Sulfonamide was firstly noted as anti-bacterial in 1900’s by Gerhard Domagk; a Nobel Prize winner in 1939. In his attempt to save his daughter from streptococci killing infection, he observed that prontosil; a sulfonamide dye, is able to selectively restrain the infectious bacteria cells. In 1936, Ernest Fourneau found out prontosil pathway in human body. He discovered that this dye was a pro-drug. It, actually changes in human body to sulfanilamide which is the anti-bacterial active agent.

This invention triggered the discoveries of other anti-bacterial members derived from this chemical group such as sulfapyridine in 1938 against pneumonia, and sulfacetamide in 1941 against urinary tract infections, and succinoylsulfathiazole in 1942 against gastrointestinal tract infections. Sulfathiazole was commonly used during World War II to cure soldier wounds’ infections. On the contrary, sulfanilamide was not very used due to its greater human toxicity. Later on, sulfisoxaide, sulfamethoxazole, sulfacetamide, mafenide and sulfadiazine silver were discovered, and those four agents are the sulfonamide anti-bacterial agents have been in the clinical use so far.

Sulfonamide anti-bacterial medications; also called sulfa drugs, are competitive inhibitors of p- amino benzoic acid in the folic acid metabolism cycle in the organisms . 45 They have a common core structure shown in Figure 2.

They can be classified as Oral absorbable, oral non-absorbable, and topical agents.4 Oral absorbable agents are also divided into short acting agents such as sulfisoxaide, medium acting agents such as sulfamethoxazole and long acting agents such as sulfasalazine.

Oral non absorbable agent group includes only sulfasalazine, while topical agents have sulfacetamide, mafanide, and silver sulfadiazine. Chemical structures of these groups are shown in Figure 3, and their properties are shown in Table 1. Sulfonamides that do not contain this aromatic amine group undergo different metabolic pathways. 6

We all know that diuretics play an effective role in hypertension treatment.19 There are many pharmaceutical combinations between them and anti-hypertension agents.20 In general, diuretics such as carbonic anhydrase inhibitors, thiazides and loop diuretics are sulfonamide compounds. The chemical structures of these sub-group members are shown in Figure 7. Loop diuretics are considered safer and high ceiling diuretics. Their efficacy has linear relationship with their doses, to the contrary of thiazides which are low-ceiling diuretics.2122 These properties can be attributed to the reason that the loop diuretics are sulfonamide derivatives not thiazide ones.

Figure 8 shows the common core structure of thiazide diuretics, and Figure 9 presents thiazide family members. Loop diuretic common core structure is presented in Figure 10; where X can be N or C, while Figure 11 presents different members of it. Table 3 presents diuretic compounds’ properties.

Thiazide acts at the proximal part of the distal tubule. They interfere with Sodium transfers which increases excretion and urine volume. This results in a reduction of blood volume.23 These diuretics are well absorbed after oral administration, well distributed and undergo a hepatic metabolism. Since their effect target tissues are the kidney , renal failure decreases their efficacy. Thiazides must be taken in awareness with beta-blockers. Together are considered a high risk to cause diabetes in people with impaired glucose tolerance, features of the metabolic syndrome, or obesity.

Many sulfonamide compounds are 5-HT3 receptor antagonists. As a consequence, they work as anti depressants such as Naratriptan and Sumatriptan.23Figure 12 shows chemical structures of these compounds, and Table 4 presents their properties.

Celecoxib, rofecoxib, and valdecoxib are sulfonamide derivative work as anti-inflammatory agents.24 Their mechanism of action is selectively inhibiting Cyclo-Oxygenase-2 Enzyme (COX-2 enzymes).25 This prevents prostaglandins and other inflammatory substrate production. Figure 13 illustrates their chemical structures. Table 5 presents their properties.

Comparing the common core structures between the different groups of sulfonamides based on their bioactivity, we conclude to:

Anti-Bacterial agents: NH₂ bounded to aromatic group is free with no bounded moieties. while R₁ connected to NH₂ in sulfonamide group could be H or any heterocyclic group.

Anti-hyperglycemic agents: Substituting aromatic NH₂ with R1 ( this could be NH₂ or Alkyl moiety). It also has sulfonylurea moiety instead of sulfonamide group where R₂ connected to urea moiety could be Alkyl, Aromatic group, or heterocyclic group.

Herbicides: They also have sulfonylurea group, but it has R₁ in Orto position instead of the aromatic NH₂ which was in the para position. R₂ moiety connected to sulfonylurea group is aromatic heterocyclic group.

When the sulfonamide group is free of moieties from NH₂ side. While R₁ connected to SO₂ group differs between the pharmacologic groups as follows:

Carbonic anhydrase inhibitors: R₁ is aromatic hetero cyclic group.

Thiazides: R₁ is aromatic cycle, where Cl or F is in orto position. In para position, heterocyclic group or a moiety that has SO₂ could bound.

Loop diuretics: R₁ is aromatic cycle with groups in orto or para positions.

Serotonin ant-agonists: R₁ is alkyl moiety connected to hetero cycle which might be aromatic or non-aromatic.

Anti-inflammatory agents: R₁ is Aryl group where in para position there is heterocyclic group.

Studies have proved non-cross allergic reactivity among sulfa based structure drugs. In fact, allergy incidences toward these medications happen commonly in antibacterial sulfa drugs, but not in the other sulfa based compounds. 30

However, sulfonamide diuretics are not far from the risk of cross-reactivity of sulfonamide allergy. Patients who are allergic to other sulfonamides showed doubled allergic reactivity toward sulfonamide diuretics. 31