ADVERTISEMENTS:
In this article we will discuss about:- 1. Discovery of Sulfonamides 2. Structure of Sulfonamides 3. Mode of Action 4. Effectiveness.
Discovery of Sulfonamides:
The discovery of the sulfonamides or sulfa drugs in 1935 by Professor Gerhard Domagk (Fig. 45.1) and his team was a pioneering achievement in the war against infections, for which Domagk received the 1939 Nobel Prize for Medicine.
Sulfonamides were the first drugs that could be used systematically against a broad spectrum of bacterial infections—and Prontosil was the most effective of them all. One of the first patients to be successfully treated with the product was Domagk’s six-year-old daughter.
Structure of Sulfonamides:
Sulfonamides or sulfa drugs were the first antimetabolites to be used successfully as chemotherapeutic agents to inhibit the growth of bacteria. They are structurally related to sulfanilamide, an analogue of p-aminobenzoic acid that is used in the synthesis of folic acid (Fig. 45.2).
The discovery of the first sulfa drug resulted from the large scale screening of chemicals for activity in curing streptococcal diseases in experimental animals.
There are numerous sulfonamides that possess the same basic structure related to p-aminobenzoic acid. The sulfonamides, however, differ from each other primarily by virtue of the different substituents in its R’ position as shown in Fig. 45.3. Table 45.5 shows some examples of sulfonamides and their different substituents.
Mode of Action of Sulfonamides:
The mode of action of sulfonamides is the inhibition of tetrahydrofolic acid (THFA) synthesis. Many bacteria require p-aminobenzoic acid (PABA) as a precursor to their synthesis of the essential coenzyme tetrahydrofolic acid (THFA). PABA is a structural part of the THFA acid molecule.
The selective action of sulfonamides is explained by the fact that the PABA molecule and a sulfonamide molecule are so very similar that the sulfonamide may enter the reaction in place of the PABA and block the synthesis of an essential cellular constituent, which in this case is THFA, as shown in Fig. 45.4.
The cellular functions of the THFA co-enzyme include amino acid synthesis, thymidine synthesis, etc. Lack of this coenzyme will quite obviously disrupt normal cellular activity.
Sulfonamides will inhibit growth of those cells which synthesize their THFA from PABA and will not interfere with the growth of those cells (including mammalian host cells) which require the vitamin folic acid and reduce it directly to THFA. This accounts for the selective antibacterial action of sulfonamides and makes them useful in the treatment of many infectious diseases.
Effectiveness of Sulfonamides:
Sulfonamides are selectively toxic for many bacterial pathogens because the latter synthesize their own folic acid and can not effectively take up this chemical from outside. In contrast, humans must obtain it in their diet because they can not synthesize folic acid by their own.
It is therefore the sulfonamides do not affect the human host. However, as many as 5% of the patients provided sulfonamide doses experience adverse side effects mainly in the form of allergic responses such as fever, hives, and rashes.
