1.1. introduction s - inflibnetshodhganga.inflibnet.ac.in/bitstream/10603/70190/10/10_chapter...

Synthesis and Characterization of Pharmaceutically Important Nitrogen Containing Heterocycles

1.1. Introduction

ulfa drugs were the first ever synthetic chemical compounds which were scientifically

used for the cure and prevention of bacterial infections in human beings.1

It has been

estimated that 16-21% of annual antibiotic usage, making sulfonamide as the most

important group of antibiotics consumed by human being.

In 1932 German bacteriologist and pathologist Gerhard Domagk first observed

antibacterial effect of sulfonamide, he studied the effect of Prontosil on Streptococcus

infection in mice. Later French researchers proved the active agents which are responsible

for this activity is due to para-aminobenzenoic acid a metabolic product released by

Prontosil. By 1940s sulfonamides were widely used as drugs all over the world, sulfa

drugs became standard in first-aid kits during World War II for treating open wounds and

intestinal infections.

Compounds containing sulfonamide group as part of their molecular structures are known

as sulfa drug. Upon close observations it has been revealed that compounds containing

sulfonyl group attached directly to benzene ring and NH2 group at para position of the

same benzene ring are necessarily the most important structural features of the

sulfonamides to exhibit antibacterial activity. Most of these sulfa drugs are insoluble in

water, but their sodium salts are easily soluble in water. Many sulfanilamide derivatives

were used as Sulfa drugs, such as Sulfathiazole (against bacterial infections), Sulfadiazine

(against urinary tract and intestinal tract infections) and Sulfamethazine (against urinary

tract infections).1

The sulfonamides in particular are inhibitors of folic acid synthesis in the living system

which assists in the thriving condition for bacteria. Interestingly, when the mechanism of

action of the sulfa drugs is studied it is known that they are competitive inhibitors of

dihydropteroate synthase enzyme which is a bacterial enzyme responsible for the merging

of p-aminobenzoic acid (PABA) (1) into dihydropteroic acid an immediate precursor of

folic acid. For humans and higher animals folic acid is a part of diet but for most of the

bacteria folic acid (2) is produced in their metabolism from simpler starting materials.

Thus, growth inhibition of invading microorganisms can be carried out by sulfa drugs

without harming the host.

S


It can be justified that these sulfonamide derivatives have been serving their greatest

purpose in the treatment of human health problems, upon certain specific organisms.

Folic acid is synthesized by bacteria using many enzymes, in particular dihydropteroate

synthetase which in turn facilitates the attachment of p-aminobenzoic acid to a pteridine

ring system. Because of bacteriostatic (chemical agents that slow or stop bacteria from

reproducing, but not killing them completely) nature of sulfonamide, they will compete

with the p-aminobenzoic acid for the active site on the enzyme and bacteria starves to

death as they are unable to distinguish between p-aminobenzoic acid and

p-aminobenzene sulfonamide.2

Hence sulfa drugs are known as bacteriostatic drugs rather than bactericidal drugs i.e.3

1. They act by slowing the growth of the bacteria rather than by killing them completely.

2. They cause no potentiation or inhibition of immunologic responses nor the phagocytic

mechanisms of the host.

3. They have no effect which could be interpreted as concerned with the neutralization of

bacterial toxins. Particularly sulfa drugs interfere with the synthesis of one of the

vitamin B complex members (folic acid) present in all living cells.


All though sulfa drugs were relatively safe to use, skin rashes, fever, nausea, vomiting

and even mental confusion were the common side effects gone through by the patients.

The resistant developed by the bacterial strains and accumulation of sulfa drugs in

inflamed tissue and skin which gets retained in the tissue for long periods after

medication has been stopped, was the main drawback. In present decades increased drug

resistance by the bacterial strains, development of new more effective and less toxic

antibiotics many of the sulfa drugs lost their significance as antibiotics. Resistance

developed against sulfonamide by bacterias are probably is the consequence of an altered

enzymatic organization of the bacterial cell; the alteration may be due to, less affinity of

dihydropteroate synthase for sulfonamides, decreased bacterial active efflux of the drug

or permeability, alternative metabolic route for the synthesis of an essential metabolite or

increase in production of an essential metabolite or counter metabolites for drugs.

But, sulfa drugs are still used profusely in treating urinary tract infections, prevention of

infections of burns and also in the treatment of certain forms of malaria. Many sulfa drugs

are prescribed in combination with certain antibiotics which can be used to treat variety of

health conditions. Sulfa drugs are being synthesized to act according to the mode of

action from past to present day, which is to compete with the essential metabolite of the

bacteria in its reproduction. From this point of view, research is done in recent decades by

keeping the future of chemotherapy in view, chemist have been designing, synthesizing

and testing their sulfonamides to get an ideal sulfa drug which can counter act all

bacterial infectious diseases with less toxicity and minimized or no side effects.

A note on preparation and thermal properties of some piperazine polysulfoamides was

published by Robert C Evers and Gerhard F. L. Ehlers4 in view of finding information

regarding the thermal properties. The polymer (3) (4) (5) and (6) (Polysulfonamides)

synthesized were of low molecular weight. Aromatic piperazine sulfonamides were

subjected to softening range determinations by using Themogravimetric Analysis (TGA)

and Differential Thermal Analysis (DTA) successfully. Polysulfonamides were

appreciably less stable than the aromatic piperazine polyamides represent earlier.

(3)


(4) (5)

(6)

In search of antipsychotic agents free from extrapyramidal side effects James F. Muren et

al.,5 synthesized a series of 9-[3-(1-piperazinyl)propyl)]thioxanmides (7). Synthesis of

molecules was done to identify the efficient central depressant activity of thioproperazine

which is retained in thioxanthene analog and secondly to estimate structural orientation at

the side chain nitrogen and sulfonamide nitrogen atom. Two synthetic routes were

employed for the synthesis of target molecules, both the synthetic routes involves

sulfonation and alkylation of thioxanthene as important steps. The sulfonated

thioxanthene derivatives were treated with different amines and followed by addition of

1-bromo-3-chloropropane to yield important intermediate which was further treated with

substituted piperazine. All the synthesized compounds were evaluated for their ability to

depress non discriminated avoidance behavior in rats, antagonize tremors and catalepsy in

monkeys. Out of tested series, first compound of the series with methyl and secondary

anime group showed potent biological activity.

.

(7)

R = CH3, (CH2)2OH, CH2(CH2)2OH, SO2CH3, SO2N(CH3)2;

R1 = N(CH3)2, NH2, NHCH3


In continuation of the search for thioxanthene sulfonamides having piperazine moiety as a

psychopharmacological agent James F. Muren et al.,6 synthesized the target molecules in

three different synthetic routes. In every case isomers were obtained in which cis-isomer

proved to be more efficient than the trans-isomers of the title compounds. Selected

derivatives were tested for their antipsychotic activity in mice and disrupt conditioned

avoidance behavior in rats. Out of all the selected compounds, compound (8) and (9)

exhibited greater activity than standard compound chlorpromazine.

(8) (9)

R = CH2CH2OH, CH2CH2CONHCH3

Marie Jasephe Brienne et al.,7 in search of new antifilarial agents, reported the synthesis

of a number of novel epoxisulfonamides (10) and ethylenesulfonamides (11) with

piperazine and many secondary and primary amines as part of the molecular structure.

Synthetic strategy involved epoxidation, sulfonation, rearrangement reactions and

chloramine coupling to yield final compounds. Some of the synthesized compounds

showed moderate antifilarial activity against Molinema dessetae and Proechimys oris

small Brazilian rodents.

(10) (11)

R = CH3, C6H5, 4-Cl-C6H4, 3,4-Cl2-C6H3, 2-CH3-C6H4, 3-CH3-C6H4, 4-CH3-C6H4,

4-NO2-C6H4; R1 = N(CH3)2, Morpholine, N-methylpiperazine, N-propylpiperazine,

N-phenylpiperazine, N-CO2Et-Piperazine, Pyrrolidine, N-(3-CF3-C6H5)piperazine

An attempt to discover effective antitumor drugs, particularly against refractory solid

tumors was reported in editorial communication by Hiroshin Yoshino et al.,8 Because of

difficulty faced when testing for antitumor activity using in vivo studies on murine


leukemia‘s for solid tumors. They synthesized a series of N-(2-anilino-3-pyridyl)benzene

sulfonamide (12) analogs which were synthesized via chloramine coupling, reduction and

followed by treating the intermediate obtained with appropriate sulfonyl chlorides. Out of

the compounds tested, one compound (R = OCH3, X = N and Y = COH) showed

substantial in vitro antiproliferative activity.

(12)

R = CH3, OCH3; X = CH, N; Y = COH, CH, COCH3, N

Timonthy F. Herpin et al.,9 synthesized piperazine-2-carboxamide derivatives (13) and

(14) by two novel general solid phase routes which involved solution and solid phase

chemistry in view of discovering lead libraries. The objective was to maximize the

coverage of chemical space using limited number of compounds while keeping the

physical properties of the compounds same as typical range of orally prescribed

compounds. 15000 single compounds were produced using IRORI directed sorting

technique

(13) (14)

R = 1-(3-aminopropyl)pyrrolidin-2-one, 3-(1H-imidazol-1-yl)propan-1-amine, N,N-

dimethylpyrrolidin-3-amine, 2-(piperidin-1-yl)ethanamine, Pyridin-3-ylmethanamine,

R2 and R

3 = 2-BrCH2COOH, 2-(4-(bromomethyl)phenyl)acetic acid, 1-(2-

chloroacetyl)pyrrolidine-2-carboxylic acid, 2-Br-1-(piperazin-1-yl)ethanone

I. P. Shveduite et al.,10

synthesized a new series of arylsulfonyl derivatives of piperazine-

2,6-dione and studied their anti-inflammatory activity. Coupling of sulfonyl chloride and

piperazine-2,6-dione hydrochloride was done by heating in presence of pyrimidine,


followed by addition of appropriate sulfonyl chloride to obtain 4-sulfonyl substituted

derivatives of piperazine-2,6-dione (15). All the piperazine-2,6-dione derivatives were

evaluated for their anti-inflammatory activity on carrageenan and bentonite induced foot

edema in rat models. Introduction of methyl group to phenyl ring or replacing phenyl ring

with naphthalene ring showed remarkable increase in the anti-inflammatory activity of

the target molecules.

(15)

R = C6H5, 4-CH3C6H5, 4-NO2CH3C6H4, 3-NO2CH3C6H4, 4-CH3NHC6H4, 2-naphthyl

In effort to discover new generation of cyclic matrix metalloproteinase (MMP5)

inhibitors Biswanath De et al.,11

designed and synthesized sulfonyl piperazine based

MMP inhibitors. Synthesis was started by Boc protection of dl-piperazine carboxylic

acid, followed by reacting with p-methoxybenzenesulfonyl chloride and subsequently

deprotection of Boc group using thionyl chloride in presence methanol. Product obtained

was treated with sulfonyl chlorides, alkyl halides, isocyanates and acyl halides to obtain

methyl esters of sulfonyl piperazine derivatives. Further methyl ester was treated with

hydroxyl amine in presence of alcoholic potassium hydroxide to obtain target hydroxamic

acid of bissulfonyl piperazine derivatives (16). All the compounds were tested for

antagonistic activity against matrix metalloproteinase protein, showed moderate

antagonistic activity.

