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Sulphonamides Unveiled: A Comprehensive Review of Mechanisms, Applications, and Therapeutic Insights

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Author Information: Shriyanshi Singh Rana*, Research Scholar, shriyanshisinghrana1@gmail.com
Amrita Singh1, Associate Professor, singh.amrital64@gmail.com

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Author Information: Shriyanshi Singh Rana*, Research Scholar, shriyanshisinghrana1@gmail.com

Amrita Singh, Associate Professor, singh.amrital64@gmail.com

Affiliation: Advance Institute of Biotech and Paramedical Sciences, Kanpur

Journal: PEXACY International Journal of Pharmaceutical Science

DOI: https://doi.org/10.5281/zenodo.8265007

Volume and Issue: Vol. 2, Number 8

Page Numbers: 44–58

Version: Version 1

URL: https://doi.org/10.5281/zenodo.8265007 (Download PDF)

Corresponding Author: Shriyanshi Singh Rana*

Publication Date: 19/08/2023

Update: Received on 15/08/2023; Accepted; 18/08/2023, Published on; 19/08/2023

Cite as- Shriyanshi Singh Rana, & Amrita Singh. (2023). Sulphonamides Unveiled: A Comprehensive Review of Mechanisms, Applications, and Therapeutic Insights. In PEXACY International Journal of Pharmaceutical Science (Version 1, Vol. 2, Number 8, pp. 44-58). Zenodo. https://doi.org/10.5281/zenodo.8265007

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Introduction

Artificial azo dyes had been researched for their movement towards streptococci, Prontosil and many other azo dyes with a sulfon amide organisation were patented in 1932. Domagk tested the new compounds and found that prontosil could effectively treat mice with streptococcal and other infections. Foerster reported the first medical case study in 1933 after administering prontosil to a baby with staphylococcal septicemia who was 10 months old and experiencing dramatic improvement.

The groundbreaking developments in chemotherapy received little attention elsewhere until Colebrook and Kenney, as well as Buttle and others, revealed their positive scientific implications with prontosil and its active metabolite, sulfanilamide, in puerperal sepsis. These reports alerted the medical community to the relatively unexplored area of antibacterial chemotherapy, and a plethora of experimental and research studies quickly followed. The development of diuretics of the carbonic anhydrase inhibitor type and sulfonylurea hypoglycaemic medications as a result of research done with sulfonamide antibiotics. Domagk won the Nobel Prize in Medicine in 1938 for his discovery of the anticancer potential of Prontosil [1].

These compounds have their familiarity as amide derivatives of sulphonic acid because they are synthesized by introduction of amino in sulphonic acid after replacing its hydroxyl group. The compounds which contain this functional group are called “sulfonamide”. The overall formula of sulfonamide RSO2NH2. The generic name “sulfonamide” is frequently used to refer to the para amino benzene sulphonamide derivatives. The para amino benzene sulphonamide is the parent compound of sulphonamides. 1 is assigned to the nitrogen atom in the compound SO2NH2, and 4 to the NH2 group.

Sulphonamides Unveiled: A Comprehensive Review of Mechanisms, Applications, and Therapeutic Insights

Fig.1- Sulphonamide Derivatives

The nitrogen atom of – RSO2NH2 is numbered as 1 and therefor the – NH2 group as 4 [2]. Individual members vary in the nature of N1 (sulfonamide N) substitution, which governs solubility, efficiency and pharmacokinetics property. a unfastened amino group within the p- position (N4) is needed for antibacterial activity [3].

Properties

Sulfanilamide is a powerful chemical at normal pressure and temperature levels. It is extremely light-sensitive and incompatible with potent oxidising agents. Sulfanilamide is more soluble in ethanol (27 mg/cm3) and acetone (200 mg/cm3) than it is in water. Due to the high electron attracting effect of the -SO2 substituent and resonance stabilisation of the resultant anion, sulfanilamide has a low specific gravity (pKa=10.4).

The sulphonamides are made up of white, crystalline powders that are only slightly soluble in water. The properties of solubility depend on the kind of substituent on the -SO2N2 group. The free amino acid NH2 is essential for antibacterial action. Although the pharmacological effects of all sulphonamides are similar, their solubility, rates of absorption, distribution, metabolism, and excretion are all different.

