9

CHAPTER-1

INTRODUCTION TO THE CHEMISTRY OF SULFONAMIDES

1.1 General:

A sulfonamide grouping is derived from a sulfonic acid group by

replacing its hydroxyl group with an amino group. Sulfonamides, also

known as sulfa drugs, have a history that dates back to almost 70-80

years. A sulfonyl group plays a very important role as a key

constituent of number of biologically active molecules [1&2].

Sulfonamides occupy a unique position in the drug industry and

exhibit a wide spectrum of biological activities [3&4].

The first clinically used sulfonamide was named prontosil I that

showed protective action against streptococci in mice [5]. Prontosil

was active in vivo, but ineffective in vitro, which led to the conclusion

that prontosil itself was not the active drug. When metabolized in the

body, prontosil produces sulfanilamide II, which is the real active

agent [5]. It acts by interfering with p-aminobenzoic acid utilization

by the infecting bacteria.

This discovery started great efforts in the investigation and

production of new sulfonamides. Several drugs containing

sulfonamide functionality are in clinical use which include

antibacterial and antifungal drugs [6&7], carbonic anhydrase

inhibitors [8-10], anti-inflammatory agents [11], anticonvulsant agents

10

[12] antimigraine agents [13], hypoglycemic, protease inhibitors [14]

and agents acting against diabetic mellitus [15]. They are also found

to have extensive applications in cancer chemotherapy [16]. Viagra, a

sulfa drug is one of the recent block bluster molecules used for

erectile dysfunction [17]. Some sulfonamides have proved to be useful

as herbicides [18] and fungicides [19]. Aryl sulfonyl substituted

derivatives have been used as protecting groups for oxygen and

nitrogen functionality [20]. Sulfonamide derivatives of azo dyes have

been reported to improve stability and lubrication [5].

1.2 Structure:

Sulfonamides are compounds, which have a general structure

represented by III. In this structure, R may be alkyl, aryl or hetero

aryl etc. R1, R2 may be hydrogen, alkyl, aryl or hetero aryl groups.

1.3 History of Sulfonamides:

In 1932, the German dye manufacturing company prepared a

red azo dye, named prontosil for its dye properties [21]. Remarkably, it

was discovered that prontosil showed antibacterial action when it was

used to dye wool. In 1935, Gerhard Domagk published the results of

his research work indicating that prontosil was capable of curing

staphylococcal infections in mice and rabbits [22]. In 1939, Domagk

earned nobel prize in medicine for this important discovery but an

11

order from Hitler prevented Domagk from accepting the honour [23].

After sulfanilamide discovery, thousands of chemical variations

were studied and the best therapeutic results were obtained from the

compounds in which one hydrogen of the SO2NH2 group was replaced

by heterocyclic ring [24]. To date more than twenty thousand

sulfanilamide derivatives, analogs and related compounds have been

synthesized. These synthesis have resulted in the discovery of new

compounds with varying pharmacological properties [24].

1.4 Classification of Sulfonamides:

The general term ‘’sulfonamides’’ has been used for derivatives

of p-aminobenzenesulfonamide (sulfanilamide), whereas specific

compounds are described as N1 or N4-substituted sulfanilamides,

depending on whether the substitution is on the sulfonamide amino

group or aromatic amino group, respectively.

Most of the sulfonamides used currently are N1-derivatives.

Based on the structural variations, Johnson [25] divided sulfonamides

into three groups as follows:

NI-acyl derivatives

NI-heterocyclic derivatives containing six-membered rings

(e.g. pyridine, pyrimidines, pyridazines and pyrazines).

NI-heterocyclic derivatives containing five-membered rings

(e.g. thiazole, oxazole, isoxazole, 1,3,4-thiadiazole and yrazole).

12

Another classification of sulfonamides is based on chemical

structure, duration of action, spectrum of activity and therapeutic

applications. The classification rate of absorption and half-life appears

to be clinically relevant. Based on this the sulfonamides are classified

into three groups [26]. 1. Short Acting. 2. Intermediate Acting. 3. Long

Acting.