(16)

R = H, CH3, C6H5, CH2CH2 CH2CH3, CH2OC6H5, SO2CH3, SO2(4-OCH3)C6H4,

3,5-dimethylisoxazole-4-sulfonyl, 2-amino-4-methylthiazole-5-sulfonyl


S. McCombie et al.,12

designed and synthesized acylsulfonyl piperazine scaffolds in view

of optimizing their structure and activity relationship, selectively on M2-Muscarinic

receptor. In the synthesis of 1-[4-(4-arylsulfonyl)phenylmethyl-4-(1-aryl-4-

piperidenyl)]piperazine derivatives (17), diketopiperazine was the key intermediate which

was treated with substituted arylsulfoanyls and acid chlorides and also different synthetic

route were adopted for synthesis has been reported here. All the aryl sulfonyl derivatives

were evaluated for their receptor binding and selectivity. There was no considerable

increase in affinity was observed compared with standard.

(17)

R = Cyclo-C3H5, C6H5, 3,4-Cl2C6H3, 2,4-Cl2C6H3, 2-ClC6H4, 2-CH3C6H4, 2-OCH3C6H4,

2-NH2C6H4, 2-AcNHC6H4, 2-HOC6H4, 2-OC6H4-C6H4; R1 = R

2 = R

3 = R

4 = H, OCH3

A new series of 2-(R)-methyl piperazine was synthesized via non-racemic route under

Suzuki‘s reaction condition by J. A. Kozlowski et al.,.13

Oxidation of sulfide to sulfone

using m-CPBA followed by Corey‘s enantioselective reduction, mesylation, Boc

protection, deprotection and finally by Fukuyama‘s conditions gave rise to free piperazine

which upon substitution with appropriate alkyl substituents gave final compounds (18) in

good yield. All the synthesized compounds tested for binding affinities on cloned human

muscarinic receptors in comparison with compound (19). One of the compounds with

sulfonyl ethyl group (20) was identified as the potent muscarinic M2 receptors selective

ligand.

(18) (19)


(20)

R = H, CN, (S)-CH3, CH3, (R)-CH3; R1 = R

2 = H, (R)-CH3, (S)-CH3.

J. I. Levin et al.,14

successfully synthesized and explored the structural and relativity

potential of a sulfonamides hydroxamate bearing novel acetylenic P1‘ groups as TNF-α

converting enzyme (TACE). One of the compound of the series bearing butoxy Pl‘

moiety (21) had shown excellent in vitro potential against the isolated TACE enzyme and

in cells. It has also exhibited good selectivity over MMP-1 and oral activity in an in vivo

model of TNF- α production.

(21)

A Ryckebush et al.,15

in search of better anti-malarial drugs for treating multidrug

resistant Plasmodium falciparum, synthesized a library of 31 sulfonamides (22).

Synthesis was carried out by solution phase method involving 4,7-dichloroquinoline as

starting material to synthesize amine which was reacted with various sulfonyl chlorides to

get the desired product. All the synthesized compounds were tested for their inhibition

against chloroquinine resistant strain; compounds with halo substitution were proved to

be potent inhibitors.

(22)

R = p-FC6H5, p-ClC6H5, p-OCF3C6H5, 4,5-Cl2-Thiophen-2-yl,

4,5-Br2-Thiophen-2-yl, 5-Br-2-OCH3C6H4


M. A. Letavic et al.,16

synthesized a new series of sulfonyl piperazine 2-hydroxamic acid

derivatives which are dual TACE/MMP-13 inhibitors. Synthesis involved the t-butyl

crotonate as starting material, which upon hydroxylation gave aminoalcohol. It was

mesylated by treating it with methanesulfonyl chloride, subsequent cyclization yielded

aziridine sulfonamide, which was treated with PPh3/DEAD to get piperazine sulfonamide.

Further it was converted to the corresponding piperazine hydroxamic acid by treating

with appropriate electrophiles. All the synthesized compounds (23) were tested for their

in vivo TACE/MMP-1 and MMP-13 inhibition property. Most of the members of the

series showed moderate in vivo activity. Sulfonyl piperazine based hydroxamic acids

showed dual TACE/MMP-13 inhibitor potency with potent TNF activity in human whole

blood.

(23)

R = H, Me, AcO, MeSO2, 4-MePhSO2, PhCH2, PhNHCO, i-PrNHCO, EtOCO

R1 = Ph, 2-MePH, 2-EtPh, 3,5-FPh, 4-FPh, 2-Me, 5-FPh, 2CF3Ph, 3-(2-Me)-Pyridyl

A series of potent and selective MC4 receptor agonists were reported by B Dyck et al.,17

.

They successfully, incorporated phenyl piperazine structure into a known MC4 specific

dipeptoid consensus sequence. Structure and activity relationship study of all the series of

compounds using in vitro cAMP functional assays in cells, transferred with the MC4

receptors was carried out. All the tested compounds were proven to be potent agonists but

some compounds (24) showed moderate potency than the others.

(24)

R = D-Tic-D-(p-Cl)-Ph;

R1 =


H. S. Patel et al.,18

reported the synthesis and antimicrobial activity of piperazine

sulfonamides to discover new potent antibacterial agents. Sodium salt of substituted

phenol was reacted with 4-acetamidobenzene sulfonyl chloride, followed by acid

hydrolysis gave a primary amine as adduct which reacts with chloroacetyl chloride in

chloroform to get N-chloroacetyl derivatives, further it was treated with N-phenyl

piperazine to obtain the title compounds in good yield (25). All the piperazine

sulfonamides were screened for their antibacterial activity against Bacillus subtilis,

Staphylococcus aureus, Salmonella typhi, Escherichia coli bacterial strains. Some of the

derivatives substituted with nitro, chloro and bromo groups were proved to be good

antibacterial agents.

(25)

R = H, Cl, Br; R1 = H, Br; R

2 = H, CH3, NO2, Cl, Br

Erik S. Vermeulen et al.,19

in order to discover novel 5-HT7 receptor inverse agonists,

synthesized aryl piperazine and 1,2,3,4-tetrahydroisoquinoline based aryl sulfonamides.

Substituted aryl sulfonyl amides were synthesized in three steps, first addition of

bromoacetonitrile to 1,2,3,4-tetrahydroisoquinoline (6-CH3O-THIQ) or 2-methoxy

piperazine (2-MPP) followed the conversion of nitrile group to amine and further treating

it with different sulfonyl chloride to yield the substituted sulfonamides (26). Evaluation of

the compounds interactions with the 5-HT7 receptor was done for all the synthesized

compounds, N-ethyl substituted sulfonamides showed good agonistic activity.


Computational studies were done on the basis of results obtained using molecular docking

using 5-HT7 receptor protein.

(26)

R = C6H5, 4-CH3-C6H4, 4-OCH3-C6H4, 1-naphthyl;

R1 = 2-MPP, 6-OCH3-THIQ; R

2 = H, C2H5: n = 2, 3

N-(6-chloronaphthalen-2-yl)sulfonylpiperazine derivatives (27) were synthesized and

evaluated for their potency as S4 binding element by Noriyasu Haginya et al.,20

synthetic

route involved β-sulfonation and chlorination of 2-chloronapthalene to give intermediate

sulfonyl chloride which was further treated with tert-butyl-1-piperazine carboxylate,

resulting compound was condensed with various carboxylic acids to get target molecules.

S4 binding studies were carried out on all the compounds to identify the anti-fXa agent.

One compound 4-(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carbonyl)-1-

(naphthalen-2-ylsulfonyl)piperazine-2-carboxamide was orally potent anti-fXa activity

and activity was also confirmed by X-ray crystal study.

(27)

R = H, COC2H5, CONH2;

.R1 =


In view of developing antitumor agents that block intercellular protein kinase B/AKt

activation, Ching-Shih Chen et al.,21

developed novel antitumor agents. They replaced

(2,3-dihydro-benzoyl[1,4]dioxane)carbonyl group with aryl sulfonyl functional groups

which resulted in increase in the efficiency in functions AKt deactivation and piperazine

sulfonamide derivatives (28) apoptosis. All the compounds were tested for their ability to

induce apoptotic action in human androgen prostate tumor cancer cells. Two compounds

were very effective in inducing apoptosis in their lowest of concentrations compared to

all the compounds tested.

(28)

R = 4-Cl-C6H4, 4-Br-C6H4, 4-I-C6H4, 4-NO2-C6H4, 2-NO2-C6H4, 4-CH3-C6H4, 4-CF3-

C6H4, 4-OCH3-C6H4, 4-tert-but-C6H4, 4-carbonyl-C6H4, 4-carboxyl-C6H4, 2,5-diCl-C6H3,

2,4-diNH2-C6H3, 2-carboxyl-4-Cl-5-F-C6H2, 3-carbonyl-4,6-diCl-C6H2, 5-Cl-thienyl,

C. Fotsch et al.,22

synthesized substituted aryl sulfonamides containing piperazine as part

of their structure in search of Melanocortin subtype-4 (MC4R) agonists an G-protein

coupled receptor which regulates feeding behavior in rodents. Compounds for this study

were derived from sulfonation of phenyl piperazine followed by N-alkylation of

sulfonamide and deprotonation to give an important intermediate compound (29). Which

was further treated with Boc protected amino acids, carboxylic acids, ketones and

aldehydes to obtain probable MC4R agonists compounds (30) (31) and (32) out of which

of compound (30) proved to possess potent activity as MC4R agonists.

(29) (30)


(31) (32)

R = CH3, Bn, Ph; R1 = H, CH3, CH2Cyclopropyl, (CH2)2NH2, (CH2)2CH3;

R2 = CH3, C2H5, tert-Amyl, Cyclohexyl; X, Y, Z = N, CH2, n = 0 or 1

Prakesh G. Jagtap et al.,23

discovered a series of potent poly(ADP-ribose)polymerase-1

(PARP-1) inhibitors by modifying Indeno[1,2-c]isoquinolinone core, which has been

proven to possess polymerase-1 inhibiting ability. Novel Indeno[1,2-c]isoquinolinone

derivatives (33) were synthesized using multiple synthetic routs involving Schotten-

Baumann acylation, nitration and amination. Sulfonamide derivatives of Indeno[1,2-

c]isoquinolinone synthesized using chlorosulfonic acid was further treated with

appropriate amines. All the derivatives of Indeno[1,2-c]isoquinolinone were screened for

potent activity as PARP-1 inhibitors and considerable activity was observed in all the

molecules.