Structure-activity relationship

Sulfonamides have a generic structure where R can be hydrogen, alkyl, aryl, or hetero aryl groups, and R1/R2 can also be any of these [5].

A large range of sulfonamide derivatives were synthesised during the early stages of the sulfonamide investigations, making it possible to establish a link between particular structural traits and the antibacterial propensity of newly produced compounds. First off, the activity of sulfonamides depends on the presence of a free aromatic NH2 group in the Para-position with respect to the sulfonamide group. The sulfonamide action is decreased by the additional substituent in the ortho and meta positions of the benzene ring.  

Sulfanilamide’s N1-monosubstituted derivatives are active substances whose degree of activity rises with the addition of heteroaromatic substituents. Compounds that have two substitutions in the N1 position are inert. In addition, the benzene ring and the sulfonamide group must be joined directly. The action is likewise reduced or completely lost when the benzene ring is substituted with a different cyclic structure. The primary form of sulfonamide antibacterial medications is the first sulfanilamide (4-amino benzene sulfonamide). Due to the production of more effective drugs, the clinical importance of sulfanilamide is not significant because it is used in therapy very infrequently today. However, sulfanilamide is the fundamental structural and functional component of the entire family of antibacterial sulfonamides.[6]

Toxicological effect

Any drug that is taken as medicine has adverse effects. When used against certain viral diseases, like the common cold, antibiotics occasionally are utilised in a way that is harmful and of little value. As a result, antibiotics are not always the best option because they may expose the patient to unnecessary risks due to associated toxicological side effects. The duration and dosage of the medicine, the presence of the heterocyclic ring in N1 substituted SN, its solubility in blood and other biological fluids, the patient’s age and nutritional status, kidney condition, and so on are some of the elements affecting the toxico-logical effect of SN pharmaceuticals [7]. 

According to a research report by Boufas et al. (2014) [8], SNs are moderately hazardous for blood cells, with sulfadiazine being the least harmful of the SN group of medications while sulphanilamide derivative was found to be more toxic overall. SN medications can cause severe acute hemolytic anaemia (the breakdown of red blood cells), which can lower blood platelets [9]. The potential for SMZ’s environmental toxicity exists, especially when it occurs close to water [10].

Animal testing for SDZ’s toxicity revealed that it is less toxic than other SNs while still being extremely powerful against common pathogens, and as a result, has been used to treat human bacterial infections. A putative rise in SDZ’s harmful antimicrobial properties after its pH-dependent chemical breakdown and a decrease in toxicity at higher pH were suggested by measurements of the substance’s toxicity in water and other water bodies [11–12].

Pharmacological Effects

a- Antimicrobial

A large class of synthetic bacteriostatic antibiotics known as sulfonamide compounds is still in use today to treat bacterial infections as well as other illnesses brought on by various microorganisms. Prior to the development of penicillin in 1941, these medications, often known as sulfa medicines, were the mainstay of treatment for bacterial infections. Additionally, several therapeutically utilised medications like diuretics, carbonic anhydrase inhibitors, and antiepileptics contain the main sulfonamide portion. Sulfonamides are antimicrobial medications with a wide range of activity that work against both Gram-positive and some Gram-negative bacteria, including intestinal species [13].

Sulfonamides exhibit strong activity against Klebsiella, mild activity against Proteus mirabilis and Enterobacter species, and good activity against E. coli, but no inhibitory effect against pseudomonas aeruginosa and Serratia species. They work well against Chlamydia genus species. Sulfonamides are also effective against protozoa (Toxoplasma gondii) and fungi (Pneumocystis carinii).Sulfonamides vary in strength but not in their antibacterial action spectrum [14, 15].

Inhibition of dihydrofolic acid synthesis is a desirable target for bacteriostatic drugs due to bacteria’s inability to obtain dihydrofolic acid from their environment as part of microorganisms’ DNA manufacture. Early sulfonamides like sulfanilamide were successful in inhibiting these enzymes. Pteridine diphosphate and p-aminobenzoic acid are combined to start the production of dihydrofolic acid, which can then be formed through an amide coupling with glutamic acid. Sulfanilamide functions as a competitive inhibitor and has a core structure that is similar to that of p-aminobenzoic acid. Due to a paucity of acidic terminals available to couple with glutamic acid, the second phase of the process results in the interruption of dihydrofolic acid synthesis [16].

b- Carbonic anhydrase inhibitors

Bicarbonate and carbon dioxide are converted one into the other by carbonic anhydrases. Carbonic anhydrases primarily affect physiological pH, respiration, CO2 transport, excretion of electrolytes, control, and homeostasis. Humans contain sixteen CA isozymes, ranging from CA I to CA XV, with various subcellular localizations [17–19].

