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INTRODUCTION, BIOLOGICAL SIGNIFICANCE
AND CHEMISTRY OF THE REACTIONS
INVOLVED IN
• SCHIFF BASE • THIAZOLIDINONE • AZATIDINONE • PYRIMIDINES
CCHHAAPPTTEERR 22
SYNTHESIS AND CHARACTERISATION OF SOME NEW SULPHUR BASED HETEROCYCLES
Page : 15
CHEMISTRY OF THE SCHIFF BASE
Schiff bases, named for Hugo Schiff, are formed when any primary amine
reacts with an aldehyde or a ketone under specific conditions. They are organic
compounds with the general formula RR′C═NR″, where R and R′ represent hydrogen,
an alkyl or an aryl and R″ is an alkyl or aryl; in the latter case, Schiff bases are also
called anils. Schiff bases are crystalline or oily substances that are insoluble in water
and soluble in organic solvents. They are weak bases, forming salts with acids in an
anhydrous medium; in aqueous acid solutions they undergo hydrolysis to yield an
amine and aldehyde. The majority of Schiff bases are stable in alkaline solutions.
Schiff bases undergo hydrogenation to give secondary amines (RR ′CH-NHR″) and
add on many compounds containing mobile hydrogen, such as β-dicarbonyl
compounds, ketones, and imines. They are produced mainly by the condensation of
aldehydes or ketones with primary amines. The reaction was first completed by H.
Schiff in 1864 (hence the name of the compounds). Schiff bases are valuable
intermediate products of organic synthesis, for example, in the preparation of
secondary amines and various heterocyclic compounds. The Schiff bases known as
azomethine dyes are used for dyeing acetate and synthetic fibers; they are also used in
color photography to reduce the photosensitivity of photographic emulsions.
Structurally, a Schiff base (also known as imine or azomethine) is a nitrogen
analogue of an aldehyde or ketone in which the carbonyl group has been replaced by
an imine or azomethine group [1], Many methods for the synthesis of Schiff bases [2-
4] have been developed and the simplest method appears is to condense by boiling
them into alcohols. Aldehydes and ketones react with primary amine (R-NH2) and
with other ammonia derivatives (Z-NH2) to form Schiff base (imine). An imine is a
compound with a carbon-nitrogen double bond (-CH=N-).
[I] [II]
Schiff bases are some of the most widely used organic compounds. They are
used as pigments and dyes, catalysts, intermediates in organic synthesis, and polymer
stabilizers.
SYNTHESIS AND CHARACTERISATION OF SOME NEW SULPHUR BASED HETEROCYCLES
Page : 16
BIOLOGICAL SIGNIFICANCE:
Schiff bases have also been shown to exhibit a broad range of biological
activities including antimicrobial [5-17], anti-inflammatory [18-22], analgesic [22],
anti-tubercular [23-25], antimycobacterial [26, 27], antioxidant [28], antiviral [29] and
inhibitors [30].
Thiacetazone and Nitrofyrazone are the drugs which have Schiff base in their
structures which are responsible for their biological activities.
Thiacetazone
Nitrofyrazone
Dimmock et al have synthesized acetylhydrazones [III] provided good
protection against convulsions while the oxamoylhydrazones [IV] were significantly
less active [31].
a
[III] [IV]
4-Aminobutyric acid (GABA) is the principal inhibitory neurotransmitter in
the mammalian brain. GABA hydrazones [V] were synthesized and evaluated for
their anticonvulsant properties in different animal models by Ragavendran et al [32].
[V]
Lima and coworkers have synthesized [(4-N, N-dimethylamino benzylidene-3-
(3, 4-methylenedioxyphenyl) propionyl hydrazine] [VI] was more potent than
dipyrone and indomethacine are used as standard anti-inflammatory / antinociceptive
drugs [33].
SYNTHESIS AND CHARACTERISATION OF SOME NEW SULPHUR BASED HETEROCYCLES
Page : 17
[VI]
Kucukguzel and coworkers have synthesized N’-(4-methoxybenzamido)
benzoyl] a-N2-[(5-nitro-2-furyl)methylene]hydrazine [VII] inhibited the growth of
several bacteria and fungi [34].
[VII]
Turan-Zitouni et al have prepared some 5-bromoimidazo[1, 2-a]pyridine-2-
carboxylic acid benzylidenehydrazide [VIII] and screened their antimicrobial activity
[35].