(33)

R = H, F, NO2, NH2, N(CH3), Morpholine, N-Methylpiperazine;

R1 = H, F, NO2, NH2, N(CH3), OCH3, Morpholine, 4-F-Phenylpiperazine, Pyrazole,

Morphline, 3-methylpiperidine,N-propyl amine

M Lee et al.,24

in search of new template for 5-HT serotonin receptor ligands synthesized

4-sulfonyl analogs of 1-(1-napthyl)piperazine (34), bearing tryptaminergic substituents

known to be tolerant and impart enhanced 5-HT6 receptor affinity. Synthetic route

involved acylation, Boc protection and deprotection, reduction of nitro group using SnCl2

and Suzuki coupling reaction conditions. All the 4-sylfonyl analogs of

1-(1-napthyl)piperazine investigated for their 5-HT6 serotonin receptor activity. All the


derivatives were revealed to be moderately successful ligands for 5-HT6 serotonin

receptors.

(34)

R = H, 4-Br, 4-Ph, 4-COPh, 4-CH2Ph, 4-SO2Ph, 4-SO2C6H4NH2-p, 3-Et, 3-Ph

F Mincione et al.,25

designed and synthesized an novel series of thioureido substituted

sulfonamides (35) by reacting 4-isothiocyanato ethyl benzenesulfonamide with

piperazines. N-substituted piperazine, hydrazines amino acids bearing moieties that can

lead to enhanced water solubility. All the newly synthesized compounds proved to be

good carbonic anhydrase inhibitors and some were also very effective in reducing

elevated intraocular pressure in animal models.

(35)

n = 0 or 2; R =

J I Levin et al.,26

opted for the synthesis of potent sulfonamide hydroxamate TACE

inhibitors bearing a butynyloxy P1 group. Compounds (36) and (37) of the synthesized

series demonstrated excellent results, compound (36) possess very good selectivity for

TACE over MMP-1 and compound (37) was the most potent among all the series of

compounds by inhibiting LPS stimulated TNF production in cells, whole blood and in

vivo. They also showed excellent oral potency in the standard model of human RA.


(36)

(37)

V Garaj et al.,27

reported the synthesis of a novel series of aromatic benzenesulfonamides

incorporated with 1,3,5-triazine moieties. Key intermediates in the synthetic route are

dichlorotriazinyl benzene sulfonamides (38), were derivatized by reacting with variety of

nucleophiles. All the synthesized compounds were tested for the inhibition of three

physiologically relevant carbonic anhydrase isomers. Aromatic benzene sulfonamides

derivatives (39) incorporated with triazine ring having amino, hydazino, ethylamino,

dimethylamino were the most active inhibitors of the series.

(38) (39)

X = N, O, NH, Cl; R = H, CH3, C2H5, NH2, C6H5, CH2CH2NEt2, n-butyl,

isopropyl, n-propyl, CH3, n-propyl, [HN(CH2CH2)2N]CH2CH2

J. N. Narendra Sharath Chandra et al.,28

successfully synthesized N-alkylated and N-

sulfonated derivatives of 1-[bis(4-fluorophenyl)-methyl]piperazine containing biphenyl

ring attached to piperazine nucleus. Under nucleophilic substitution reaction 1-[bis(4-

fluorophenyl)-methyl]piperazine were reacted with different alkyl halides and alkyl,

arylsulfonyl halides. Reaction of 1-[bis(4-fluorophenyl)-methyl]piperazine with alkyl,

arylsulfonyl halides were carried in presence of triethylamine and dichloromethane to

yield 1-[bis(4-fluorophenyl)-methyl]piperazine derivatives (40) expecting that biphenyl

ring attached to piperazine increase the antimicrobial activity against Gram-positive


bacterias like Staphylococcus aureus, Streptococcus pneumonia, Bacillus cereus and

Bacillus subtilis, Gram-negative bacterias like Escherichia coli, Pseudomonas

aeruginosa, Proteus vulgaris and Salmonella typhi. Compounds containing tert-butyl

group on the phenyl ring and dichloro group on the phenyl ring found to be potent

antibacterial agents.

(40)

R = CH3, Ph, 4-CH2-Ph, 4-tertBut-Ph, 4-Cl-Ph, 2,6-diCl-Ph

Christa E. Muller et al.,29

designed a potent and selective adenosine A2B receptor

antagonist sulfonamides by the aminolysis of 4-nitrophenyl sulfonates. Substituted

sulfophenyl xanthine was used as starting material which was reacted with chlorosulfonic

acid and subsequently treated with different amine to yield sulfonylaminophenyl xanthine

derivative (41). Investigations of structural activity relationships at adenosine receptors

were done successfully.

(41)

R = OH, NHCH2C6H4, NH(CH2)2C6H4, NH(CH2)2OH, NHCH2COOH, N(C3H7)2, NHPh,

N-Ph-piperazine, NHCH(CH3)2; R1 = CH3, (CH2)2CH3; R

2 = H, CH3, (CH2)2CH3

Daniel Fattori et al.,30

designed and synthesized novel Bradykinin hB2 receptor

antagonists molecules, by incorporating sulfonyl and piperazine groups. These groups

were introduced to obtain compounds having high molecular polar surfaced areas which

show high permeability in intestinal mucosa membrane and epithelium tissue. Numerous

derivatives of sulfonamides were synthesized from starting material 2,6-dichlorotoluene

which reacted with chlorosulfonic acid to give sulfonyl chloride, further it was treated


with tert-butyl ester of α,α-dimethyl glycine to give sulfonamides followed by

bromination and nucleophilic substitution reaction with hydroxyquinolines afforded the

desired compounds. All sulfonamide derivatives were evaluated for binding activity and

as well as in vitro functional activity on the hB2 receptor. Out of all compounds tested one

compound N-(1-(4-(2-amino-5-(dimethylamino)pentanoyl)piperazin-1-yl)-2-methyl-1-

oxopropan-2-yl)-2,4-dichloro-3-(((2,4-dimethylquinolin-8-yl)oxy)methyl)benzene

sulfonamide (42) exhibited excellent binding and in vitro functional activity on the hB2

receptor.

(42)

Successful modification by K Briner et al.,31

in compound (43) in search of structure

based ligands for melanocortin-4 receptors resulted in compounds with polar groups

along with aliphatic hydrophobic groups. Synthesis involved reduction using lithium

aluminum hydride, Swern oxidation, reductive amination using NaBH(OAc)3 and finally

Strecker synthesis for the synthesis of α,α-disubstituted cyclopentyl derivatives. Key

intermediate observed during the synthesis was N-Boc piperazine phthalimide derivative

(44) with aliphatic substitution instead of benzylic group, these groups showed only 5 to

10 fold decrease in affinity compared to compounds with bulky groups against MC4

receptors. Upon treating with different sulfonamides, amides and carbamates yielded the

final compounds (45) with smaller aliphatic groups.

(43) (44)


(45)

R = H, SO2CH3, COCH3, C2H5; R1 = H, COCH3, SO2CH3, C4H8, morpholine,

succinimide; R2 = TIC, IIN, H, F, OCH3, C6H11, CH2CH(CH3)2, C6H11CH2

S Talath et al.,32

in search of new antibacterial and antitubercular agents reported the

synthesis of N-Sulfonyl fluoroquinolonic derivatives (46). Amino group of the starting

compound was acetylated, followed by conversion of thiol to thionylchloride. It was

further treated with a secondary amine to form sulfonamide bond. The obtained prefinal

compound was base hydrolyzed to get the target molecules 2-amino-5-mercaptio-1,3,4-

thiadiazoles in good yield. Compounds tested for the antibacterial activity against Gram

positive bacteria and in vitro antitubercular activity, few compounds were found to be

moderately active.

(46)

R = ; R1 = H, NHCOCH3, NH2; R

2 = H, F, OCH3; R

3 = R

4 = H, CH3

Novel hydroxamic acid histone deacetylase (HDAC) inhibitors were designed and

synthesized by S K Anandan et al.,33

possessing zinc chelating head group attached

directly to the thiazole ring with a piperazine and sulfonyl functionality. All the

sulfonamides analogous were found to be having equivalent potency against isolated


enzyme and in cell. Some of the sulfonamide analog (47) were found to be more potent

and chemically stable HDAC inhibitor.

(47)

R = 2-Naphthyl, 4-CF3OPh, 4-CH3Ph, 4-BiPh, 4-CF3Ph, 3,4-(CH3O)2Ph, 4-NO2Ph

In continuation of the previous work reported by Daniel Fattori et al.,34

which involved

design and synthesis of sulfonamides in view of discovering better hB2 receptor.

Synthesized a series of benzene sulfonamides, one compound N-(4-(4-(2-amino-5-

(dimethylamino)pentanoyl)piperazine-1-carbonyl)tetrahydro-2H-pyran-4-yl)-2,4-dichloro

-3-(((2,4-dimethylquinolin-8-yl)oxy)methyl)benzene sulfonamide (48) promised to be

better bradykinin bronchoconstriction antagonist.

(48)

In context of developing new potent anticancer agents Jae Chul Jung et al., 35

reported the

synthesis of sulfonamides, starting from L-proline by using various steps involving

benzylation, sulfonation and coupling of sulfonyl chloride with appropriate amines in

presence of DIPEA a coupling agent and base DMAP in methylene dichloride to give

1-[substituted]-L-proline benzyl esters. All the synthesized compounds were tested for

their in vitro antiproliferative activity. Piperazine sulfonamides (49) were reported as

most potent series evaluated for Histon deacetylase [HDAC] inhibitors.

R = CH2CH2OH, CH2CH2-(N-methyl piperazine)

(49)


T Guo et al.,36

successfully designed and synthesized tetrahydroquinone and pyrroline

sulfonamide carbonates (50) and (51). Synthesis began with hydrogenation of quinoldic

acid followed by LAH reduction, TMS protection of resulting alcohol, sulfonylation,

TMS protection and Swern oxidation. After witting coupling, DIBAL-H reduction gave

prefinal compound alcohol, which upon treating with different amines to give target

molecules. All the synthesized compounds were evaluated against -secretase a key

enzyme involved in the production of -amyloid peptides which play a critical role in the

onset and progress of Alzheimer‘s disease (AD). Out of the synthesized compounds,

cyclic amines sulfonamides carbamates and tetrahydroquinoline sulfonamide carbamates

with one and three carbon chain linkers, were proven to be potent -secretase inhibitors.

(50) (51)

n = 0, 1, 2, 3; R =

C. S. Ananda Kumar et al.,37

in need of developing 1-benzhydryl-sulfonyl piperazine

derivatives as inhibition of human breast cancer cells. A novel series of sulfonyl

piperazine derivatives synthesis was reported, synthesis of 1-benzhydryl-sulfonyl

piperazine derivatives (52) was initiated by Grignard reaction between benzaldehyde and

phenyl magnesium bromide to give benzhydrol. Hydroxyl group of benzhydrol was

replaced with chlorine in presence of thionylchloride to get benzhydryl chloride which

undergoes chloramine coupling with piperazine to get important intermediate which is

further treated with different sulfonyl chloride resulted in the synthesis of target

molecules. Anti-cancer activity was studied for all the synthesized target molecules. Out


of all the compounds screened for their anti-cancer activity against MDA-MB-321 human

breast cancer cell compound containing tert-butyl phenyl ring showed very good activity.