1. Short Acting: sulfonamides with a half-life less than 10 hours.

(e.g. sulfamethazole, sulfisoxazole and sulfanilamide have been

used for the treatment of urinary tract infections).

2. Intermediate Acting: Sulfonamides with a half-life between 10-

24 hours. (e.g. sulfamethoxazole and sulfadiazine have been

used for various infections especially active against invasive

aspergillosis in AIDS patients).

3. Long Acting: Sulfonamides with a half-life longer than 24

hours. (e.g. Sulfadimethoxine and Sulfadioxine have been used

for the treatment of ulceration colitis).

In addition to this, there are different types of sulfonamides

which have been used in various types of infections [26] such as

mucous membrane, sulfabenzamide (V), superficial ocular

infections, sulfaacetamide sodium (VI), urinary infections,

sulfadiazine (VII) and sulfamethazole (VIII), anticancer and others.

13

1.5 SULFONAMIDES AS THERAPEUTIC AGENTS:

1.5.1 Antibacterial and antifungal:

Sulfonamides are a class of broad-spectrum synthetic

bacteriostatic agents. They inhibit multiplication of bacteria but do

not actively kill bacteria. They have been used against most gram-

positive and many gram-negative organisms, some fungi and certain

protozoa. A large number of substituted sulfonamide derivatives are

used in pharmaceutical preparations as antibacterial and antifungal

agents [27]. Some of the important sulfonamide derivatives, which

have commercial importance, are shown in Table-1.1.

Table-1.1: Some important sulfonamide derivatives used as

antibacterial and antifungal agents of commercial importance.

Drug name Therapeutic use Structure

Sulfamethoxazole

Bacteriostatic

antibiotic (Short-acting)

Sulfisomedine

Antibiotic

(Short-acting)

14

Sulfamethizole

Antibiotic (Short-acting)

Sulfadimidine

Antibacterial (Short-acting)

Sulfapyridine

Antibacterial (Short-acting)

Sulfafurazole

Antibiotic activity

against a wide range of Gram-

negative and

Gram-positive (Short-acting)

Sulfathiazole

Topical

antimicrobial (Short-acting)

Sulfadiazine Antibiotic

(Intermediate-

acting)

Sulfamoxole Antibacterial

15

1.5.2 Sulfonamides as carbonic anhydrase inhibitors:

Carbonic anhydrase is an enzyme that helps to regulate the acid-

base balance and pH in blood and other tissues. One of the functions

of the enzyme is to interconvert carbon dioxide and bicarbonate.

Carbonic anhydrase inhibitors are a class of pharmaceuticals that

suppress the activity of carbonic anhydrases. The clinical use has

been established as antiglucoma agents, diuretics, and antiepileptic in

the management of mountain sickness, gastric and duodenal ulcers,

neurological disorders or osteoporosis [28-30]. Some of the important

sulfonamide derivatives, which are of commercial importance, are

shown in Table-1.2.

Table-1.2: Some important sulfonamide derivatives used as

carbonic anhydrase inhibitors of commercial importance.

Drug name Therapeutic use Structure

Acetazolamide

CA Inhibitor

Methazolamide

CA Inhibitor

Dorzolamide Ophthalmological

Zonisamide Anticonvulsants

16

Topiramate

Anticonvulsants

Clopamide Diuretics

Furosemide Diuretics

Bumetanide Diuretics

Chlortalidone Diuretics

1.5.3 Sulfonamides as anticancer agents:

Anticancer drugs are used to control the growth of cancerous

cells. Cancer is commonly defined as the uncontrolled growth of cells,

with loss of differentiation and commonly with metastasis, spread of

the cancer to other tissues and organs. Cancers are malignant

growths. In contrast, benign growths remain encapsulated and grow

within a well-defined area. Benign tumors, if untreated may be fatal,

due to pressure on essential organs, as in the case of a benign brain

17

tumour. Surgery or radiations are the preferred method of treating

growth, which has a well defined location. Drug therapy is used when

the tumour is spread, or may spread to other areas of the body. Some

of the sulfonamides exhibit anticancer activity. A few examples are

given in Table 1.3.