[VIII]
Mamolo and coworkers have synthesized [5-(pyridine-2-yl)-1, 3, 4-thidiazole-
2-yl]acetic acid (3, 4-diaryl-3H-thiazole-2-ylidene)hydrazide [IX] and tested for their
in vitro anti mycobacterial activity [36].
[IX]
Sinha and coworkers have synthesized N-arylidene-N-[2-oxo-2-(4-aryl-
piperazin-1-yl) ethyl] hydrazide derivatives [X] containing isonicotinic acid
hydrazide-hydrazones and evaluated their anti mycobacterial activity [37].
SYNTHESIS AND CHARACTERISATION OF SOME NEW SULPHUR BASED HETEROCYCLES
Page : 18
[X]
Various diclofenac acid hydrazones [XI] were synthesized and evaluated for
their in vitro and in vivo anti mycobacterial activities by Sri ram et al [38].
[XI]
Terzioglu and Gursoy have synthesized some novel 2, 6-dimethyl-N’-
substituted – phenylmethyleneimidazo [2, 1 – b] [1, 3, 4] thiadiazole – 5 -
carbohydrazides [XII] showed the most favorable cytotoxicity [39].
[XII]
Demirbas et al have synthesized new hydrazide-hydrazones containing 5-oxo-
[1, 2, 4] triazole ring [XIIIa] and studied their antitumor activity in breast cancer [40].
[XIIIa]
Gursoy and Guzeldemirci-Ulusoy have synthesized 6-amino-4-aryl-2-oxo-1-
(1-pyrid-3-yl- or 4-yl-ethylidene-amino)-1, 2-dihydro pyridine-3, 5-dicarbo-nitrile
[XIIIb] and studied their antitumor activity [41].
SYNTHESIS AND CHARACTERISATION OF SOME NEW SULPHUR BASED HETEROCYCLES
Page : 19
[XIIIb]
Schiff bases derived from 2-[(2, 6-dichloroanilino) phenyl] acetic acid
(diclofenac acid) [XIV] were synthesized and studied for their anti inflammatory,
analgesic and ulcerogenicity activites by Bhandari et al [42].
[XIV]
Valentina et al have synthesized Some substituted 1, 2, 4 - triazo-5-thione
Schiff base [XV] and studied their antioxidant activity [43].
[XV]
Bawa and Kumar have synthesized Schiff base of 8-methyl-tetrazolo[1, 5-a]
quinoline [XVI] and evaluated their anti-inflammatory and antimicrobial activities
[44].
[XVI]
A series of sulfapyridine-polyhydroxyalkylidene (or arylidene)-imino
derivatives [XVII] have been prepared and reported for antitumor activity by Kamel
et al [45].
[XVII]
SYNTHESIS AND CHARACTERISATION OF SOME NEW SULPHUR BASED HETEROCYCLES
Page : 20
Schiff base of 4-(2-aminophenyl)-morpholines [XVIII] have been synthesized
and studied for their analgesic, anti-inflammatory, antibacterial and antifungal
activities by Panneerselvam and his co-workers [46].
[XVIII]
Kamal Vashi and H. B. Naik [47] have prepared a series of 2-hydroxy-3-
chloro-5-ethyl-N-(p-tolyl)-chalconimines [XIX]. The synthesized schiff bases were
screened for their antibacterial activity.
NCl OH
CH3
CH3(IV)
[XIX]
Santosh Kumar et al. [48] have studied the antimicrobial activity of the schiff
bases of sulfonamides. Among these schiff bases of sulphanilamide, compound
bearing trimethoxy group [XX] and furan ring [XXI] has shown good activity.
S
O
O
NH2N
O
O
O
CH3
CH3
CH3
S
O
O
NH2N
O
(V) (VI) [XX] [XXI]
Michael J. Hearn et al. [49] have prepared isoniazid schiff base [XXII] which
displayed good activity against M. tuberculosis.
N
O
NHN
(XI) [XXII]
A series of novel schiff bases of isatin was synthesized and anticonvulsant
activities have been screened by Chinnasamy Rajaram Prakash et al. [50]. Among the
compounds synthesized, [XXIII] showed excellent anticonvulsant activity.