(52)

R = CH3, 4-CH3C6H5, 4-Cl-C6H4, 4-tert-butyl-C6H4, 2-naphthyl, 3,5-dimethylisoxazole

A new series of potent thiol containing aryl sulfonamide were developed as Tumor

Necrosis Factor α (TACE) inhibitors by B Govinda Rao et al.,38

. Synthesis involved

sulfonation of various cyclic 3-hydroxy-secondary amines with 4-butyloxy

benzenesulfonyl chloride followed by Mitsunobu reaction to get thioesters. This upon

hydrolysis and acidification yielded in thiols as the final derivatives. Structure activity

relationship and matrix metalloproteinases selectivity of all the series of compounds were

tested. Out of which one compound (53) was proved to be potent against the isolated

TACE enzyme and good selectivity over MMP-2, -7, -8, -9 and -13. Compound (53) also

showed good binding to TACE enzyme which was confirmed by x-ray crystal study.

(53)

Tracy J. Jenkins et al.,39

in search of potent antagonists for human chemotactic cytokines

receptors (CCR8), successfully synthesized naphthalene piperazine sulfonamides. They

designed number of schemes keeping amino naphthalene sulfonyl chloride as key core

moiety in synthesizing piperazine sulfonamides. All the naphthalene sulfonamide

derivatives prepared were evaluated for in vitro binding assay for their affinity towards

human chemotactic cytokines receptors; compound (54) showed potency equivalence to

standard antagonists.


(54)

In search of effective 5-HT6 receptor antagonists Ae Nim Pae et al.,40

synthesized a series

of aryl sulfonyl piperazine derivatives using 3-chloro-1-substituted propanone as starting

material. Upon reduction of 3-chloro-1-substituted propanone in presence of NaBH4 and

THF followed by addition of substituted phenol in presence of DIAD and

triphenylphosphine in THF gave important intermediate compound, which underwent

Buchwald coupling with different piperazine sulfonamide derivatives to give the

arylpiperazine derivatives (55) in good yield. All the derivatives were screened for DNA

binding assay to serotonin 5-HT6 receptor. Out of all the compounds tested, compounds

containing trifluoro, methyl and ethyl groups showed excellent antagonistic property.

(55)

R= C2H5, C6H5; R1 = CF3, CN; R

2 = H, 2-Cl, 3-Cl, 4-Cl, 2-F, 3-F, 4-F

2-CH3, 3-CH3, 4-CH3, 33-OCH3, 3,4-diCH3

T Asberom et al.,41

discovered a new series of tetrahydroquinoline sulfonamides in search

of -secretase inhibitors. Synthesized compounds (56) were studies for their structure and

activity relationship of carbamates substituents. Simple aliphatic carbamates showed

modest -secretase activity but two fold potency was observed when nitrogen heteroatom

was incorporated in the side chain of piperazine derivatives and side chains possessing

terminal free amine groups. Fluoro substituent on the quinolone ring was found to be the

most potent of the series.


(56)

X = H, 5,7-F2, 5,8-F2, 6F, 7F;

R =

C. S. Anand Kumar et al.,42

synthesized new 1-benzhydryl-4-phenylmethane sulfonyl

piperazine (57). Benzaldehyde upon Grignard reaction with phenyl magnesium bromide

yielded alcohol which underwent nucleophilic substitution reaction in presence of thionyl

chloride and MDC, followed by treatment with piperazine to obtain 1-benzhydryl

piperazine as intermediate. Obtained intermediated was further reacted with phenylmethyl

sulfonyl chloride to obtain the title compound.

(57)

Y Shi et al.,43

designed and synthesized a new series of amino(methyl)pyrrolidine

sulfonamides in search of potent and specific FXa inhibitors. All the compounds were

tested for anti FXa activity showed good activity further structure and activity

relationship revealed compounds (58) (59) and (60) were better FXa inhibitors with

similar P1 and P4 pharmacophores.


(58)

(59)

(60)

Irena Svedaite et al.,44

synthesized a new series of 4-arylsulfonylpiperazine-2,6-diones

(61) via acylation of hydrochloride salt of piperazine-2,6-dione with appropriate sulfonyl

chlorides and then followed by aminolysis in presence of 30% aqueous ammonia which

yielded corresponding aryl sulfonyl derivatives of iminodiacetic acid (62).

(61) (62)

R= C6H5, 2-NO2-C6H4, 2-F-C6H4, 4-NO2-C6H4, 3-NO2-C6H4

In an effort to discover antineoplastic agents Samir M. El. Moghazy Aly et al.,45

successfully synthesized four different series of triazene and triazenopiperazine

sulfonamide derivatives (63) (64) (65) and (66). 2-chlorobenzoic acid was made to react

with anthranilic acid, obtained product underwent cyclodehydration in presence of H2SO4


to afford acridone-4-carboxylic acid as intermediate. This intermediate upon chlorination

yielded carbonyl chloride which was reacted with 4-(2-hydroxythyl)piperazine-1-

yldiazenylbenzene sulfonamide derivatives and further treated with appropriate

sulfonamides, followed by acid hydrolysis yielded target molecules in good yield. All the

synthesized piperazine sulfonyl derivatives were tested for their antitumor activity against

breast cancer cell line.

(63)

(64)

(65)

(66)

R = H, pyrimidine, 2,4-dimethylpyrimidine, COCH3, CNHNH2

V Padmavathi et al.,46

reported the synthesis of novel class of symmetrical and

unsymmetrical 1,3,4-oxadiazoles (67). Along with the synthesis of oxadiazoles


interconversion of oxadiazoles to thiadiazoles (68) and triazoles (69) were also

accomplished with the help of suitable nucleophiles such as thiourea in THF and n-

butanol in hydrazine hydrate.

(67) (68)

(69)

n = 0 and 1

K. S. Rangappa et al.,47

synthesized a novel1-benzhydryl-4-(2-nitro-

benenesulfonyl)piperazine molecule (70), via Grignard reaction between benzaldehyde

and phenyl magnesium bromide to yield alcohol. Further the hydroxyl group was

substituted with chlorine to get diphenyl methyl chloride which on Buchwald coupling

with piperazine yielded 1-benzhydryl piperazine. This further underwent nucleophilic

substitution reaction with 2-nitro-benzene sulfonyl chloride. Characterization was done

using single crystal X-Ray diffraction technique.

(70)

Hea Young Park Choo et al.,48

in an effort to develop 5-HT7 antagonists, designed and

synthesized piperazine sulfonamide derivatives, keeping phenyl piperazine propyl amine

as core and substituted with appropriate substituted benzene and naphthalene

sulfonamides to obtain two varieties of 5-HT7 inhibitors. Totally twenty four substituted

piperazine sulfonamides (71) were synthesized successfully and evaluated for their


antagonist activity against 5-HT7 receptors. Compounds which possessed trifluoro

methyl, methoxy and fluorine substitution on phenyl group of piperazine ring showed

good activity. Out of all the compounds tested one compound having methoxy

substitution on both phenyl group of piperazine and phenyl group of sulfonamide showed

greater activity than the rest.

(71)

R = C6H5, 3-CF3-C6H4, 4-CF3-C6H4, 2-OCH3-C6H4, 3-OCH3-C6H4, 4-OCH3-C6H4,

3-F-C6H4, 4-CF3-C6H4, 3,4-Cl2-C6H3, CH2-C6H5, 4-NO2-C6H4, 4-COCH3-C6H4,

phenyl acetate, 1-(tetrahydrofuran-2-yl)ethanone; R1 = 4-OCH3C6H5, C10H7

M Sun et al.,49

reported the tandem mass spectrometry fragmentation of selected aromatic

sulfonamides in the positive ion mode and showed the fragmentation patron in three

major pathways, one by the direct cleavage of sulfonamides (S-N) bond (72), aryl-sulfone

(C-S) bond (73) and SO2 elimination by rearrangement (74). Finally they discovered that

substitution of electron withdrawing group, enhance the formation of a positive charge

facilitating the SO2 elimination.

(72) (73)

(74)

R = R1 = R

2 = CH3, C2H5

In view of identification of novel and efficient sulfonyl piperazine derivatives

incorporated with morpholinothieno and pyrimidine ring systems as orally prescribable

phosphatidylinositol-3-kinase (PI3K) inhibitors. Adrian J. Folkes et al.,50

synthesized


number of derivatives via there different scheme to obtain the title compounds. All the

derivatives were screened for anticancer activity against phophatidylinositol-3-kinase

protein. Compound (75) possessing piperazinesulfonyl methyl as part of the molecular

structure proved to be excellent PI3K inhibitor, which was taken further for human

clinical trial.

(75)

Kwang Seop Song et al.51

in view of developing CB1 cannabinoid receptor ligands. They

designed and synthesized sulfonamides derivatives (76) containing 1-benzhyrdruyl

piperazine moiety. Multiple series of 1-benzhyrdruyl piperazine derivatives containing

sulfonamides, amides, carbamate, urea oxamide were also synthesized. About thirty two

compounds were synthesized and evaluated for CB1 receptor binding assay. Among

tested compounds, two compounds containing 2,4-dichloro and 4-chlorophenyl ring

system showed potent inhibition activity.

(76)

R = , ,


Goutham Panda et al.,52

successfully synthesized a novel series of piperazine

sulfonamides of benzene and isoquinolidine derivatives. They synthesised compounds by

nucleophile substitution reaction, of benzene sulfonyl chloride and isoquinoline sulfonyl

chloride with different substituted amines in presence of triethylamine. All the derivatives

displayed good activity against tested bacterial strain P. falciparum, out of which two

compounds (77) and (78) showed very good activity.

(77) (78)

A new series of diaminobenzene and aminobenzene intermediates were synthesized from

sulfonamides and azo dyes by L Wang et al.,53

in view of studying their structure and

activity relationship studies on their dyeing and fastening properties. Synthesized

sulfonamides derivatives (79) were studied for their spectrophotometric properties, colors

of azo dyes and crystallographic study using X-ray diffraction technique. All the

Synthesized sulfonamides derivatives successfully showed good structure and reactivity

relationship.