Topiramate (TPM, anticonvulsant), Zonisamide (ZNS, anti-glaucoma), and Acetazolamide (AZA, anti-glaucoma). are well-known for their capacity to block CAs, and their X-ray crystal structures, which demonstrate tight binding of the inhibitors to CA II, CA VA, and CA VB[99][100], have been determined. It’s interesting to note that obese patients who participated in clinical studies as a side effect saw significant weight loss.Thus, by inhibiting CA II, VA, and VB, the rate of lypogenesis can be decreased, which can be used as anti-obesity drugs[20, 21].

c- Antiviral

i- HIV inhibitors

Additionally, sulfonamides have anti-HIV protease action. The HIV protease is a homodimer that has two aspartyl active sites (Asp and Asp), which can break bonds like Tyr-Pro and Phe-Pro2. In order to offer the multi-drug therapy known as the Highly Active Anti-Retroviral Therapy, a number of HIV protease inhibitors have reached clinical availability.

These inhibitors are frequently used with reverse transcriptase inhibitors. Comparing non-peptidic protease inhibitors to traditional peptide-based protease inhibitors, it was discovered that they exhibit greater bioavailability and a slower excretion rate. Amprenavir and Tipranavir are two protease inhibitors that are produced from sulfonamides [22, 23].

ii- Herpes viruses (HSV and HCMV) protease inhibitors

Herpes viruses have an icosadeltahedral capsid enclosed by an amorphous tegument and are enveloped, linear double strand DNA viruses with a characteristic shape. The size of the viral genomes, which encode for between 70 and 200 gene products, ranges from 125 to 230 kilobases (kb) [24]. Three sub-families of eight human herpes viruses have been found thus far.

This enzyme, which is a member of the serine PR family as opposed to the HIV PR previously addressed, is distinguished by a specific catalytic triad of the types His, His-Ser within the active site, along with other comparable proteases isolated from various herpes viruses [25].

It has been found that type (I) -methylpyrrolidine-5,5-trans lactam derivatives block the HCMV alaprotease by acylating the active site nucleophile Ser 132 in a reversible and time-dependent manner.Ala-Ser peptide bonds are hydrolyzed by this serine PR. The 6-me group in the S1 sub site, the N-4-cyclopropyl carbonyl moiety in the S1 sub site, and the large, hydrophobic aryl sulfonyl pyrrolidine 2-carbonyl moiety in the S3 sub site are where compounds of type (II) bind to this PR.

The most effective action (IC50 of 0.34 uM) and selectivity against similar serine proteases (such as elastase, thrombin, or acetyl cholinesterase) were displayed by derivatives integrating the dansyl-(S) – proline moiety in this location. [26]. Although no precise biological information is provided, some halogeno-ketone sulphonamide derivatives (II-IV) have also been described as strong inhibitors (inactivates) of the HCMV protease.35 These substances contain reactive halogeno ketone moieties that react with the catalytically important Ser 132 in the active site of the protease to inactivate it, as well as secondary sulphonamide (II, III) or secondary and primary sulphonamide groups (IV) in their molecules. [25].

d- COX-II specific inhibitors

Arachidonic acid is converted into prostaglandins and thromboxane by the enzyme cyclooxygenase (COX). COX(I-III) is one of three isoforms of cyclooxygenase. Gastric injury may result from COX-I inhibition since cyclooxygenase-I is expressed in platelet aggregation and mucosal protection through prostaglandin synthesis. Inflammation, cell division, and angiogenesis all cause the induction and expression of cyclooxygenase-II. The COX-I variation known as cyclooxygenase-III is known to be inhibited by paracetamol [27–29].

