Sulfad

Sulfonamide (or sulphonamide) functional group chemistry (SN) forms the basis of several groups of drug. In vivo sulfonamides exhibit a range of pharmacological activities, such as anti-carbonic anhydrase and anti-t dihydropteroate synthetase allowing them to play a role in treating a diverse Sulfad of disease states such as diuresis, hypoglycemia, thyroiditis, inflammation, and glaucoma. Sulfamethazine (SMZ) is a commonly used sulphonamide drug in veterinary medicine that acts as an antibacterial compound to treat livestock diseases such as gastrointestinal and respiratory tract infections. Sulfadiazine (SDZ) is another frequently employed sulphonamide drug that is used in combination with the anti-malarial drug pyrimethamine to treat toxoplasmosis in warm-blooded animals. This study explores the research findings and the work behaviours of SN (SMZ and SDZ) drugs. The areas covered include SN drug structure, SN drug antibacterial activity, SN drug toxicity, and SN environmental toxicity.

Keywords: Sulfonamide, Sulfamethazine, Sulfadiazine, Toxicology, Environment, Bio-macromolecules

Introduction

Sulfonamides (SN) or sulfanilamides belong to an important class of synthetic antimicrobial drugs that are pharmacologically used as broad spectrum for the treatment of human and animal bacterial infections (Seydel 1968; Supuran et al. 2003). SN structures are organo-sulphur compounds containing the -SO2NH2 and/or -SO2NH- group and are characteristic of the existence of sulfanilamide group and a distinct 6- or 5-membered heterocyclic rings. SNs are not readily biodegradable and have potential to cause various unfavourable side effects including diseases of the digestive and respiratory tracts (Sultan 2015) (with some of the SN drug non-allergic reactions include diarrhoea, nausea, vomiting, dizziness, candidiasis, folate deficiency, and headaches (Mathews et al. 2015)). When used in large doses, SN drugs may cause a strong allergic reaction with two of the most serious being Stevens–Johnson syndrome and toxic epidermal necrolysis (Shah et al. 2018). The overall incidence of adverse drug reactions to sulfanamide allergy is approximately 3–8%, close to that seen for penicillin (Giles et al. 2019; Warrington et al. 2018). A key determinant feature of this allergic response involves substitution at the N4 arylamine group position such as is found in sulfamethoxazole, sulfasalazine and sulfadiazine (Dibbern and Montanaro 2008; Tilles 2001). Other SN drugs which do not contain the arylamine group tend not to induce the allergic response and may therefore be safely taken (Giles et al. 2019; Khan et al. 2019). As a result of this allergy effect, SNs are classified into two groups: (i) anti-bacterial sulfonamides (with an aromatic amine) and (ii) non-antibacterial sulphonamides (without an aromatic amine) (Igwe and Okoro 2014; Yousef et al. 2018; Zawodniak et al. 2010).

SN-derived drugs developed up till the present include sulfamethazine, sulfadiazine, sulfamethoxazole, sulfasalazine, sulfisoxazole, sulfamerazine, sulfadimethoxine, sulfafurazole, and sulphanilamide (“Antibacterial Agents, Sulfonamides” 1944; Hehui et al. 2021; Supuran 2017) (Table ​(Table1).1). Among these SN derivatives, the first to be developed in 1906 was sulphanilamide, although it was not used as an antimicrobial agent until the late 1930s (Ballentine 1981; Fernández-Villa et al. 2019). Sulfamethazine (SMZ) and sulfadiazine (SDZ) are among the derivatives of sulphonamides group of antibiotic drugs that contain the aromatic amine group. SMZ and SDZ are commonly used in veterinary medicine as an antibacterial compound to treat livestock diseases such as gastrointestinal and respiratory tract infections (Rama et al. 2017). SMZ has been used in animal feeds or feed additives to promote growth in animals (Awaisheh et al. 2019; Burbee et al. 1985; Chattopadhyay 2014; Dixon-Holland 1992). SDZ on the other hand is used primarily on the treatment of infection caused by the burn wounds (Banerjee et al. 2019; Dai et al. 2010; Hosseini et al. 2007). SDZ is also used in combination with the anti-malarial drug pyrimethamine to treat toxoplasmosis in mammals (Hossein Eshghia et al. 2011; Islam et al. 2013; Winters and Janney 2015). There are several reports about SN, SMZ, and SDZ that deal with its environmental effects, antibacterial effects, and its interactions with specific bio-macromolecules (Bendjeddou et al. 2016; Biošić et al. 2017; Chen et al. 2012; Genç et al. 2008a; Islam et al. 2016; Qadir et al. 2015). It is the intention of the present review article to critically assess these reports.The typical structure of a tertiary SN involves a central sulfur atom, with two doubly bonded oxygens, that is also bonded to a nitrogen atom (existing as a substituted amine) and an aniline group (Fig. ​(Fig.1a)1a) in which R1/R2 may also be hydrogen, alkyl, aryl, or hetero aryl groups. An alternative means of describing the prototypical SN drug structure is an organic compound consisting of aniline derivatized with a sulfonamide group (Pareek et al. 2013; Sonu et al. 2017). The difference in the derivative structure of SN (Fig. ​(Fig.1a)1a) between SMZ and SDZ (Fig. ​(Fig.11 b and c) lies in the extra dimethyl group that is present in the 4th and 6th carbon of the pyridine ring. The IUPAC name of SN is 4-aminobenzenesulfonamide, and the two derivative drugs are 4-amino-N-(4, 6-dimethylpyrimidin-2-yl) benzene sulphonamide for SMZ and 4-amino-N-(pyrimidin-2-yl) benzene-1-sulphonamide for SDZ respectively (Robertson et al. 2020; “Sulfamethazine and Its Sodium Salt” 2001).