(79)

R = Piperidine, Morphine, NHCH2CH3, NH(CH2)2OH,

NH(CH2)3Br, C6H5, 2OCH3C6H5

A Scilimati et al.,54

successfully synthesized and evaluated 3-adenoceptor agonist

activity of tertiary amine nitrogen atom of piperazine sulfonamides. Various piperazine

sulfonamides were synthesized by ten different synthetic routes. All the sulfonamides

derivatives were examined as compounds bearing a non-aromatic linker on right and left


hand sides of the moiety. Among all the compounds evaluated for activity, compounds

(80) (81) (82) and (83) bearing tertiary nitrogen atoms were found to be most potent 3-

adenoceptor agonist belonging to the aryloxypropanolamine, arylethanolamine, piperidine

sulfonamide and piperazine sulfonamide class respectively

(80)

(81)

(82)

(83)

In view of discovering piperazine sulfonamide as potential radioligand with

subnanomolar affinity and adenosine A2B receptor antagonists, Borrmann et al.,55

synthesized a new series of 1-alkyl-8-(piperazine-1-sulfonyl)xanthenes (84). The target

molecules were synthesised by multiple steps, which involved condensation of substituted

diaminouracils with 4-(p-nitrophenoxysulfonyl)benzoic acid using coupling agent N-(3-

(dimethylamino)-propyl)-N-ethylcarbodiimide (EDC), ring closer reaction of

corresponding xanthine derivatives, followed by aminolysis gave desired sulfonamides.

All the derivatives were tested for their A2B antagonist activity out of which 1-ethyl-8-(4-

(4-(4-trifluoromthylbenzene)piperazine-1-sulfonyl) phenyl)xanthine and 8-(4-(4-(4-

chlorophenyl)piperazine-1-sulfonyl)phenyl)xanthine were potent.


(84)

R = 4-CF3-C6H4, 4-Cl-C6H4; R1 = CH2CH3

S. Naveen et al.,56

synthesized new 1-benzhydryl piperazine derivatives. Title compound

1-benzhydryl-4-tosylpiperazine (85) was synthesized from benzophenone which was

converted to benzhydryl piperazine via chlorination and Buchwald coupling reaction, the

intermediate benzhydryl piperazine was reacted with p-toluene sulfonyl chloride in

presence of triethylamine. X-ray crystallography studies was carried out confirmed the

tetrahedral configuration of the molecule.

(85)

A novel series of aryl sulfonamides containing guanidine in combination with secondary

amines such as piperidine and piperazine was successfully synthesized by P Zajdel et

al.,57

in search of potent 5-HT1A, 5-HT2A and 5-HT7 receptors. Upon evaluating all the

synthesized compounds for their antagonistic activity, sulfonamides possessing N-alyyl-

N1-dialkylguanidines (86) and (87) displayed very good activity and were proven 5-HT1A,

5-HT2A and 5-HT7 receptors. This structural morphology resulted in high selectivity

towards 5-HT1A/5-HT7 receptors and proved guanidine core is a promising

pharmacophore.

(86)


(87)

M L de Castro Barbosa et al.,58

reported the design, synthesis and pharmacological

evaluation of N-phenyl-acetamide sulfonamides. Synthesis of N-phenyl-acetamide

sulfonamides derivatives was planned by structural modification on well-known

prototype paracetamol molecule. This resulted in increase in area volume and electrostatic

potential of paracetamol analogues which in turn gave potent analgesic agents. Out of the

synthesized compounds evaluated, compounds (88) (89) and (90) were found to be

important pharmacophores. They also conflated and affirmed the results obtained from

the pharmacological studies were in good accordance with molecular modeling studies.

(88) (89) (90)

Y. Wang et al.,59

synthesized a series of camphor sulfonamide derivatives in search of

efficient and selective CXCR3 antagonists. Aryl halide was reacted with Boc protected

piperazine, followed by deprotection to get secondary amide which was treated with

(1S,4R)-camphor derived sulfonyl chloride to get important intermediates N-aryldiamine

sulfonamide. Intermediate possessing carbonyl group present on the camphor ring was

subjected to numerous reactions to obtain different series of derivatives. All the

derivatives were evaluated for their activity as CXCR3 antagonists. Two compounds (91)

and (92) out of the tested series are potent CXCR3 inhibitors.


(91) (92)

Vasant B Jagrut et al.,60

reported an efficient synthetic route for the synthesis of 1,3,4-

oxadiazoles with sulfonamido pharmacophores. 4-aminobenzoic acid was used as the

starting material which was converted in to 4-(toluene-4-sulfonamido)benzoic acid

followed by esterification and treatment of hydrazine hydrate yielded hydrazide as key

intermediate. This was further treated with an aldehyde in acetic anhydride to get 1,3,4-

oxadiaole derivatives (93).

(93)

R = 4-OCH3C6H5, 4-ClC6H5, 4-FC6H5, 4-BrC6H5, C6H5

A series of novel piperazine sulfonamide derivatives were designed and synthesized by

J. Cumming et al.,61

in search of β-secretase inhibitor which causes Alzheimer‘s disease,

also known as Beta-Site APP Cleaving Enzyme-1 (BACE1). Synthesis was carried out by

stereo selective Aldol addition reaction of piperazine with alpha amino aldehyde to give

adduct, which on debenzylation in presence of palladium gave primary amine. Primary

amine was then coupled with substituted phthalic acid in presence of coupling agent EDC

and HOBT to yield amide which was subjected to hydrogenation, sulfonation and

followed by deprotection of Boc group to give BACE1 inhibitor. All the piperazine

sulfonamide derivatives were evaluated for their BACE1 inhibitor property, out of which

some of the derivatives (94) showed exceptional activity as potent BACE1 inhibitor.

Keeping m-tolylsulfonamide piperazine derivative as core member of isophthalamide,

variations were carried out at the nonprime side binding part of the piperazine

sulfonamide derivative. Compound (95) displayed significant potency as β-secretase

inhibitor.


(94) (95)

R = SO2-2-CH3-C6H4, SO2-2-CH3-C6H4, SO2-3-Cl-C6H4

Identification of effective substituted piperazine sulfonamides as antiplasmodial agents

against Plasmodium falciparum was carried out by D. C. Martyn et al.,62

They

successfully identified two piperazine sulfonamides (96) which were having three

structural features like furanyl ring, thiourea and chloro phenyl or nitro phenyl groups.

Replacement of furan ring showed no change in the antiplasmodial activity but

replacement of thiourea with variety of functional group and heterocycle pyrimidine

showed significant loss of activity. It was concluded that thiourea is an important

functional group along with sulfonamides, to show antiplasmodial activity.

(96)

R = -Cl, -NO2

K. C. Patel et al.,63

synthesized sulfonamide substituted novel sydnones by condensing

bissydnone sulfonyl chloride (97) with different amine derivatives of N-substituted

piperazine to obtain bissydnone sulfonamides (98) in good yield. All the synthesized

compounds were tested for their in vitro antibacterial activity against Staphylococcus

aureus, Streptococcus pneumonia and Escherichia coli and Pseudomonas aeruginosa

bacterial strains. All the tested compounds showed moderate antibacterial activities.


(97)

(98)

R = Piperazine, N-C2H5-Piperazine, N-CH3-Piperazine, N-Ph-Piperazine, Pyrazole,

N-2,5-diCl-Ph-Piperazine, N,N-(C2H5)NH substituted piperazine

Palle et al.,64

synthesized 2-(4-substitutedsulfonylpiperazine-1-yl-methyl)-3-aryl-

quinozoline-4(3H)-one successfully by using simple, efficient and novel method which

involved cyclization of anthranilic acid by treating it with chloroacetyl chloride under

reflux to obtain cyclized product 2-( chloromethyl)-3-phenylquinazolin-4(3H)-one.

Which was then refluxed with N-Boc piperazine, acetonitrile, potassium iodide and

potassium carbonate to yield tert-butyl-4-[(3,4-dihydro-4-oxo-3-phenylquinazoline-2-

yl)methyl]-piperazine-1-carbonate. It was hence treated with isopropyl alcohol and dilute

hydrochloric acid at room temperature which resulted in Boc deprotection. The

intermediate obtained was further treated with different substituted sulfonyl chloride to

obtain 2-(4-substituted-sulfonyl-piperazine-1-yl-methy)-3-aryl-quinozolin-4(3H)-one

(99).

(99)

R = CH3, C6H5; R1 = C6H5, 3-OCH3C6H4, 2-CH3C6H4,

3,4-diFC6H3, 3-ClC6H4, 3-FC6H4,


Kevin G. Liu et al.,65

in view of identifying selective antagonists for 5-HT6 protein which

causes central nervous system diseases like Schizophrenia and Alzheimer‘s reported the

synthesis of 3-sulfonylpiperazinylindazole derivatives (100). Numerous sulfonyl

piperazine derivatives were synthesized by substituting, substituted piperazine at different

position on indazole ring. All the synthesized compounds were tested for functional

activity in 5-HT6 receptor cyclase assay, few compounds showed potency against 5-HT6

receptors.

(100)

R = H CH3; R1 = H, CH3, C2H5, n-propyl, iso-propyl, n-butyl, butane

R2 = 3-F-C6H4, 4-Cl-C6H4, 4-CH3-C6H4, 1-naphthylbenzene, 3-OCH3-Ph, 4-CF3-C6H4

Qiuye Wu et al.,66

first identified xanthone sulfonamides as antiatherogenic agents,

inhibitor of acyl CoA cholesterol acyltransferase (ACAT), which catalysis the

esterification of intermolecular cholesterol. They synthesized derivatives of xanthone

sulfonamides using 2,4,5-trimethoxybenzene chloride as starting material. Friedel-Crafts

acylation of the 1,3,5-trimethoxybenzene gave benzophenone and followed by

dimethylation of ring system and cyclization in presence of TBAOH, sulfonation gave the

prefinal sulfonyl chloride, which was treated with different amines to get title compounds.

Compounds were evaluated for antiatherogenic activity, one the compound (101) prove to

be good ACAT inhibitor.

(101)


In view of discovering potent and efficient dual inhibitors of PI3K enzyme inducing

cancer and mTOR protein which regulates cell growth and cell proliferation. Timothy P.

Heffron et al.,67

designed and synthesized small molecules by keeping

morpholinothienopyrimidine as core moiety and substituting piperazine sulfonamide on

thienopyrimidine ring system (102). Optimization and testing of all the compounds for

their PI3K and mTOR activity led to the discovery of number of PI3K and mTOR

inhibitors. Out of which one compound having 2-sulfonylmethyl benzene substituted at

6th

position on thienopyrimidine showed excellent potency as PI3K and mTOR inhibitor.

(102)

R = H, 1-methyl-4-(methylsulfonyl)piperazine, N-ethyl-N-methylmethane sulfonamide,

(methylsulfonyl)benzene, (4-methylpiperazin-1-yl)(phenyl)methanone

M. A. Sridhar et al.,68

synthesized a novel 1-benzhydryl-4-methanesulfonyl piperazine

(103). It was synthesized using benzophenone which on reduction with NaBH4 in

methanol gave diphenol methanol. It was treated with thinoyl chloride and followed by

Buchwald coupling yielded 1-benzhydryl piperazine. This intermediate was treated with

methyl sulfonyl chloride to obtain the title compound. Structure of the compound was

confirmed using IR, 1H NMR and elemental and spectral analysis along with X-ray

crystallographic study.

