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Synthesis and Characterization of Pharmaceutically Important Nitrogen Containing Heterocycles
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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
Synthesis and Characterization of Pharmaceutically Important Nitrogen Containing Heterocycles
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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.
Synthesis and Characterization of Pharmaceutically Important Nitrogen Containing Heterocycles
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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)
Synthesis and Characterization of Pharmaceutically Important Nitrogen Containing Heterocycles
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(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
Synthesis and Characterization of Pharmaceutically Important Nitrogen Containing Heterocycles
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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
Synthesis and Characterization of Pharmaceutically Important Nitrogen Containing Heterocycles
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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,
Synthesis and Characterization of Pharmaceutically Important Nitrogen Containing Heterocycles
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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
Synthesis and Characterization of Pharmaceutically Important Nitrogen Containing Heterocycles
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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)
Synthesis and Characterization of Pharmaceutically Important Nitrogen Containing Heterocycles
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(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
Synthesis and Characterization of Pharmaceutically Important Nitrogen Containing Heterocycles
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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 =
Synthesis and Characterization of Pharmaceutically Important Nitrogen Containing Heterocycles
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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.
Synthesis and Characterization of Pharmaceutically Important Nitrogen Containing Heterocycles
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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 =
Synthesis and Characterization of Pharmaceutically Important Nitrogen Containing Heterocycles
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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)
Synthesis and Characterization of Pharmaceutically Important Nitrogen Containing Heterocycles
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(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
Synthesis and Characterization of Pharmaceutically Important Nitrogen Containing Heterocycles
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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.
Synthesis and Characterization of Pharmaceutically Important Nitrogen Containing Heterocycles
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(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
Synthesis and Characterization of Pharmaceutically Important Nitrogen Containing Heterocycles
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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
Synthesis and Characterization of Pharmaceutically Important Nitrogen Containing Heterocycles
Page 18
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)
Synthesis and Characterization of Pharmaceutically Important Nitrogen Containing Heterocycles
Page 19
(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
Synthesis and Characterization of Pharmaceutically Important Nitrogen Containing Heterocycles
Page 20
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)
Synthesis and Characterization of Pharmaceutically Important Nitrogen Containing Heterocycles
Page 21
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
Synthesis and Characterization of Pharmaceutically Important Nitrogen Containing Heterocycles
Page 22
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.
Synthesis and Characterization of Pharmaceutically Important Nitrogen Containing Heterocycles
Page 23
(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.
Synthesis and Characterization of Pharmaceutically Important Nitrogen Containing Heterocycles
Page 24
(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.
Synthesis and Characterization of Pharmaceutically Important Nitrogen Containing Heterocycles
Page 25
(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
Synthesis and Characterization of Pharmaceutically Important Nitrogen Containing Heterocycles
Page 26
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
Synthesis and Characterization of Pharmaceutically Important Nitrogen Containing Heterocycles
Page 27
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
Synthesis and Characterization of Pharmaceutically Important Nitrogen Containing Heterocycles
Page 28
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
Synthesis and Characterization of Pharmaceutically Important Nitrogen Containing Heterocycles
Page 29
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 = , ,
Synthesis and Characterization of Pharmaceutically Important Nitrogen Containing Heterocycles
Page 30
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
Synthesis and Characterization of Pharmaceutically Important Nitrogen Containing Heterocycles
Page 31
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.
Synthesis and Characterization of Pharmaceutically Important Nitrogen Containing Heterocycles
Page 32
(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)
Synthesis and Characterization of Pharmaceutically Important Nitrogen Containing Heterocycles
Page 33
(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.
Synthesis and Characterization of Pharmaceutically Important Nitrogen Containing Heterocycles
Page 34
(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.
Synthesis and Characterization of Pharmaceutically Important Nitrogen Containing Heterocycles
Page 35
(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.
Synthesis and Characterization of Pharmaceutically Important Nitrogen Containing Heterocycles
Page 36
(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,
Synthesis and Characterization of Pharmaceutically Important Nitrogen Containing Heterocycles
Page 37
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)
Synthesis and Characterization of Pharmaceutically Important Nitrogen Containing Heterocycles
Page 38
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
Synthesis and Characterization of Pharmaceutically Important Nitrogen Containing Heterocycles
Page 39
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
Synthesis and Characterization of Pharmaceutically Important Nitrogen Containing Heterocycles
Page 40
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
Synthesis and Characterization of Pharmaceutically Important Nitrogen Containing Heterocycles
Page 41
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)
Synthesis and Characterization of Pharmaceutically Important Nitrogen Containing Heterocycles
Page 42
(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)
Synthesis and Characterization of Pharmaceutically Important Nitrogen Containing Heterocycles
Page 43
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.
Synthesis and Characterization of Pharmaceutically Important Nitrogen Containing Heterocycles
Page 44
(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.
Synthesis and Characterization of Pharmaceutically Important Nitrogen Containing Heterocycles
Page 45
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
Synthesis and Characterization of Pharmaceutically Important Nitrogen Containing Heterocycles
Page 46
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-
Synthesis and Characterization of Pharmaceutically Important Nitrogen Containing Heterocycles
Page 47
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
Synthesis and Characterization of Pharmaceutically Important Nitrogen Containing Heterocycles
Page 48
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.
Synthesis and Characterization of Pharmaceutically Important Nitrogen Containing Heterocycles
Page 49
(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.
Synthesis and Characterization of Pharmaceutically Important Nitrogen Containing Heterocycles
Page 50
(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.
Synthesis and Characterization of Pharmaceutically Important Nitrogen Containing Heterocycles
Page 51
(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.
Synthesis and Characterization of Pharmaceutically Important Nitrogen Containing Heterocycles
Page 52
(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.
Synthesis and Characterization of Pharmaceutically Important Nitrogen Containing Heterocycles
Page 53
(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
Synthesis and Characterization of Pharmaceutically Important Nitrogen Containing Heterocycles
Page 54
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
Synthesis and Characterization of Pharmaceutically Important Nitrogen Containing Heterocycles
Page 55
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
Synthesis and Characterization of Pharmaceutically Important Nitrogen Containing Heterocycles
Page 56
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.
Synthesis and Characterization of Pharmaceutically Important Nitrogen Containing Heterocycles
Page 57
(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.
Synthesis and Characterization of Pharmaceutically Important Nitrogen Containing Heterocycles
Page 58
(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
Synthesis and Characterization of Pharmaceutically Important Nitrogen Containing Heterocycles
Page 59
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-
Synthesis and Characterization of Pharmaceutically Important Nitrogen Containing Heterocycles
Page 60
(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.
Synthesis and Characterization of Pharmaceutically Important Nitrogen Containing Heterocycles
Page 61
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