The authors have declared that no competing interests exist.
Sulfonamide group is a magic group introduced as the main core for different bio-activities in drug industry. According to its substitutes, literature divides sulfonamide derivatives to antibacterial sulfonamides and non-anti-bacterial sulfonamides. As Data was collected from different sources such as Drug Bank.com and Pubchem.com databases and then was analyzed, we found that these compounds are different in their pharmacokinetics and pharmacodynamics; in addition to their sulfa cross allergy property. We presented these differences from these compounds changes in their chemical structure, in a way to build a solid base that can be depended on for developing new drugs from these compounds that interact with different receptors.
Sulfonamide derivatives medical groups’ discovery can be more similar to a string of distinguished pearls. They have in common the same main core but they differ in their bioactivities;
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 .
They can be classified as Oral absorbable, oral non-absorbable, and topical agents.
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
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Sulfisoxazole | 1.01 | 267.303 | 6 |
Sulfamethoxazole | 0.89 | 253.276 | 10 |
Sulfadoxine | 0.7 | 310.328 | N\A |
Sulfasalazine | 3.8 | 398.393 | 5- 10 |
Sulfacetamide | -0.96 | 214.239 | 7-12.8 |
Mafenide | N\A | 186.229 | N\A |
Silver Sulfadiazine | N\A | 357.136 | N\A |
This group of drugs is commonly used in type 2 diabetes treatment.
Studies on sulfonamide bioactivities expanded when Laboratories proved that sulfa drugs stimulated beta cell release of insulin.
In 1956, Germany introduced tolbutamide; sulfa drugs derivative, as the first sulfonylurea compound to be in clinical use for diabetes treatment. Other first generation sulfonylurea compounds; acetohexamide, tolazamide, and chlorpropamide were available in the German market.
Glyburide and glipizide; more potent sulfonylurea members entered the US drug market in 1984; after more than a decade of their usage in Europe.
The mechanism of anti-hyperglycemic agents action is the increase of insulin hormone secretion from pancreatic beta cells.
The common core structure of these compounds is presented in
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Tolbutamide | 5.16 | 2.3 | 270.347 | 7 | |
Tolazamide | 3.6 | 2.69 | 311.4 | 7 | |
Acetohexamide | 6.6 | 2.3 | 324.395 | N\A | |
Carbutamide | N\A | 1.01 | 271.335 | N\A | |
Chlorpropamide | 5.13 | 2.2 | 276.735 | 36 | |
Glycyclamide | N\A | N\A | 296.119 | N\A | |
Metahexamide | 3 | N\A | 311.4 | N\A | |
Glyburide | N\A | 4.9 | 494.003 | 2-4 | |
Gliclazide | N\A | 2.6 | 323.411 | 6-15 | |
Glipizide | 5.9 | 1.91 | 445.538 | 3-5 | |
Glibornurinde | N\A | N\A | 276.735 | N\A | |
Gliquidone | N\A | 4.5 | 527.636 | N\A | |
Glisoxepide | N\A | N\A | 449.526 | N\A | |
Glyclopyramide | N\A | N\A | 303.761 | N\A | |
Glymidine | 6.92 | 1.27 | 309.34 | 4 | |
Glimiiride | N\A | 3.9 | 490.619 | 5 |
It is worth mentioning that not all sulfonylurea derivatives are anti-hyperglycemic agents. Most of them are herbicides.
We all know that diuretics play an effective role in hypertension treatment.
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Acetzolamide | 7.2 | -0.45 | 222.237 | 9 |
Brinzolamide | N\A | -1.8 | 383.496 | 111 day |
Dichlorophinamide | 7.4 | 0.2 | 305.144 | N\A |
Dorzolamide | N\A | -1 | 324.428 | 4 months |
Methazolamide | 7.3 | 0.13 | 236.264 | 14 h |
Sulthiame | N\A | N\A | 290.352 | N\A |
Metolazone | 9.72 | 2.5 | 365.832 | 14 h |
Bendroflumethiazide | 8.5 | 1.19 | 421.409 | 8.5 |
Chlorothiazide | 6.85 | -0.24 | 295.712 | 2 h |
Chlortalidone | N\A | 0.85 | 338.762 | 40 h |
Clopamide | N\A | N\A | 345.842 | N\A |
Diazoxide | 8.74 | 1.2 | 230.666 | 28 h |
Hydrochlorthiazide | 7.9 | -0.07 | 297.728 | 14.8 |
Hydroflumethiazide | 8.9 | 0.36 | 331.284 | 27 h |
Indapamide | 8.8 | 2.2 | 365.832 | 14 |
Xipamide | N\A | N\A | 354.805 | N\A |
methyclothiazide | 9.4 | 1.42 | 360.224 | N\A |
Bumetanide | N\A | 2.6 | 364.416 | 60-90 min |
Furosemide | N\A | 2.03 | 330.739 | 1.5 |
Piretanide | N\A | 3.92 | 362.4 | N\A |
torasemide | N\A | 2.3 | 348.421 | 3.5 |
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.
Many sulfonamide compounds are 5-HT3 receptor antagonists. As a consequence, they work as anti depressants such as Naratriptan and Sumatriptan.
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335.466 | 5-8 |
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295.401 | 2.5 |
Celecoxib, rofecoxib, and valdecoxib are sulfonamide derivative work as anti-inflammatory agents.
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Celecoxib | 3.47 | 381.373 | 11 |
Rofecoxib | 1.56 | 314.355 | 17 |
Valdecoxib | 2.67 | 314.359 | 8-11 |
These include protease inhibitors with activity against Human Immunodeficiency Virus Type 1 ( HIV-1) such as amprenavir and fosamprenavir,
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Amprenavir | ------- | 2.2 | 505.63 | 7.1-10.6 |
Fosamprenavir | 1.7 | 2.2 | 585.609 | 7.7 |
Dapsone | 2.41 | 0.97 | 248.3 | 28 |
Ibutilde | -------- | 4.31 | 384.579 | 6 |
Probencid | 3.4 | 3.21 | 285.358 | 6-12 |
Sotalol | ------ | 0.24 | 272.363 | 12 |
Zonisamide | 10.2 | 0.36 | 212.223 | 63 |
Topiramate | ------- | -0.7 | 339.359 | 21 |
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.
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.
This paper has presented a number of compounds that were derived from this unique chemical group with a variety of pharmacological effects that served human health. We consider sulfa drugs are a great discovery. One can develop chemical structure as potential drugs in the future by substituting R moieties or adding halogens or inserting any changes the researcher finds necessary in sulfonamide structure for his drug development. One can also have molecular modeling for one compound from different sub-activity groups to find out if they have any effect on the other compounds receptors in a way to develop new agents from the same chemical group.