Ibuprofen and conventional COX inhibitors are known to have low selectivity, which increases the risk of ulcer, bleeding, and gastroduodenal erosion. However, COX-II specific inhibitors can reduce inflammation-related symptoms like pain without having the negative side effects of conventional COX inhibitors. Pfizer has created the COX-II specific inhibitors celecoxib and valdecoxib for the treatment of rheumatoid arthritis (RA) and osteoarthritis (OA) [30, 31].

e- Protease inhibitors

A group of crucial biological enzymes known as cysteine proteases are involved in the destruction of proteins, cell death, and inflammation. Additionally, these enzymes have been linked to a variety of disease states, such as arthritis, osteoporosis, Alzheimer’s disease, cancer, and malaria. Caspase is an example of a cysteine protease enzyme, which cleaves at the Ala-Asp residue (thus the name) and is closely related to necrosis, infection, and bapoptosis.

There are currently 11 caspases known, namely caspases 1 through 10 and 13. Not all caspases are directly involved in apoptosis; instead, the effector (executer) caspases (CASP-3, CASP-6, and CASP-7) are responsible for activating the initiator caspases (CASP-2, CASP-8, and CASP-9) prior to apoptosis. As a result, rather than being caused by a single enzymatic activity, apoptosis is caused by a network cascade of caspases [32–34].

f- Histone deacetylase 6 inhibitors

The kidney issue that autosomal dominant polycystic kidney disease (ADPKD) primarily causes, the progressive development of multiple renal cysts, cannot be treated with a standard therapy. The Ca2+ channel PC2 (pkd2) and the signalling molecule PC1 (pkd1) are two protein chains that are each expressed by a pair of genes and are linked to ADPKD. The main feature of ADPKD is aberrant cAMP signalling, however the underlying molecular mechanism is unknown.

A model showed that histone deacetylase 6 inhibitors (HDAC6i) reduce intracellular Ca2+ by preventing the release of ER Ca2+ [35, 36]. According to their hypothesis, HDAC6i predominantly inhibits cell growth and proliferation by sharply lowering Ca2+ and cAMP levels.Their findings identified therapeutic goals that could be useful as prospective treatments for ADPKD. One of the most recent developments in cancer therapy was the modulation of immuno-modulatory pathways through the use of epigenetic modifiers. Among these, HDACs are excellent targets because there are many commercially available, broad-spectrum inhibitors of these zinc-containing enzymes [37].

g- Sphingosine kinase inhibitors

Sphingosine kinase has two known isoenzymes, SphK1 and SphK2. While SphK1 and SphK2 isoforms exhibit precise changes in subcellular localization and substrate selectivity, they catalyse the same reaction—the phosphorylation of sphingosine to produce the chemical sphingosine-1-phosphate (S1P)—differentially. A bioactive lipid known as S1P compound activates the S1P1-5 family of G protein-coupled receptors [38]. The SphK1 enzyme is primarily found in the cytosol, whereas the SphK2 isoform is primarily found in the nucleus. Rats with double knockouts of the SphK1 and SphK2 isoforms show severely impaired neurogenesis and angiogenesis, which results in the mortality of the embryo.

The study of novel isoenzyme elective inhibitors has been sparked by the discovery of new SphK inhibitor chemicals as a result of the identification of the SphK1 structure. The inhibitor chemicals have helped to make clear the crucial functions of SphK enzymes in the involvement in inflammatory signalling and in the regulation of major oncogenes. In fact, none of the most often used inhibitors were able to cause cancer cell death.

h- Sulfonamides as a cure of some diseases

Sulfonamides are extremely beneficial in the management of more complicated disorders. Sulfonamide derivatives have been used as carbonic anhydrase inhibitors (CAI) in a range of applications, such as anti-hyperthyroidism, antitumor, and anticancer medicines, following the theory that they could have enzyme inhibitor activity in a wide variety of biological pathways [39–46].

i- Alzheimer’s disease

There have been significant new trends in drug development over the past ten years that are focused on employing sulfonamide derivatives in multi-target methods to treat dementia and Alzheimer’s disease. Following the development of N-bridged bicyclic sulfonamide-based inhibitors of -secretase as potential new anti-AD drugs, focus shifted from inhibiting -secretase to prevent amyloid buildup to inhibiting two cholinesterase enzymes of the cholinergic system, which is involved in neurotransmission, memory, and other cognitive functions.