The typical structure of a tertiary SN involves a central sulfur atom, with two doubly bonded oxygens, that is also bonded to a nitrogen atom (existing as a substituted amine) and an aniline group (Fig. ​(Fig.1a)

1a) in which R1/R2 may also be hydrogen, alkyl, aryl, or hetero aryl groups. An alternative means of describing the prototypical SN drug structure is an organic compound consisting of aniline derivatized with a sulfonamide group (Pareek et al. 2013; Sonu et al. 2017). The difference in the derivative structure of SN (Fig. ​(Fig.1a)

1a) between SMZ and SDZ (Fig. ​(Fig.1

1 b and c) lies in the extra dimethyl group that is present in the 4th and 6th carbon of the pyridine ring. The IUPAC name of SN is 4-aminobenzenesulfonamide, and the two derivative drugs are 4-amino-N-(4, 6-dimethylpyrimidin-2-yl) benzene sulphonamide for SMZ and 4-amino-N-(pyrimidin-2-yl) benzene-1-sulphonamide for SDZ respectively (Robertson et al. 2020; “Sulfamethazine and Its Sodium Salt” 2001).

There are a number of published methods for the synthesis of sulfonamides in different research papers (Naredla and Klumpp 2013; Shah et al. 2018) yet the most frequent and common method involves a reaction of aliphatic or aromatic sulfonyl chloride with ammonia which produces a greater yield as compared with that of other methods (Bahrami et al. 2009; Dominique Guianvarc’h et al. 2004). The initial compound for the sulphonamide synthesis is benzene which follows six more steps to procure the product. Benzene undergoes nitration to give nitrobenzene which is then reduced by the reducing agent tin and hydrochloric acid to give anilinium ion and is further converted to aniline using sodium hydroxide. Acetanilide produced via acetylation in the aqueous medium then reacts with chlorosulfonic acid to give 4-acetamidobenzenesulfonyl chloride. The intermediate thus formed gives 4-acetamidobenzene sulphonamide in the presence of ammonia. The final step of the synthesis involves hydrolysis in acidic medium to form 4-aminobenzenesulfonamide (sulphanilamide). The schematic representation for the synthesis of sulfonamide drug is shown in Fig. ​Fig.2

2 (Tacic et al. 2017). Further derivatives were synthesized using 4-acetamidobenzenesulfonyl chloride with 4,6-dimethylpyrimidin-2-amine (obtained from reacting pentane-2,4-diol with gaunidine) for SMZ (Lu and Rohani 2010; Ross and Plainfield 1968) and pyrimidine-2-amine (obtained from reacting malonaldehyde with gaunidine) for SDZ (Donizete et al. 2005; Ma et al. 2015; Shun-ichi Yamada et al. 1950) respectively, as shown in Fig. ​Fig.3

Sulphonamides are an important class of antibiotic drugs with a wide range of activity, being very effective against gram-positive and certain gram-negative bacteria (White and Cooper 2003). Some of the susceptible gram-negative bacteria include Klebsiella, Salmonella, Escherichia coli, and Enterobacter species; however, sulfonamides show no inhibitory activity (bacterial resistance) against Pseudomonas aeruginosa and Serratia species.(Lavanya 2017). Sulphonamides are utilized in the treatment of tonsillitis, septicemia, meningococcal meningitis, bacillary dysentery, and number of infections of urinary tract (Seneca 2015; Wiedemann et al. 2014). Sulfonamides also show inhibitory activity against some fungi (Pneumocystis carinii) and protozoa (Toxoplasma, Coccidia) (Chio et al. 1996; McFarland et al. 2016). There are many published reports showing antibacterial action by sulphonamide, sulfamethazine, and sulfadiazine drugs (Blanchard et al. 2016; Majewsky et al. 2014; Peng et al. 2015; Reddy et al. 2012; Tailor and Patel 2015; Ueda et al. 2020). SN and its derivatives showed pronounced antimicrobial activity when used against bacterial infections caused by Nocardia, Staphylococcus aureus and Escherichia coli (Genç et al. 2008b; Isik and Özdemir-Kocak 2009a). Increased antibacterial activity of the SN drug group was seen upon substitution with electron withdrawing groups such as the nitro group (Genç et al. 2008a; Isik and Özdemir-Kocak 2009b; Radha Mothilal and Thamaraichelvan 2016; Tailor and Patel 2015; Vagdevi 2018).

Mechanism and mode of action

Antibiotics are chemotherapeutic agents used to inhibit or kill bacteria. Sulphonamides are competitive antagonists and structural analogues of p-aminobenzoic acid (PABA) in the synthesis of folic acid which is essential for the further production of DNA in the bacteria (Zessel et al. 2014). Similarity between the structures (Fig. ​(Fig.5)

5) of SN and PABA allows SN to inhibit and replace PABA in the enzyme dihydropteroate synthetase (whose activity is important for the production of folate) and eventually inhibits the formation of dihydrofolate, tetrahydrofolate and also subsequently inhibits bacterial DNA growth and cell division or replication (Fig. ​(Fig.6)

6) (Pareek et al. 2013). SN drugs along with trimethoprim are used to prevent the synthesis of tetrahydrofolate which further stops DNA replication. The effects of the drug give rise to hindrances in cell division, making the SN drugs bacteriostatic rather than bactericidal (Bohni 1976; Nemeth et al. 2015; Wood and Austrain 1941).