(103)

1,4-benzodioane-2-carboxylic acid a chiral building block used in the designing and

synthesizing chiral therapeutic agents was taken up by K. N. Mohana et al.,69

They

synthesized sulfonyl piperazine derivatives containing 1,4-benzodioxane-2-carbonyl

(104) as core moiety to discover new antimicrobial and antioxidant agents. Target


molecules were synthesized by nucleophilic substitution reaction of benzodioxane

carbonyl piperazine with different substituted phenyl sulfonyl chlorides. All the

synthesized piperazine sulfonamide derivatives were screened for their antibacterial,

antifungal and antioxidant activity, such compound 4-(2-triflouromethyl)benzene

sulfonyl-1-(1,4-benzodioxane-2-one)piperazine proved to be important pharmacophore as

antibacterial and antifungal agents.

(104)

R = 4-CH3C6H4, 2CF3C6H4, 4-ClC6H4, 2-NO2C6H4, 2,5-DiClC6H3, 4-Isobut-C6H4

A novel series of benzhydrylpiperazine derivatives bearing an asymmetric carbon atom

were synthesized by L Gao et al.,70

in view of discovering potent and selective hCB1

inverse agonists. Synthesis of asymmetric benzhydrylpiperazine was carried out using

Davis-Ellmann type sulfonamide chemistry. Synthesized compounds were tested for their

CB1 antagonists property and pharmacokinetic profiles studies. Enantiomers (105) and

(106) were studied, compound (106) was found to be more potent than its isomer,

enhanced activity against hCB1 and oral bioavailability and good efficiency in in vivo

condition was also observed.

(105) (106)

Y Yan et al.,71

in search of new injectable integrin α2 3/αIIb 3 dual antagonists, focused

on a series of mimetic of RGD tripeptide sequence. Small molecular antagonists 102

tricyclic piperazine/piperidine furnished molecules (107) and (108) by combinational use

of comparative molecules field analysis (CoMFA), comparative similarity indices

analysis (CoMSIA) and molecular docking reveal the requisite 3D structural features


impacting for there antagonistic activity. Statistical results of their work satisfied internal

and external predictability, along with good consistency between CoMFA and CoMSIA

counter maps and the docking results were observed proving the reliability and robustness

of the models.

(107)

(108)

R1 = , , ;

R2 = H, F; R

3 = H, F, Cl, CF3; R

3 = H, CH3, OH

Sulfonyl piperazine analogs were synthesized by Dennis B. Mekay et al.,72

in order to

study the structure and activity relationship on negative allosteric modulators of human

neuronal nicotinic receptors. Piperazine sulfonamides (109) were tested for their binding

activity against negative allosteric modulators of human α4-β2 (Hα4β2) and human α3-β4

(Hα3β4) nicotinic receptors resulted in highest potency in selected compounds.

Compounds having 2-flurobenezene, 4-fluorobenzene and N-3a,7a-dihydr-1H-indazole

groups showed highest potency against the receptors.

(109)

R = C6H5, 2-F-C6H4, 4-F-C6H4, 4-OCH3-C6H4, 4-dihydro-1H-pyrazole,

3,7-dihydro-1H-indazole; R1 = C6H5, 2-F-C6H4, 4-F-C6H4, Pyridine, 4-OCH3-C6H4


Tim Luker et al.,73

synthesized a new series of twenty seven Zwitterions bearing sulfonyl

piperazine (110) as core moiety and studied their activity as chemoattractant receptors

homologous to Th2 lymphocyte receptors. All the Zwitterions were screened for their

capacity to bind to the CRTh2 receptors they showed moderate to good activity. Chirality

introduced in to the lead molecules showed very good potent activity.

(110)

R = CH2COOH, CH2CH2COOCH3, CH2CH2COOH; R1 = Cl, CF3;

R2 = SO2C6H5, SO2CH2C6H5, SO2-4-F-C6H4, COC6H5, COCH2C6H5, CH2C6H5,

In view of identifying quinazoline sulfonamides as potent anticancer agents Jonathan B.

Baell et al.,74

designed and synthesized quinazoline sulfonamides by designing two

synthetic pathways. First path involved reaction of 2,4-dinitrobenzene with N-Boc

piperazine and followed by deprotection of Boc group. Deprotected product underwent

cyclization, followed by Suzuki coupling to give quinazoline sulfonamide derivatives

(111). In second synthetic path tert-butyl-4-(4-cyano-3-nitrophenyl)piperazine-1-

carboxylate was reduced and converted to amino quinazoline using formamide acetate,

followed by acid hydrolysis of the Boc protecting was carried out to give intermediate

compound. Intermediate obtained was coupled with appropriate sulfonamides in presence

of copper (I) iodide and palladium tetrakis(triphenylphosphine)palladium(0) to yield

another set of quinazoline sulfonamide derivatives (112). All the compounds were tested

for binding affinity for Bcl-x2 and Bcl-2 proteins. Only few compounds showed potent

inhibition against the proteins.

(111)


(112)

R = NO2, CF3SO2; R1 = NH2(CH3), n-Morpholine

Uday Chandra Kumar et al.,75

successfully studied and reported the comparative

molecular field analysis, molecular similarity indices analysis and docking studies on

novel series of aryl sulfonyl piperazine derivatives (113) as antagonists of human 5-HT6

receptor. All the derivatives were subjected to in silico study and observed for their

binding affinity towards the binding site, which confirmed the molecules were potent and

also gave an idea to improve the drug receptor interaction, by modifying the structural

part of the molecule.

(113)

R = C2H5, C6H5; R1 = CF3, CN; R

2 = H, 2-Cl, 3-Cl, 4-Cl, 2-F, 3-F,

4-F, 2-CH3, 3-CH3, 4-CH3, 3-OCH3, 3,4-(CH3)

B. A. Shainyan et al.,76

in their short communication reported the synthesis of N-methyl-

N-(2-phenylethenyl)trifuoromethanesulfonamide by modifying the lead biologicaly

important molecule 2,5-diphenyl-1,4-bis((trifluoromethyl)sulfonyl) piperazine (114),

which was previously synthesized using N-(2-phenylethyl)trifluoromethyl sulfonamide.

The same starting material on methylation using methyl iodide followed by bromination

and debromination gave the target molecule (115) in good yield.

(114 ) (115)


A novel convenient synthetic method was developed by Shalini Saingar et al.,77

for the

synthesis of substituted 1H-1,4-diazepines as core moiety, an biologically important one.

Acetanilide on sulfonation in presence of chlorosulfonic acid gave

4-(acetylamino)benzenesulfonyl chloride which on condensation with piperazine in

presence of pyridine in acetic anhydride gave N-[4(1-piperazinylsulfonyl)

phenyl]acetamide further it was brominated to get [N4-(4-acetylamino) benzene

sulfonylpiperazinyl]-N1-1-bromopropane which on Knoevenagel condensation with

various β - diketones and β - ketoesters yielded corresponding derivatives. These

derivatives on reaction with ethylene diamine in presence of sulfuric acid underwent

dehydrative annulations to afford new series of substituted [N4-(4-acetylamino)benzene

sulfonylpiperazinyl]-N1-propyl-1H-1,4-diazepne (116). All the synthesized derivatives

were tested for antibacterial activity against Staphylococcus aureus and Klebsiella

pneumonia, Antifungal activity against Aspergillus niger and Candida albicans and

anthelmintic activity. All the compounds showed significant activity.

(116)

R =

Synthesis of aniline substituted pyrimidine sulfonamides and their apoptosis inducing

ability study was successfully carried out by Ahamed kamal et al.,78

. Series of aniline

substituted pyrimidine sulfonamide derivatives were synthesized using precursor‘s

2-methyl-5-nitroaniline, substituted acetophenone and 2-methyl-5-nitroaniline on treating

with HNO3 resulted in corresponding guanidine. Which on coupling with chalcones

obtained from reaction of substituted acetophenone with DMF-DMA gave corresponding

nitropyrimidines. Further upon reduction in presence of SnCl2 gave amino compounds;

these amino compounds were finally treated with appropriate sulfonyl chlorides to obtain

title compounds. All the compounds were screened for inhibition of cell proliferation

activity. Out of all the tested compounds, compounds (117) and (118) showed moderate

inhibition while compound (119) proved to be more potent than the other two.

http://www.google.co.in/url?sa=t&rct=j&q=&esrc=s&source=web&cd=1&cad=rja&ved=0CCkQFjAA&url=http%3A%2F%2Fen.wikipedia.org%2Fwiki%2FAspergillus_niger&ei=eXoMUoqUNYGJrAeJoICIAQ&usg=AFQjCNHGQboHsX44LkjT_K6PW1CHhp4eyQ&bvm=bv.50768961,d.bmk

http://en.wikipedia.org/wiki/Candida_albicans


(117)

(118)

(119)

Synthesis and antimicrobial evaluation of novel sulfonamide derivatives (120) was

successfully carried out by Al-Mudhafar M M J et al.,79

. Synthesis involved the

modification of the monosubstituted sulfonamide side by N-dialkylation within the

heterocycle system. This modification was done to improve the antimicrobial activity of

the sulfonamides. However, diminished activity was observed.

(120)

R = , , , ,

In view of identifying the in vitro efficacy of a novel series of N-benzene sulfonamide

derivatives against Trypanosoma cruzi and Leishmania parasitize and also to compare

their trypanocidal and leishmanicidal profile. P Bilbao Ramos et al.,80

synthesized a new

series of N-benzenesulfonamide derivatives and predicted the probable mechanism of

action of selected sulfonamides with PUC 18 plasmid DNA. Investigation was done using

nuclease activity assays and also studied cytotoxicity assay on macrophages,

antileishmanial and anti trypanocidal cellular targets of these sulfonamides in treating

parasites were searched with the help of transmission and scanning electron microscopy.


Out of all the tested compounds, compound (121) (122) and (123) were very good against

Leishmania spp promastigotes and by nuclear studies on interaction of sulfonamides as

revealed benzenesulfonamide as potent active agents.

(121) (122) (123)

Stefan Berg et al.,81

discovered a novel potent and highly selective glycogen synthase

kinase-3β (GSK3 β) inhibitors by synthesizing piperazine sulfonamides containing

pyrazine nucleus. They reported the synthesis of new series of substituted pyrazine

piperazine sulfonamide (124). Of all the compounds synthesized only few compounds

were screened for inhibition of tau phosphorylation, pan-kinase selectivity and blood-

brain barrier permeability. Moderate activity was observed in the tested compounds

against chronic degenerative disease causing protein for Alzheimer‘s disease.

(124)

R =

R1 =

B A Shainyan et al.,82

in their short communication took previously synthesized

N-(2-phjenylethenyl)-trifluromethane sulfonamides (125) and brominated it to get

N-(2-bromo-2-phjenylethenyl)-trifluromethane sulfonamides. Later it was debrominated

by using trimethylamine, to get 2,5-diphenyl-1,4-bis(trilfuromethylsulfonyl)piperazine

(126) was obtained as byproduct. To avoid formation of byproduct, N-(2-bromo-2-

phjenylethenyl)-trifluromethane sulfonamide was first subjected to methylation using

methyl iodide N-methyl-(2-bromo-2-phjenylethenyl)-trifluromethane sulfonamide

obtained was brominated and followed by debromination with alcoholic alkali afforded


N-methyl-N-[€-2-phenyl]trifluromethane sulfonamide (127) as final desired product in

good yield.