Acetylcholinesterase (AChE) and butyryl cholinesterase (BChE) catalyse the hydrolysis of the neurotransmitter acetylcholine (ACh), which stops cholinergic neurotransmission in the brain. AChE levels in AD are reduced as a result of the buildup of tau and amyloid-protein deposits, oxidative stress, and other factors. As a result, some attention was given to developing AChE and BChE inhibitors for symptomatic therapy [47].

j- Anticancer

Sulfonamides continue to be one of the most researched chemicals with pharmacological activity as anticancers and have also played a significant role in drug discovery research. New acridine sulfonamide/carboxamide compounds containing 5-amino-1,3,4-thiadiazole-2-sulfonamide derivatives were reported to have inhibitory effects on human carbonic anhydrases in 2018 [43].

Since 2005, there has been an increase in interest in the use of sulfonamides to inhibit carbonic anhydrase (CA). After demonstrating that CA IX isozyme was a druggable target, Supuran’s group showed that aromatic sulfonamides have enhanced activity towards this enzyme. A library of aromatic sulfonamides with varying substituents at the triazine moiety was used for the investigation [48].

k- Other diseases

According to various recent studies, the sulfonamide derivatives of metformin may also have anticoagulant and antifibrinolytic properties. As a result, they may be tested in the development of potential drug candidates for treating Type 2 diabetes mellitus (T2DM), which is best identified by means of its impaired balance between coagulation and fibrinolysis in addition to its traditional sign of hyperglycemia [49]. A powerful multi-functional inhibition of aldose reductase (ALR2)/aldehyde reductase (ALR1) was demonstrated by Ji et al [50].

after the creation of a series of acyl sulfonamide derivatives of quinoxalinone.This discovery is significant for the management of diabetes mellitus because ALR2 regulates the rate of phosphorylation of glucose in the polyol pathway under euglycemic settings. Patients with metabolic acidosis, hyperglycemia, and elevated ketone bodies in the bloodstream who yet have serum glucose levels within normal ranges experience euglycemic circumstances. It is frequently the case that a variety of circumstances play a part in the patient’s situation, thus the multi-goal healing approach and multitarget chemicals can be extremely beneficial [50].

l- Other applications of sulphonamides

Many sulfonamides have been utilised therapeutically, and most recently, Sildenafil (Viagra), which is used to treat erectile dysfunction, is a highly well-known example. Nitric oxide (NO), which is released from the brain, binds to guanylate cyclase and causes a build-up of cyclic guanosine monophosphate (cGMP), which relaxes smooth muscle and increases blood flow to the male organ, causing erection. Viagra causes an extended erection by blocking the enzyme phosphodiesterase-5, which breaks down cGMP [51].

There are other techniques in sulfonamide chemistry to broaden fresh medication candidates for difficult-to-treat diseases besides the synthesis of benzosulfonamide analogues with ring moieties and altered tail systems. Recent research has shown that copper(II) complexes with N-sulfonamide ligands have anticancer effects against HeLa cells [52].

Quinoline compounds containing sulfonamide moieties are also frequently used in the creation of anticancer medications, particularly those that target particular subtypes of breast cancer.On a chain of acetylenic quinolinesulfonamide derivatives, for example, [53] synthesised and carried out molecular docking experiments and discovered several rather efficient compounds. Derivatives of naphthalene-1-sulfonamide have recently been developed as effective and selective inhibitors of fatty acid binding protein 4, a potential therapeutic target for atherosclerosis and diabetes [54].

Additionally stated were novel 3,4-disubstituted pyrrolidone sulfonamide derivative designs and syntheses.The substances were discovered to be interesting candidates for medication development to treat schizophrenia and other mental illnesses and to be selective and powerful competitive inhibitors of the glycine transporter [55]. Sulfone pyrrolidine sulfonamides were used as antagonists of transient receptor potential vallinoid-4 (TRPV4) with in vivo activity in a pulmonary edoema model in a different study [56].

Conclusion

Sulfonamides and their derivatives, along with continued advancements in their traditional use as antibiotics, antiviral, or antifungal agents, continue to play a vital role in the design and development of innovative drugs against a variety of complicated disorders. The use of sulfonamide derivatives as multi-target drugs increased recently as the multi-target strategy to drug discovery began to receive well-deserved recognition. It has been demonstrated that sulfonamide derivatives are used in a variety of drug development processes during the duration of this research. despite the fact that single-target programmes are immensely widespread and numerous, their use as multitarget agents has only recently increased.

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