Table-1.3: Some important sulfonamide derivatives used as

anticancer agents of commercial importance.

Drug name Therapeutic use Structure

Batabulin Anticancer

Pazopanib Anticancer

Tamsulosin Anticancer

ABT-751 Anticancer

E-7070 Anticancer

E-7820 Anticancer

18

1.5.4 Sulfonamides as Antiviral and Anti-HIV Agents:

Human immunodefficiency virus (HIV) has affected more than

36 million people world wide [31]. Some of the sulfonamides possess

activity against HIV protease. Ohtaka et. al. [32] showed that TMC-

126 displays 13-fold higher potency than that of amprenavir [32]. A

few examples of antiviral /anti HIV agents are given in Table 1.4.

Table-1.4: Some important sulfonamide derivatives used as anti-

HIV agents of commercial importance.

Drug name Therapeutic use Structure

Darunavir HIV infection

Protease inhibitor

Tipranavir HIV infection Protease inhibitor

class

Amprenavir Anti-HIV

19

TMC-126 Anti-HIV

PNU-103017 Anti-HIV

1.5.5 Sulfonamides as COX-2 specific inhibitors:

Traditional COX-2 inhibitors such as ibuprofen are known to

have low selectivity and hence may induce ulcer, bleeding and

gastroduodenal erosion. COX-2 selective inhibitor is a non-steroidal

anti-inflammatory drug (NSAID) that directly targets COX-2, an

enzyme responsible for inflammation and pain. However, a specific

COX-2 inhibitor reduces undesirable side effects [33]. Some of the

sulfonamide derivatives act as COX-2 inhibitors, for example

Celecoxib and Valedecoxib, which were developed by Pfizer, as COX-2

specific inhibitors for the treatment of osteo-arthritis and rheumatiod

arthritis [34&35]. Some of the COX-2 inhibitors are given in table 1.5.

20

Table-1.5: Some important sulfonamide derivatives used as Non-

steroidal anti-inflammatory agents of commercial importance.

Drug name Therapeutic use Structure

Celecoxib Non-steroidal

anti-inflammatory

Valdecoxib Non-steroidal

anti-inflammatory

Parecoxib Non-steroidal

anti-inflammatory

1.5.6 Sulfonamides as anti-migraine agents:

An antimigraine drug is a medication intended to reduce the

effects or intensity of migraine headache. Examples are the triptans.

Triptans are a new class of compounds developed for the treatment of

migraine attacks [36]. The first one of this class is sumatriptan. The

newer triptans are zolmitriptan, naratriptan, avitriptan, almotriptan

and frovatriptan which display high antogonist activity mainly at the

serotonin 5-HT1B and 5-HT1D receptor subtypes. Some of the

21

sulfonamide derivatives act as antimigraine agents. A few examples

are given in Table 1.6.

Table-1.6: Some important sulfonamide derivatives used as anti-

migraine agents of commercial importance.

Drug name Therapeutic use Structure

Sumatriptan

Migraine

headaches

Avitriptan

Migraine

headaches

Almotriptan

Migraine

headaches

Naratriptan Migraine headaches

1.5.7 Sulfonamides as Male Erectile Dysfunction:

Erectile dysfunction is defined as the consistent inability to

maintain an erect penis. Many factors can contribute to the on set of

ED [37]. This problem may be due to physical or psychological causes

may be stress, performance anxiety etc. A large number of

sulfonamides have been used as therapeutic cure for this problem. A

very well known recent example is sildenafil citrate salt which is

22

marketed widely with brand name viagra by Pfizer group. A few

examples are given in Table 1.7.

Table-1.7: Some important sulfonamide derivatives used as

curative agents for male erectile dysfunction of commercial

importance.