(125) (126) (127)

P Zajdel et al.,83

in view of identifying potent CNS multiple receptors 5-HT1A/5-HT2A/

5-HT7 and D2/D3/D4 scaffolds, they synthesized two new series of quinolone and

isoquinoline naphthalene sulfonamides derivatives containing piperazine as one of their

structural ring system. Different naphthalene sulfonyl chlorides were coupled with

different primary amines to get novel flexible quinolone and isoquinoline sulfonamides.

In the second scheme N-Boc benzyl alcohol was treated with p-toluene sulfonyl chloride

followed by deprotection of Boc and simultaneously treated with different naphthalene

sulfonyl chlorides to get semi rigid azinesulfonamides. Pharmacological evaluation of

both the series of compounds lead to the discovery of two molecules (128) and (129) with

significant potency, out of these two compounds, compound (129) was discovered to be

the most potent of all the other compounds tested.

(128)

(129)

Synthesis and structural activity relationship of substituted piperazine sulfonamides

against tissue transglutaminase 2(TG2) a multifunctional protein, well known for its

calcium dependent enzymatic protein cross linking activity causing Huntington‘s disease

was reported by John Wityok et al.,84

. They synthesized numder of substituted piperazine

sulfonamides by optimizing the structure of proven compound 2-((4-oxo-3,5-diphenyl-


3,4-dihydrothieno[2,3-d]pyrimidin-2-yl)thio)acetohydrazide. All the compounds were

tested against Cys 277 of TG2 protein to study inhibition extent, compound N-(4-((4-

(tetracyclo[5.2.1.03,8

.05,8

]decane-3-carbonyl)piperazin-1-yl)sulfonyl)phenyl)acrylamide

(130) showed high potency against TG2 protein.

(130)

C I Fincham et al.,85

designed and synthesized a new series of α,α-cycloalkylglycine

sulfonamide derivatives (131) and (132), which was previously identified by them as

selective human B2(hB2) receptor antagonists. The replacement of amide bonds and

introduction of piperadine and piperazine in the receptor structure resulted as major

determinate for binding recognition and binding affinity. It also increases solubility of

compound, which helped in modulating the pharmacokinetics and pharmacodynamics

properties of these molecules. All the synthesized compounds were studied for their

structure and reactivity relationship in view of understanding their differences in the

functional activities of compounds which otherwise are so similar in structure and binding

potency.

(131) (132)

R = , acyl, alkyl; X = C, N

2-(4-methylpiperazine-1-yl-methyl)-1-(arylsulfonyl)-1H-indol (133) was successfully

synthesized and screened for their 5-HT6 receptor ligand activity by Anil K. Shinde et

al.,86

further to study the change in affinity towards the 5-HT6 receptor 2-(4-methyl

piperazine-1-ylmethyl)-1-(arylsulfonyl)-1H-indol was synthesized with chloro group at

third position of the indol nucleus, which yielded target molecule substituted 3-chloro-2-

piperazinylmehtyl-N-arylsulfonyl indol (133) derivatives. In vitro 5-HT6 receptor binding


assay was carried out on all the compounds in which one of the derivatives (134) showed

highest affinity towards 5-HT6 receptor confirming that halogen substitution on indol core

increases the binding affinity.

(133) (134)

R = -H, 6-Cl, 5-Br; R1 = -H, 2-Cl, 2-Br, 4-F, 4-CH3; R

2 = -H, -Cl

Amjad M. Qandil et al.,87

synthesized the substituted phenyl piperazine bearing

benzimidazole (135) which is an analogs of sildenafil and vardenafil commercially

available drugs. Reaction of phenylethylenediamine with o-anisaldehyde to obtain

benzimidazole in the presence of oxidizing agent 1,4-benzoquinone, followed by selective

chlorosulfonation of benzimidazole containing o-anisaldehyde ring at para position gave

sulfonyl chloride. Further it was coupled with different substituted piperazine derivatives

and secondary amine in presence of triethylamine base tiyield title compounds. All the

compounds were characterized successfully using NMR and MS spectroscopic analysis.

(135)

R = , , ,

Synthesis of aryl sulfonyl piperazine derivatives of benzothiazole were carried out by

Faisal Hayat et al.,88

though series of steps are involved nitration of chloro-benzothiazole,

chloramine couplings of chloro-nitro-benzothiazole-6-amine with different sulfonyl

chloride in presence of NaH and DMF gave different aryl sulfonamide derivatives of

benzothiazole (136). All the synthesized compounds were evaluated for their in vitro

activity against human recombinant 5-HT6 serotonin receptor. Compounds showed good

binding affinity and showed good selectivity towards 5-HT6 over 5-HT4 and 5-HT7.


(136)

R = C6H5, 4-CH3C6H4, 4-OCH3C6H4, 4-IsoproC6H4,

4-FC6H4, 4-ClC6H4, 4-CF3C6H4, 4-NO2C6H4, 1-Naphthyl,

8-Quinolinyl, Thiophen

Zhao-Kui Wan et al.,89

synthesized a series of piperazine sulfonamide derivatives in

search of 11β-hydroxysteroid dehydrogenase type-1 (11β-HSD1) inhibitors as therapeutic

target for the treatment of diabetes. They synthesized piperazine sulfonamides by

changing the functionalities which are capable of forming hydrogen bond interactions

with the enzyme. Synthesis of target molecules involved reduction of previously reported

molecule HSD-016 using n-butyllithium and interconversion of nitrile groups to

carboxamide resulted in intermediates as chiral isomers which was further treated with

LDA in THF to get methyl-4,4,4-trifluoro-2,3-dioxobutanoate and further on amidation

gave target molecules. All the synthesized compounds were tested for inhibition ability

against 11β-HSD1 enzyme. Among all the tested compound, compound (R)-3,3,3,-

trifluoro-2-(5-(((R)-4-(4-fluoro-2-(trifluromethyl)phenyl)-2-methylpiperazine-1-yl)

sulfonyl)thiophen-2-yl)-2-hydroxy propane amide (137) was potent 11β-HSD1 inhibitor.

(137)

Ahmed kamal et al.,90

successfully synthesized a novel series of oxazolidino

sulfonamides in search of a potent antimicrobial agent. Chiral azide derivatives were

taken as initiators, azide group was reduced to obtain chiral amines which were reacted

with appropriate aryl/heteroaryl sulfonyl chlorides in presence of triethylamine. Further

the deprotection of Boc group on the piperazine gave corresponding oxazolidinone

sulfonamides (138). Oxazolidinone sulfonamide derivatives showed moderately potent

antimicrobial activity.


(138)

R = 4-F-C6H4, 3-Cl-C6H4, 4-COCH3-C6H4, 3-Cl-4-F-C6H3,

2-Cl,4-F-C6H3,3,5-Cl2-C6H3, 4-CF3-C6H4, 2-Thiophenyl;

2-Acetamido-4-methyl-5-Thiazolyl, 8-Quinolinyl-

R Ulus et al.,91

synthesized a novel series of acridine and bisacridine sulfonamide and

evaluated their cytosolic carbonic anhydrase inhibitory potency. Synthesis of the target

molecules involved, reduction of 4-nitro-N-(4-sulfonylphenyl)benzamide followed by

coupling the intermediate with cyclic-1,3-diketones and aromatic aldehydes. Among all

the, compounds investigated compound (139) and (140) were identified as the very

effective hCA VII inhibitors.

(139)

(140)

E Rushingwa et al.,92

reported a novel methodology for the synthesis of potent and

biologically important nicotinic acid sulfonamides derivatives (141). Latent reactivity and

protecting group of 2-pyridinesulfonamide is discussed on the observation of pyridine

participating in base mediated nitrogen to carbon rearrangement. Nitrogen to carbon

rearrangement on the last step of synthesis involved treatment of N-benzylpyridine-2-

sulfonamide with sodium hydride and suitable acyl chloride gave N-substituted pyridine

sulfonamide; it was then treated with 1.5 equivalent lithium diisopropylamide (LDA) at

-78 oC resulted in rearrangement to give the corresponding nicotinic acid sulfonamides.


(141)

R = OCH3, C6H5, OC(CH3), C(CH3)3, CHClCH3, CH3, C5H11,

CH(C6H5)CH2CH3, CH2CH2CHCH2, NHCH2CHCH2

X Ning et al.,93

in view of developing efficient multifunctional neuroprotective agents

against oxidative and inflammatory injury, designed and synthesized an new series of (E)-

3,4-dihydroxy styryl sulfonamides and their 3,4-deacetylated derivatives, which are

caffeic acid phenylester (CAPE) analogous, which improve blood brain barrier

permeability. It was acetylated to achieve CAPE analogous in good yield, all the

synthesized compounds were tested for their neuroprotective properties using several

experimental models. Out of all the tested derivatives compounds (142) and (143) were

proven to be the potent molecules.

(142) (143)

In development of promising new path way for the treatment of diabetes and several

metabolic phenotypic syndromes, S Hofer et al.,94

designed and synthesized a series of

benzazol-2-yl piperazine sulfonamides (144). They used molecular modeling approach,

classical bioisosteres studies and discovered the arylsulfonyl piperazine scaffold as 11 -

hydroxysteriod dehydrogenase 1 inhibitors. All the synthetsised molecules upon

biological evaluation showed that electron donating substituents in the phenyl ring are

active inhibitors in all cell free assays. Out of the entire derivatives undergone biological

assay in cell free zone, compound (145) was proven to be the best pharmacophore

showing IC50 ( M) 0.7±0.2 and no residual activity at 20 M was observed.


(144) (145)

R = H, CH3, tBut, OCH3, COOH, CO(NHOH);

R1 = H, OCH3, NO2, COOH, CO(NHOH): X = N, N-CH3, O, S

G Debevec et al.,95

through the use of solid phase chemistry efficiently discovered four

distant sulfonamide scaffolds, synthesis of a series of sulfonamides linked heterocycles

derived from the libraries of compounds (146) (147) (148) and (149). A novel series of

guanidine sulfonamides (150) and piperazine sulfonamides (151) were successfully

represented.

(146) (147) (148)

(149) (150) (151)

R = CH3, CH2CH2OH, CH3-4-PhC6H5; R1 -CH2-napthalene,

-CH2C6H5; R2 = -CH2C6H5, -CH(CH3)CH2CH3, -CH2OH

P Zajdel et al.,96

synthesized a novel series of quinolone and isoquinoline sulfonamides

which are analogous of aripiprazole by replacing ether and amide functionality with

sulfonamides. Pharmacological investigation was carried out on all the synthesized

compounds to achieve agonists for 5-HT1A, D2 and 5-HT2A/5-HT7 antagonists and to

achive better antidepressant and antipsychotic properties. Compounds (152) and (153)

were proven to be potent antidepressants and compound (154) was proved to be the better

antipsychotic agent.