SYNTHESIS AND CHARACTERISATION OF SOME NEW SULPHUR BASED HETEROCYCLES
Page : 21
NH
O
N
N
O
O
O CH3
CH3
CH3 [XXIII]
Synthesis and in vitro anti-HIV activity of some new schiff base ligands
derived from 5-amino-4-phenyl-4h-1, 2, 4-triazole-3-thiol has been reported by Najim
A. Al-Masoudi et al. [51] some of the synthesized compound [XXIV] were found to
be the most active inhibitors in cell culture against HIV-1.
N
N
N
SH
N
R
[XXIV]
P. Valentina and co workers [52] have ssynthesized a series of schiff bases of
3-substituted 1, 2, 4 triazo -5 thione. All the compounds were evaluated for its
antioxidant activity by hydrogen peroxide scavenging method. The result showed that
compound [XXV] has significant antioxidant activity.
N
N N
SHN
Ar
[XXV]
SYNTHESIS AND CHARACTERISATION OF SOME NEW SULPHUR BASED HETEROCYCLES
Page : 22
GENERAL METHODS FOR THE SYNTHESIS OF
SCHIFF BASE: M. C. Sharma, N. K. Sahu et al [53] have reported new N-(5-methyl-4-oxo-
thiazolidin-3-yl)-nicotinamide which have been synthesized by condensation of
nicotinic acid hydrazide with various aromatic or heterocyclic aldehydes to yield the
schiff bases and also synthesized 4-thiazolidinone derivatives by cyclo condensation
of schiff bases with 2-mercaptopropionic acid in dioxane.
N
O
NH NH2
N
O
NH N
R
N O
NH N
R
S
CH3
O
R - CHO Dry dioxane
2-mercaptopropionic acid Sie-Tiong Ha et al [54]. have mentioned the synthesis of new mesogenic schiff
base esters with polar chloro substituent using ethanol and aliphatic acid with the
catalytic amount of DDC.
NH2OH
O
OHCl+
Cl
NR - COO
1. Et OH, reflux
2. R - COOH,DMAP DCC
4, 4’-diaminodiphenylsulphone was condensed with various aromatic or
heterocyclic aldehyde in ethanol in the presence of concentrated sulphuric acid as a
catalyst to yield the schiff base has been reported by S. J. Wadher, M. P. Puranik et al.
[55].
NH2 S
OH
OH
NH2+O
R
R
R
N S
OH
OH
N
R= Arom at ic Aldehyde
H2SO4
EtOH
Arshi Naqvi and co worker[56] have mentioned the non classical methods like
water based reaction, microwave synthesis for the preparation of schiff bases using 3-
chloro-4-fluoro aniline and several benzaldehydes. These methodologies constitute an
energy-efficient and environmentally benign greener chemistry version for schiff
bases formation. O
ClF
NH2
R+
N
Cl
FR
M.W
Nuray Ulusoy Güzeldemirci and co workers [57] have discovered very simple
route for the preparation of thiazolidinone. The reaction of 1- (α, α-diphenyl-α-
SYNTHESIS AND CHARACTERISATION OF SOME NEW SULPHUR BASED HETEROCYCLES
Page : 23
hydroxy)acetyl-4-alkyl/arylthiosemicarbazides with ethyl 2-bromopropionate in the presence of sodium acetate -4-thiazolidinone derivatives.
Hai Jian Yang et al. [58] and Zhaoqi Yang et al.[59] have discovered a microwave-assisted preparation of a schiff-base. The efficient condensation of salicylaldehyde and aryl amines without solvent as a part of environmental friendship reaction in organic synthesis.
O
OH
Ar NH2+NH
OH
ArM.W.
New schiff bases derived from 2-aminopyridene and 2-aminopyrazine have
been synthesized using salicylaldehide and different heterocyclic amine in ethanol by Abdullah M. Asiri et al.[60]
X
N NH2 OH
O
+
OH
X
N N
EtOH,
Reflux
X= C, N A. M. Lopez-Periago et al. [61] have synthesised schiff base macrocycles
using supercritical CO2 as both solvent and acid catalyst. The preparation of trianglimines and schiff base has been successfully achieved using diamino cyclohexane and aromatic dialdehyde.