Drug name Therapeutic use Structure

Sildenafil Male Erectile Dysfunction

Vardenafil Male Erectile

Dysfunction

Acetildenafil Male Erectile

Dysfunction

Sulfoaildenafil Male Erectile

Dysfunction

23

1.5.8 Sulfonamides as Antimalarial Agents:

Malaria is one of the most infectious epidemic diseases caused

by protozoa parasites on the genus falciparum. Approximately 500

million people world wide are known to be suffering with this disease

every year causing 2.5 million deaths, mainly children in African

countries [38]. A few examples of anti malarial sulfonamides are given

below.

Table-1.8: Some important sulfonamide derivatives having anti

malarial properties of commercial importance.

Drug name Therapeutic use Structure

Sulfadoxine Antimalarial

Sulfamethoxy

pyridazine

Antimalarial

1.5.9 Sulfonamides as anti-diabetic Agents:

Anti-diabetic medications treat diabetes mellitus by lowering

glucose levels in the blood. With the exception of insulin exenatide

and pramlintide, all are administered orally and are thus also called

oral hypoglycemic agents or oral antihyperglycemic agents. There are

different classes of anti-diabetic drugs and their selection depends on

the nature of the diabetes, age and situation of the person as well as

other factors.

24

Diabetes mellitus type 1 is a disease caused by the lack of

insulin. Insulin must be used in Type I which must be injected.

Diabetes mellitus type 2 is a disease of insulin resistance by

cells. Treatments include (1) agents which increase the amount of

insulin secreted by the pancreas, (2) agents which increase the

sensitivity of target organs to insulin, and (3) agents which decrease

the rate at which glucose is absorbed from the gastrointestinal tract.

Table-1.9. Some important sulfonamide derivatives used as

antidiabatic agents of commercial importance.

Drug name Therapeutic use Structure

Glimepiride

Antidiabatic drug

Gliclazide Antidiabatic drug

Tolbutamide Antidiabatic drug

Tolazamide Antidiabatic drug

Acetohexam

ide Antidiabatic drug

25

Gliquidone Antidiabatic drug

Glipizide Antidiabatic drug

1.6. SYNTHESIS OF SULFONAMIDE DERIVATIVES:

Due to the broad applicability of sulfonamides, a wide variety of

methods have been reported in literature for the preparation of

sulfonamides [39&40]. Some of the most common and recent methods

are illustrated briefly below.

1.6.1 Sulfonamides from sulfonylchlorides and sulfonic acids:

A general method for the synthesis of sulfonamides involves the

coupling of sulfonyl chloride with primary or secondary amine or a

substituted amine. Sulfonyl chlorides can be prepared from the

corresponding sulfonic or sulfinic acid by reaction with SOCl2, PCl5 or

POCl3, or by bubbling of chlorine gas through thiols in aqueous acid

[41-45].

…………….. Scheme – 1.1

Rad et. al. [46] developed a mild and efficient method for the

synthesis of sulfonamides. The reaction of amine sulfonate salt (XI)

with cyanuric chloride, using triethylamine as base and anhydrous

26

acetonitrile as solvent at room temperature gives the corresponding

sulfonamide (XII) in good to excellent yields.

…………….. Scheme – 1.2

Kataoka et. al. [47] prepared the alkyl and aryl sulfonamides

(XIV) by treatment of corresponding sodium sulfonates (XIII) with

triphenylphosphine dibromide followed by reaction with amines.

…………….. Scheme – 1.3

Chavastri et. al. [48] prepared sulfonamides (XV) using

trichloroacetonitrile-triphenylphosphine complex from sulfonic acid

(IX) in dichloro methane solvent and achieved optimum yield when

(Cl3CCN:PPh3: sulfonic acid) is used in the ratio 3:3:1.

…………….. Scheme – 1.4

Luca et. al. [49] reported an easy method for the synthesis of

sulfonamides (XVI) in good yields from sulfonic acids (IX) by

27

performing the reaction of sulfonylchlorides, generated, in situ with

amines under microwave irradiation.

…………….. Scheme – 1.5

Wright et. al. [50] reported a method for the formation of

sulfonamide (XVIII) from thiols (XVII). Oxidation of a thiol using

sodium hypochlorite resulted in the sulfonyl chloride, which on

treatment with benzylamine gave the sulfonamide.

