the chemical diversity: the more diverse the library the better would be the chances of obtaining a hit for the Sulphonamides (Chakkodabylu, 2000).
Due to there being many compounds which are similar to sulphonamides the screening of the libraries would provide the analogues of compounds already made for these targets.
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Chakkodabylu R.S., (2000) How many leads from HTS?, Drug discovery today, 5, 2, 43-44
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Fullerton D.S. (1998) Sulfonamides, Sulfones, and Folate Reductase Inhibitors with Antibacterial Action in Textbook of organic medicinal and pharmaceutical chemistry (5th edition), edited by Delgado J.N. and Remers W.A., Lippincott-Raven publishers. 223-233
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Patrick G.L., (2001) Antibacterial agents in An introduction to medicinal chemistry, 2nd edition, Oxford university press, 375-431
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Kucers A., Crowe S., Grayson M.L. and Hoy J., (1997) The use of antibiotics, A clinical review of antibacterial, antifungal and antiviral drugs (5th edition). 805-835