NH2
NH2
O
O
+CO2
N
N
N
N
N
N
SYNTHESIS AND CHARACTERISATION OF SOME NEW SULPHUR BASED HETEROCYCLES
Page : 24
REACTION MECHANISM:
R-CHO + H2N- R’ R-_CH = N- R’ + H2O
Addition of amine is carried out under mild acid catalysis to yield
an aldehyde. The acid catalyst protonates the carbonyl oxygen and
promoted the attack of nucleophillic amines.
R
H
O +
H
O+
HR
H
O
H
NH2
R'
..
R
H
OH
NH
H
R
R'+
R
R'
H
OH
NH
+ H
- H+
+
(Adduct product)
The adduct formed in this reaction undergoes a further reaction to
eliminate water and form a carbon nitrogen double bond.
H
N R'R
H
N+
H
..
R
H
NH
OH2 R
R'
R
R'
H
OH
NH
..
..
R'
..
+
H +
- H2O
- H
SYNTHESIS AND CHARACTERISATION OF SOME NEW SULPHUR BASED HETEROCYCLES
Page : 25
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SYNTHESIS AND CHARACTERISATION OF SOME NEW SULPHUR BASED HETEROCYCLES
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CHEMISTRY OF THIAZOLIDINONE: Thiazolidinone, which belong to an important group of heterocyclic
compounds have been extensively explored for their application in the field of
medicine. Thiazolidinone, in which a carbonyl group at position 2(I), 4(II) or 5(III)
have been subjected of extensive study in the recent past. Numerous reports have
appeared in the literature which highlight their chemistry and use.
S
NH
O S
NHO
S
NH
O
(I) (II) (III) 4-Thiazolidinones are derivatives of thiazolidinone with carbonyl group at 4-
position (II). Substituent in the 2, 3 and 5 positions may be varied, but the greatest
different in structure and properties is exerted by the groups attached to carbon atom
at the 2-position and two nitrogen atom at the 3-position. The cyclic structure was
assigned after recognisation of mercaptoacetic acid as a primary product of hydrolysis
of 3-phenyl-2-phenylimino-4-thiazolidinones.
BIOLOGICAL SIGNIFICANCE:
A series of new 4-thiazolidinones were synthesized N'-(4-substituted-phenyl)-N"-1-[(3'-substituted phenyl)-6-tetrazolyl]-thiocarbamide(s) by Sawale, Archana [1].Which was further reacted with chloro acetic acid in presence of anhydrous sodium acetate and acetic acid to form new 4-thiazolidinone(s). The synthesized 4-thiazolidinones were screened against E. coli for their antibacterial activity. Some of the compound showed good antibacterial activity.
Prasad, Ashok; et.al [2] have prepared N-(2-aryl-4-oxothiazolidin-3-yl)-2-(5-(naphthalenyloxymethyl)-2-thioxo-1, 3, 4-oxadiazol-3(2H)-yl)acetamide. All the newly synthesized compounds were evaluated for their antibacterial and antifungal activities.
Yang, Yu-Shun; Zhang et.al [3] have performed the best in the thiazolidinone series (MIC values: 3.13-6.25 µg/mL). They also demonstrated strong broad-spectrum antimicrobial activity. Two compounds exhibited the most potent E. coli FabH inhibitory activity with IC50 of 4.6 and 8.4 µM. comparable with the pos. control DDCP (IC50 =2.8 µM). Docking simulation was performed to position compound [IV] and [V] into the E. coli Fab H structure active site to determine the probable binding model.
SYNTHESIS AND CHARACTERISATION OF SOME NEW SULPHUR BASED HETEROCYCLES
Page : 30
[IV] [V]
Chandramohan, S.; Elayaraja, R. et.al [4] have prepared three novel
substituted thiazolidin-4-one derivatives. The synthesized compounds showed good
antibacterial activity against Escherichia coli, Staphylococcus aureus, Pseudomonas
aeruginosa and Salmonella typhi.
Gaikwad, Sajeevan et.al [5] have synthesized 5-(4-substituted-aryl)-7-
(naphtho[2, 1-b]furan-2-yl)-2H-thiazole[3, 2]pyrimidine-3(5H)-one derivatives. The
newly synthesized compounds were evaluated for their anti microbial activity.