…………….. Scheme – 1.6

Bonk. et. al. [51] prepared sulfonamides (XIX) from thiols (XVII).

Thus, thiol was converted into sulfonylchloride using trichloro

cyanuric acid (TCCA) and benzyltrimethylammonium chloride in water

and acetonitrile, which on further reaction with amine gave the

corresponding sulfonamide.

…………….. Scheme – 1.7

28

Bahrani et. al. [52] reported the direct oxidative conversion of

thiol (XVII) derivatives into the corresponding sulfonyl chlorides

through oxidative chlorination using combination of H2O2 and SOCl2.

This on reaction with amines, the corresponding sulfonamides (XX)

were obtained in excellent yields.

…………….. Scheme – 1.8

Barrett et. al. [53] reported the reaction of sulphur dioxide with

various organometallic reagents (XXI) to give sulfinic acid salts, which

can be directly treated with sulfuryl chloride and amine to furnish

sulfonamides (XXII) in good yields.

…………….. Scheme – 1.9

Zaho. et. al. [54] reported the Zn/CuI-mediated coupling of alkyl

halides (XXI) with vinyl sulfonamide (XXIII) in formamide (XXIV) as

solvent to obtain sulfonamide in high yields.

…………….. Scheme – 1.10

29

Huntress et. al. [55] reported chlorosulfonation of arene (XXV) to

give sulfonyl chloride and subsequent reaction with an amine affords

aryl sulfonamides (XXVI).

…………….. Scheme – 1.11

Benzyl chloride (XXVII), on reaction with thiourea, gave S-

benzylthiouronium chloride salt (XXVIII) [56]. This, on treatment with

chlorine gas, gave the sulfonyl chloride which was converted into

sulfonamide (XXIX) by treating with ammonia.

…………….. Scheme – 1.12

1.6.2 Sulfonamides from sulfenamides:

Another innovative example of sulfonamides synthesis was

illustrated in the synthesis of 6-uracilsulfonamide by Greenbaum et.

al. [57]. In this method, 2,4-dimethoxy-6-pyrimidinesulfenamide

(XXX) was oxidized to 2,4-dimethoxy-6-pyrimidinesulfonamide (XXXI)

using KMnO4 in 64% yield.

30

…………….. Scheme – 1.13

Schwam et. al. [58] also used a similar methodology for the

synthesis of 6-ethoxybenzothiazole-2-sulfonamide (XXXIII) as

potential carbonic anhydrase inhibitor in 80% yield. In this synthesis

6-ethoxy-2-benzothiazolesulfenamide (XXXII) was oxidized to get 6-

ethoxy-2-benzothiazolesulfonamide.

…………….. Scheme – 1.14

Revankar et. al. [59-62] reported the oxidation of 2-amino-9H-

purin-6-sulfenamide (XXXIV) into 2-amino-9H-purin-6-sulfonamide

(XXXV) using one equivalent of m-CPBA in 48% yield.

…………….. Scheme – 1.15

1.6.3 Sulfonamides by N-arylation:

Cao et. al. [63] reported the palladium catalysed N-arylation of

sulfonamide under microwave irradiation. Thus, 4-chloroquinoline

31

(XXXVI) reacted with benzenemethanesulfonamide (XXXVII) in the

presence of Cs2CO3 palladium catalyst in 1,4-dioxane to give 1-phenyl-

N-(quinolin-4-yl)methanesulfonamide (XXXVIII).

…………….. Scheme – 1.16

Lam et. al. [64] described an effective method for N-arylation on

sulfonamide (XXXIX) using cupric acetate and arylboronic acid

(XXXX) to get N-arylsulfonamide (XXXXI).

…………….. Scheme – 1.17

Kunz et. al. reported [65] copper-catalyzed synthesis of aryl

sulfonamides under microwave irradiation using potassium carbonate

at 195 OC.