(152)

(153)

(154)

M Sadeghzodeh et al.,97

present the synthesis of a novel series of substituted sulfonyl

piperazine derivatives as ligands for the sigma receptor. Evaluation of these derivatives as

α1 and α2 receptors with the help of radioligand bonding assays showed that compounds

(155) (156) and (157) were possessing α1 and α2 affinities, α1 affinities of sulfonyl

piperidine were great when compared to that of the sulfonyl piperazine. Furthermore

upon observing these activities, derivatives were anticipated to posses tumor imaging

property.

(155) (156)

(157)

J Slawinski et al.,98

successfully synthesized a new series of heterocyclic-4-substituted

pyridine-3-sulfonamides (158) and (159) via Buchwald coupling by convenient single

step reaction of different substituted piperazine with 4-chloro-3-pyridine sulfonamide. In

another pathway for synthesis the target molecules 4-chloro-3-pyridine sulfonamide was


done by converting into 4-hydrazinyl-3-pyridinesulfonamide, which upon

cyclocondensation with 1,3-diketones resulted in 4-(1H-pyrozole-1-yl)-3-pyridine

sulfonamide. All the piperazine and pyrazole sulfonamides were evaluated for their

inhibition activity against four isoforms of zinc enzyme carbonic anhydrase human

isozymes. Pyrazole sulfonamides were more potent than the piperazine sulfonamides

against human isozymes. Evaluation of anticancer potency of the derivatives showed

piperazine sulfonamide derivatives (160), as very good anticancer agents.

(158) (159) (160)

R1 = C6H5, 4-ClC6H5, 4-FC6H5, 2-FC6H5, 3,4-diClC6H5, 2-OCH3C6H5,

2,5-diCH3C6H5, 2-Pyridyl, 2-Pyrimidyl, CH2C6H5; R2 = CH3, CH2CH3, 3,4-diClC6H5,

R3 = H, CH3, (CH2)3CH3, (CH2)2COOC2H5, 3,4-diClC6H5

In view of expanding the structural diversity of the fenarimol series of antitrypsin cruzi

compounds M Keenam et al.,99

successfully and designed synthesized the sulfonyl

piperazine derivatives. Pharmacological evaluation of all the synthesized derivatives

using whole organism for in vitro assay reveled compounds having amides, sulfonamide,

carbamate and aryl scaffolds exhibited low nM activities. Out of all the sulfonyl

piperazine derivatives investigated one compound (161) was effective in a mouse model

which was orally dosed.

(161)

N-alkylation of sulfonamides (162) by using cyclic ethers as alkylating reagents assisted

by bronsted acids were reported by W Shi et al.,.100

Synthesis involved the use of

symmetrical and unsymmetrical ethers as alkylation regents which is an efficient


synthetic route. It is a generally applied method where the use of cyclic and acyclic ethers

as alkyl source under metal free conditions is done. It is a very useful method for

transformation of tetrahydrofuran and tetrahydropyran into their pyrrolidine and

piperidine derivatives found in natural products.

(162)

R1 = 4-CH3, 2-CH3, C6H5, 4-Br; R

1 = CH(CH3)2, CH2CH2CH2CH3,

CH(CH3)3, CH2CH2C6H5,: R2 = CH3, CH(CH3)2,

CH2(CH2)2CH3, CH2(CH3)CH2CH2CH3

A novel series of furazan and furoxan sulfonamides (163) synthesis were taken up by

K Chegaev et al.,101

in search of discovering strong α-carbonic anhydrase inhibitors and

potent antiglaucoma agents. Synthesis of these target molecules were achieved taking

phenyl sulfonamide as key starting material. Carbonic anhydrase inhibition investigation

revealed derivatives having a phenyl ring between the sulfonamide and hetero ring (164)

and (165) showed high potential only on the hCAXII isoforms.

(163) (164)

(165)

n = m = 0, 1; R = -CH3, -C2H5, -C6H5, -4Br;

R1 = -CONH2, -CN, -SO2C6H5, -CH2C6H5

Pyrazolo[4,3-e][1,2,4-]triazinesulfonamides (166) and (167) as better anticancer agents

was studied by M Mojzych et al.,102

. These molecules belogs to two groups of known

compounds one sildenafil and another aniline substituted pyrazole triazine sulfonamides.

All the novel compounds were examined for their carbonic anhydrase inhibition with

antitumor activity. These compounds were not effective against CAI and CAII, but were


potent against the tumor associated isoforms CAIX and CAXII in human breast cancer

cells. All the compounds tested showed poor to moderated activity.

(166) (167)

R = , , , , ,

, , ,

Synthesis of a new series of sulfonamide derivatives of pyrazole[4,3-e][1,2,4-]triazine has

been taken up previously by M Mojzych et al.,103

in view of identifying kinase inhibitory

activity resulting in better anticancer and antiproliferative agents. They discovered half of

the newly synthesized derivatives showed moderate activity against cancer cell lines. Out

of all the active derivatives compounds (168) and (169) were proven ab1 protein kinase

agents and antiproliferative agent‘s against leukemia cell lines. Further these two

scaffolds were taken up for the optimization of structures to increase their potency against

bcr ab1 kinase and in vitro cancer studies.

(168) (169)

A K Saluja et al.,104

designed a new series of benzene sulfonamides with 1,3,5-triazinyl

scaffold (170) and (171) as part of the structural configuration using cyanuric chloride

(172) as starting material. Synthesis was taken up in view of developing potent human

carbonic anhydrases II, IX and XII inhibitors, which are responsible for cytosolic

transmembrane and tumor associated isoforms. All the newly synthesized compounds

were tested for their pharmacological activity. All the tested compounds were proven to

be active inhibitors of human carbonic hCA II, hCA IX and hCA XII respectively.


(170) (171)

(172)

L Syrjanen et al.,105

reported the inhibitory activity of the -carbnoic anhydrase DmBCA

from drosophila melanogaster insect by using a library of forty sulfonamides and

sulfonates. Among the array of compounds evaluated benzene sulfonamides (173) were

the best DmBCA inhibitors showing inhibition range of 65.3-138nM. Along with these

molecules simple aromatic/heterocyclic sulfonamides showed inhibition constants in the

range of 0.47-6.40 M. The main intension was to develop insecticides having alternate

mechanism of action than the regular insectsides available in market.

(173)

R = 4CH3, 3-SO2NH2, 4NH2, 3NH2, 4NH2, 3Cl, 4-CH2NH2, 4-CH2CH2NH2,

3F, 4NH2, 3-Br, 4-NH2, 2-OH, 3-Cl, 5-Cl, 3-SO2NH2, 4-NH2,

In view of developing a selective carbonic anhydrase IX and XII inhibitors E Rosatelli et

al.,106

reported the flow synthesis of an novel series of secondary and tertiary aryl

sulfonamides (174) and (175). In the flow synthesis aryl sulfonyl chlorides and amines

were pumped into the reactor heater by two different pumps. The reactor heater connected

to back pressure regulator which is followed by UV detector and a fraction collector. The

obtained sulfonamides were tested for their ability to inhibit the tumor associated CAIX

and CAXII informs. Further these compounds were studied for their structure and

reactivity relationship by molecular modeling methodology.


(174) (175)

R = C6H5, -CH2C6H5, 2-methyl-1,1'-biphenyl, CH2(CH2)2N(CH3)2, CH2COOH,

Recently new series of 2-phenyl- or 3-phenyl piperazines were synthesized by Maria

Novella Romanelli et al.,107

which are structurally related to potent nootropic agents

DM235 and DM232. All the derivatives have been tested in the mouse passive avoidance

test, to measure their capacity to revert scopolamine induced amnesia. Less potency was

observed for all the tested compounds than the parent comounds, a small but important

enantioselectivity has been found for the most potent compounds (176) and (177) of the

series.

(176) (177)

Dattatray M. Akkewar et al.,108

reported the synthesis of novel series of benzoxazine-6-

sulfonamide derivatives (178) with excellent yields. Key intermediate involved in the

synthesis of target molecules was generation 3-oxo-3,4-dihydro-2H-benzo[b][1,4]

oxazine-6-sulfonyl chloride, further chlorosulfonation and acid amine coupling yielded

target molecules in good yield. Out of all the compounds evaluated for their antimicrobial

activity, some of the compounds tested showed moderate antimicrobial activity.

(178)

R = 4-CF3C6H4, 2-OCH3C6H4;

R1 = C6H4-C6H5, C6H5, 4-CH3C6H5, 4-ClC6H5

Novel series of 9-(p-toluenesulfonyl/cyclopentyl/ethoxycarbonylmethyl)-6-(substituted

amino/piperazino)purines (179) were synthesized by Meral Tuncbilek et al.,.109

They


evaluated all the compounds for their cytotoxic activities on liver Huh7, breast T47D and

colon HCT116 carcinoma cell lines. All the tested compounds showed potent anticancer

acitivity.

(179)

R = cyclopropyl, CH2-4-OCH3C6H4, CH2-2,4-2FC6H3,

CH2-2,4-2ClC6H3, CH2CH2CH2-2,4-2ClC6H3

Benjamin P. Fauber et al.,110

reported the discovery of sulfonyl piperazines (180) as

potent, selective and orally bioavailable retinoic acid receptor, Related Orphan Receptor

C (RORc or RORγ) inverse agonist property effectively as potential treatment for

psoriasis and rheumatoid arthritis inflammatory diseases. All the the compounds reported

were observed to be potent agonists.

(180)

n = 0 or 1; R = H, CH3; R1 = H, CH3,

The importance of sulfa drugs in our day today life and our literature review results

encouraged us to outspread our ideas of synthesizing sulfonamides in view of improving

their mode of action and speckled biological activities by incorporating pyrimidine,

oxadiazoles and piperazine ring system along with 1,2,4-triazolothiadiazoles. There are

limited reports on the synthesis of halogen substituted pyrimidine sulfonyl piperazines,

oxadiazole sulfonyl piperazines and bissulfonyl piperazines derivatives. Extensive

research done on 1,2,4-triazolothiadiazoles and their biological importance.

This made us to design and synthesize pharmaceutically important sulfonyl piperazine

derivatives of pyrimidine, oxadiazole, piperazine and 1,2,4-triazolothiadiazoles. It was

observed that the substituent functionality, as well as the core moiety plays a crucial role

in determining the biological activity. Hence, the synthesis of new {6-[4-chloro-2-


(trifluoromethyl)phenyl]-2-methylpyrimidin-4-yl}[4-(substitutedsulfonyl)piperazin-1-yl]

methanone, 1-(substitutedsulfonyl)-4-{5-[3-(trifluoromethoxy)phenyl]-1,2,4-oxadiazol-3-

yl}piperazine, 1-((substituted-aryl/alkyl)sulfonyl)-4-tosylpiperazines and 1,2,4-

triazolothiadiazoles was undertaken. Further four series of newly synthesized compounds

were screened for their biological activity by in vitro antimicrobial studies and in vivo

anthelmintic, anti-inflammatory and anticancer studies.


1.2. References:

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