Li, Xiaoliu; Chen, et.al [6] have prepared some thiazolidinone or
tetrahydrothiazinone fused aza sugar derivatives as anti-HIV agents. Compound [VI,
VII] showed inhibitory activity with IC50 of 4.49 µM against HIV reverse
transcriptase.
[VI] [VII]
[where in m = 1 or 2;n = 0-2; R = H, CH2OH, or CH2OTr;
P = H or hydroxy protective group]
Li, Xiaoliu et al.[7] have synthesized bi/ tricyclic azasugars fused thiazolidin-
4-one and thiazinan-4-one, by one-pot tandem Staudinger/aza-Wittig/cyclization
reaction under microwave radiation. The preliminary biological evaluation of
synthesized compounds were found to active the natural killer (NK) cells significantly
(immuno-potentiating activity) and exhibited weak inhibitory activity against
glucosidase. Yet none of these tested compounds [VIII] have obvious effects on T
cell proliferation.
SYNTHESIS AND CHARACTERISATION OF SOME NEW SULPHUR BASED HETEROCYCLES
Page : 31
[VIII]
A new series of N-[3-(10H-phenothiazin-10-yl) propyl]-2-aryl-4-oxo-5-
arylidene-3-thiazolidinecarboxamides [IX, X] were synthesized by Sharma, Ritu et
al.[8] All the compounds were screened for their antimicrobial activity against some
selected bacteria and fungi and for their anti tuberculosis activity,
[IX, X]
(R = CH Ar; Ar = Ph, 4-, 3- or 2-substituted
ClPh, BrPh, O2NPh, MeOPh, MePh, HOPh;)
4-thiazolidinonyl-quinazolin-4(3h)-ones of Diclofenac analog were designed
for a study of their biological Activity by Patel, Navin B.et.al.[9] Thiazolidinone
derivatives were screened in-vitro for their antimicrobial activity and several
compounds displayed good antibacterial as well as antifungal activity.
Rekha, S. et.al [10] have reported 5 - [[4 - (4 - methyl - 1 - piperazinyl)
phenyl] methylene] - 2, 4 - thiazolidinedione, 5 - [4 - (phenylamino)phenyl]
methylene] - 2, 4 - thiazolidinedione. The target compounds were screened for their
activity in a bovine serum denaturation (in vitro) assay (inflammation inhibitors).
They have reported all synthesized compounds were weakly active in the bovine
serum denaturation assay.
Alagawadi et.al [11] have designed new 2, 4-thiazolidinediones bearing
imidazo[2, 1-b][1, 3, 4] thiadiazole moiety. All the synthesized compounds were
evaluated for their preliminary in vitro antibacterial and antifungal activity and the
results revealed that most of the compounds showed high or moderate biological
activity against tested microorganisms.
Sharma, Nidhi et.al [12] have prepared 2-aryl-3-(benzimidazol-3-ylamino)-2-
methyl-4-thiazolidinones reported antibacterial and antifungal activity.
SYNTHESIS AND CHARACTERISATION OF SOME NEW SULPHUR BASED HETEROCYCLES
Page : 32
Maheta, S. et. al [13] have synthesized 4-chloro-2-hydroxy-N-(4-oxo-2-
arylthiazolidin-3-yl) benzamides. All the newly synthesized N-(oxo thiazolidinyl)
benzamides were evaluated for antibacterial and antifungal activities.
Murugan, V.et.al [14] have synthesized series of compounds [XI]. Among
synthesized compound they reported only three compounds have shown potent
antiulcer activity. Four compounds showed significant antibacterial activity. These
compounds were further subjected for antitubercular activity, and all of them showed
sensitivity at 50 and 100 µg/mL.
[XI].
[R =Ph, 4-MeOC6H4, 2-HOC6H, etc.].
Desai, N. C et.al [15] have synthesized several new 3-[2-(1Hbenzimidazol-2-
yl) phenyl]-2-arylthiazolidin-4-ones. All the synthesized compounds were evaluated
for antibacterial and antifungal activity against E. coli, S.aureus, P. aeruginosa, S.
pyogenes, C. albicans, A. niger, and A. clavatus.