…………….. Scheme – 1.18

Guo et. al. [66] reported the synthesis of sulfonamides (XXXXVII)

using copper (I) catalyzed coupling with aryl bromide (XXXXV) and

32

substituted sulfonamide (XXXXVI) in the presence of a ligand and

K3PO4 as base in DMF solvent.

…………….. Scheme – 1.19

1.6.4 Miscellaneous methods

Gupta and co-workers reported [67] one step synthesis of

sulfonamide (L) with aluminium chloride in toluene.

…………….. Scheme – 1.20

Katritzky et. al. [68] reported a new method for the synthesis of

N-acylsulfonamides (LIII) from N-acylbenzotriazoles (LI) using of

sodium hydride.

…………….. Scheme – 1.21

Gaby et. al. [69] reported that the reaction of 4-sulfonamido aryl

isothiocyanate derivative (LIV) with aminothiophenol (LV) under reflux

condition in DMF and triethyl amine to yield benzothizole sulfonamide

(LVI) derivative.

33

…………….. Scheme – 1.22

1.7. Applications of sulfonamides in Organic Chemistry:

Sulfonamides have been used in the field of synthetic organic

chemistry. Some of these methods are discussed below.

1.7.1 Synthesis of secondary Amines:

Kan et. al. [70] reported an efficient synthetic method for the

preparation of secondary amines using sulfonamides. In this method,

primary amine (LVII) was reacted with nitrobenzene sulfonyl chloride

(LVIII) to give the corresponding sulfonamide (LIX), which on

alkylation with appropriate alkyl halide, followed by deprotection gave

the secondary amine (LXI).

…………….. Scheme – 1.23

1.7.2 Synthesis of Isothiourea:

Reaction of p-toluenesulfonamide (LXII) with phenyl isothi

ocyanate (LXIII) and subsequent alkylation with ethyl bromoacetate

form S-ethoxycarbonylmethyliso-thiourea (LXIV) [71].

34

…………….. Scheme – 1.24

1.7.3 Enantioselective Reduction of α-Ketoesters to 1,2-Diols:

Wang et. al. [72] reported that various -ketoesters (LXV) have

been reduced to the corresponding 1,2-diols (LXVI) in high

enantioselectivity using the NaBH4/Me3SiCl system and polymer-

supported chiral sulfonamide.

…………….. Scheme – 1.25

1.7.4 Synthesis of New strongly acidic Catalytic Material:

Strongly acidic material was synthesized by Koppel et. al. [73] by

stepwise replacement of oxygen moieties by =NSO2CF3 groups in p-

toluene sulfonamide by reacting with (CF3SO2)2 CH2.

…………….. Scheme – 1.26

35

1.7.5 Novel Terminators of cationic cyclizations:

Sulfonamide group has been used as terminator of cationic

cyclization the formation of pyrrolidines in the presence of

trifluoromethanesulfonic acid [74].

…………….. Scheme – 1.27

1.7.6 Synthesis of pyrrolidines:

Jones and co-workers [75] synthesized trans-2,5-disubstituted-3-

iodopyrrolidines from 5-endo-tring iodocyclization of the (E)-homolytic

sulfonamides in excellent yield.

…………….. Scheme – 1.28

1.7.7 Synthesis of N,N-Dialkylsulfonamides under microwave

irradiation:

Zare et. al. [76] reported the Aza-Michael addition of

sulfonamides in to α, β-unsaturated ester in the presence of catalytic

amount of NaOH and tetrabutylammonium bromide (TBAB) under

micro wave irradiation to afford N,N-dialkyl sulfonamides.

36

…………….. Scheme – 1.29

1.7.8 Synthesis of Sulfonamide Chiral Ligands:

Balsells et. al. [77] prepared new class of sulfonamide chiral

ligands. These ligands are prepared from trans 1,2-

diaminocyclohexane by reaction with sulfonyl chlorides to give

aminosulfonamide compounds. These compounds are condensed with

salicylaldehyde derivatives to provide a sulfonamide Schiff bases

compound which represents a new class of chiral ligands.

…………….. Scheme – 1.30