Tomasic et.al [16] reported 2-thioxothiazolidin-4-one, thiazolidine-2, 4-dione,
2-iminothiazolidin-4-one or imidazolidine-2, 4-dione ring connected by a benzylidene
group. These compounds were designed to target the D-Glu- and the diphosphate-
binding pockets of the MurD active site and were evaluated for inhibition of MurD
ligase from Escherichia coli. The most potent compounds [XII] (R)- and (S)-I
inhibited MurD and the specific binding mode of (R)-I in MurD active site was
established by high-resolution NMR spectroscopy.
[XII]
Recently, some PPAR-γ agonists like pioglitazone, rosiglitazone, and other
newer thiazolidine-2, 4-dione (TZD) derivatives.
Raghubir et.al [17] have synthesized, thiazolidin-4-one derivatives and bio
evaluated in focal cerebral ischemia model in rats with an aim to ameliorate cerebral
ischemic damage. They have suggested that some of the synthesized thiazolidin-4-one
substituted PPARγ agonists exhibit better neuro protection and have potential to
SYNTHESIS AND CHARACTERISATION OF SOME NEW SULPHUR BASED HETEROCYCLES
Page : 33
ameliorate the ischemic damage. Therefore, this novel class of compounds could be
further suitably modified to obtain potent anti-ischemic agents, warranting clinical
exploitation.
Some new 3-[(1, 2, 4-triazolo[3, 4-b]-1, 3, 4-thiadiazol-2-yl)phenyl]-2-
arylthiazolidine-4-ones [XIII] have prepared by Parmar, Kokila et.al.[18] The
compdounds have been evaluated for antibacterial activity against B. subtilis, S.
aureus, P.aeruginosa and E. coli.
[XIII]
Ar = Ph, 4-MeOC6H5, 2-HOC6H5, etc.
Thomas, Asha B et.al [19] have synthesized N-(2-aryl-4-oxo-3-thiazolidinyl)
isonicotinamide by a novel method of stirring and sonication. Results indicate that
high yields and shorter reaction times can be achieved by employing this novel green
route method.
Several (phenylmethylene) thiazolidinedione derivatives were prepared by
Venkatesan, S .et.al [20]. The acute toxicity of these compounds were assayed by
determine of their LD50 and all compounds were interestingly less toxic than the
reference drug (diclofenac). The title compounds were evaluated in carrageenan-
induced rat paw edema model and it was discovered that they displayed activity as
inflammation inhibitors.
5-(phenylmethylene)-2-thioxo-4-thiazolidinone, (benzylidene)rhodanine
derivatives were prepared by Opletalova, et.al.[21].The title compounds were
evaluated for their lipophilicity RP-HPLC analysis and these compounds were
evaluated for their ability to inhibit photosynthetic electron transport (PET) in spinach
(Spinacia oleracea L.) chloroplasts and their ability to reduce the chlorophyll content
in freshwater algae (Chlorella vulgaris). They found that majority of the tested
compounds showed the lipophilicity of the compound and electronic properties of the
substituent were not decisive for PET-inhibiting activity. The most potent PET
inhibitor was (5Z)-5-(4-bromobenzylidene)-2-thioxo-4-thiazolidinone (IC50 = 3.0
μmol/L) and the highest algicide activity was displayed by (5Z)-5-(4-
chlorobenzylidene)-2-thioxo-4-thiazolidinone (IC50 = 2.2 μmol/L).
SYNTHESIS AND CHARACTERISATION OF SOME NEW SULPHUR BASED HETEROCYCLES
Page : 34
A series of novel 4-thiazolidinone and indolin-2-one hybrid derivatives have
been designed and synthesized and their cytotoxic activities were evaluated in vitro
against three human cancer cell lines including HT-29 (human colon cancer), H460
(human lung cancer), MDA-MB-231 (human breast cancer) by MTT assay by Wang,
Shuobing et.al.[22]. Several potent target compounds were further evaluated against
one cancer cell line SMMC-7721(human liver cancer) and one normal cell line WI-38
(human fetal lung fibroblasts). Most of the prepared compounds exhibited significant
antitumor activities against different human cancer cell lines. Compound [XIV] (IC50
= 0.025 μM,, 0.075 μM,, 0.77 μM,, 1.95 μM, ) was 52, 36, 4.8 and 3.3 times more
active than Sunitinib (IC50 = 2.2 μM,, 2.7 μM,, 3.7 μM,, 6.47 μM, )against HT-29,
H460, MDA-MB-231 and SMMC-7721 cancer cell line, respectively.
[XIV]
N-(4-oxo-2-phenylthiazolidin-3-yl)-1-(2-oxo-2H-benzopyran-6-yl)-5-
hydroxy-2-methylindole-3-carboxamides were prepared by Mulwad, et.al.[23] All the
compounds were screened for their antimicrobial activity and exhibited antibacterial
and antifungal activity.
N(1)-[(5-arylidenamino-1, 3, 4-thiadiazol-2-yl)methyl]- and N(1)-{[2-(2-aryl-
5-methyl-4-oxothiazolidin-3-yl)-1, 3, 4-thiadiazol-2-yl]methyl}-2-
methylbenzimidazoles were prepared by Srivastava, S. K et. al. [24].The newly
synthesized compounds were studied for antimicrobial activity against B. subtilis, E.
coli, K.pneumoniae, and S. aureus bacteria and A. niger, A. flavus, F. oxysporum and
T. viride fungi in vitro at 50 and 100 ppm concentrations. Some of the compounds
displayed pronounced biological activity.
(fluorenylidene) (oxo) - α-[(phenyl) hydrazinylidene] thiazoleacetonitrile and
(indenylidene) (oxo) - α-[(phenyl) hydrazinylidene] thiazoleacetonitrile derivatives
were synthesized and evaluated in-vitro against Gram-positive bacteria and Gram-
negative bacterial (Staphylococcus aureus, Escherichia coli) and zoo pathogenic fungi
(Candida albicans, Aspergillus flavus) by Metwally, Nadia Hanafy et.al [25] and it
was discovered that they displayed activity as antibacterial agents.
SYNTHESIS AND CHARACTERISATION OF SOME NEW SULPHUR BASED HETEROCYCLES
Page : 35
A series of 3-[4-(6-bromo-2-oxo-2H-chromen-3-yl)-1, 3-thiazol-2-yl]-2-
(substituted phenyl) 1, 3-thiazolidin-4-ones were synthesized by Joshi, Aakanksha
et.al.[26] The synthesized compounds were evaluated for their anti- antibacterial and
in vitro antioxidant activity.
3-[[(5-Bromo-2-hydroxyphenyl)methylene]amino]-2-thioxo-4-thiazolidinone
derivatives were synthesized by Abd. El Fattah et.al.[27].The title compounds were
evaluated against Pseudomonas sp., Escherichia coli, Bacillus subtilis,
Staphylococcus aureus, Candida albicans and it was discovered that they displayed
antibacterial activity, but not antifungal activity.
A series of 5-arylmethylidene-1, 3-thiazolidine-2, 4-diones, and 3-(7-hydroxy-
2-oxo-2H-chromen-4-ylmethyl)-5-arylidene-1, 3-thiazolidine-2, 4-diones, e.g., [XV,
XVI]. The synthesized compounds, 5-arylmethylidene-1, 3-thiazolidine-2, 4-diones
and 3-(7-hydroxy-2-oxo-2H-chromen-4-ylmethyl)-5-arylidene-1, 3-thiazolidine-2, 4-
diones, were evaluated by Cacic, Milan et.al [28] for their antioxidant activity.
[XV] [XVI].
Srikanth, L. et.al [29] have synthesized 5-[4-[7-[(1E)-3-oxo-3-phenyl-1-
propenyl]-8-quinolinyl] phenoxy]-2, 4-thiazolidinedione for a study of their anti
diabetic activity. The synthesized compounds were screened against a rat model and it
was discovered that these compounds displayed activity as oral hypoglycemic agents
in comparison with Rosiglitazone.
3-imino-2-thioxo-4, 5-dihydro-4-thiazolidinone were designed and
synthesized by Makki, Mohammad S.et.al.[30]. The title compounds were evaluated
against Escherichia coli, Bacillus subtilis, Staphylococcus aureus, Pseudomonas
vulgaris and Shigella flexneri and they reported that these compounds displayed
antimicrobial activity.
Tirlapur, Vijay Kumar; et.al [31] have prepared thiazolidin-4-ones and
pyrimidines incorporating benzo[b]thiophene. The synthesized compounds were
screened for antibacterial, antifungal, and anti inflammatory activity.
A series of thiazolidinones were prepared by Patel, Navin B et.al.[32] The in
vitro antimicrobial screening of the compounds were carried out against two Gram
SYNTHESIS AND CHARACTERISATION OF SOME NEW SULPHUR BASED HETEROCYCLES
Page : 36
positive (S. aureus, S. pyogenes), two Gram negative(E. coli, P. aeruginosa) bacteria
and three fungalspecies (C. albicans, A. niger, A. clavatus) using the broth micro
dilution method. Some of the compounds [XVII] were found to be comparable with
standard drugs.
[XVII]
Meshram, Jyotsna; et.al [33] have used Zeolite 5Å as an efficient and cost
effective catalyst for the synthesis of bis-thiazolidinones [XVIII]. Starting from bis-
imines [XIX] and mercaptoacetic acid. The drug-like properties of the products were
evaluated using Molinspiration bio informatic software and discussed.
[XVIII] [XIX]
R = Ph, 2-HOC6H4, 3-O2NC6H4, 4-MeOC6H4,
A series of nine new 5-{[3-(aryl)-1-phenyl-1H-pyrazol-4-yl] methylene}-3-
phenylthiazolidine-2, 4-diones was synthesized by Prakash, et.al.[34] All the
compounds were screened for their in vitro antibacterial (Staphylococcus aureus,
Bacillus subtilis, Pseudomonas aeruginosa and Escherichia coli) and antifungal
(Aspergillus niger and A. flavus) activity. Biological activities of these compounds
were compared with those of common available antibiotics, ciprofloxacin and
antifungal agent fluconazole. Out of the nine compounds tested for anti fungalactivity,
five showed > 50% inhibition against the A. flavus and three compounds showed >
50% inhibition against A. niger.
Singh, Arun; et.al [35] have synthesized 3-(2-(5-benzoyl-1H-
benzo[d]imidazol-1-yl) acetyl)-5-benzylidene-2-alkylthiazolidin-4-ones. All the
newly synthesized compounds were evaluated for their antibacterial and antifungal
activities.
Vandana, Tiwari; et.al [36] have used Zeolite 5A as an efficient and cost-
effective catalyst for the prepn. of 2-(2-chloro-3-quinolinyl)-3-phenyl-4-
SYNTHESIS AND CHARACTERISATION OF SOME NEW SULPHUR BASED HETEROCYCLES
Page : 37
thiazolidinone derivatives. The title compounds were evaluated for their antibacterial
activity against Staphylococcus aureus, Pseudomonas vulgaris, Pseudomonas
aeruginosa and Escherichia coli and it was discovered that several compounds
possessed broad-spectrum antibacterial activity.
Sharma, M. C.et.al [37] have prepared 2-(2-substituted-phenyl)-3-(4-{1-[2-
(1H-tetrazol-5-yl)-biphenyl-4-ylmethyl])-1H-benzoimidazol-2-yl}-phenyl)-
thiazolidin-4-ones. All the synthesized compounds were screened for Angiotensin (A
II) Receptor Antagonist antihypertensive activity with biphenyl tetrazole schiff bases
thiazoldine-4-one showed good activity compared with losartan.
Indolin-2-on-3-spirothiazolidinones, e.g. [XX], were identified by Vintonyak,
Viktor V et.al.[38] as a novel class of potent and selective substrate-competitive
inhibitors of Mycobacterium tuberculosis protein tyrosine phospgatase B (MptpB).
[XX]
Patel, Hasmukh S.; et.al [39] have synthesized 2-hydroxy-N-(4-oxo-2-
arylthiazolidin-3-yl) benzamides. All the newly synthesized compounds were
evaluated for their antibacterial and antifungal activities.
Novel thiopyrano[2, 3-d]thiazoles [XXI a, b, c, d] were synthesized by
Zelisko, N. I.; et.al [40]. Preliminary evaluation of anticancer activity of some
products was carried out.
[XXIa, b, c, d]
Aly, Ashraf A.; et.al [41] have prepared (Z)-methyl-2-arylhydrazide-4-oxo-3-
(propan-2-ylideneamino) thiazolidine-5-ylidene-acetates. Antitumor activity of
SYNTHESIS AND CHARACTERISATION OF SOME NEW SULPHUR BASED HETEROCYCLES
Page : 38
selected compounds was evaluated in hepatocellular carcinoma cells with compound
[XXII] demonstrating the highest degree of cell proliferation inhibition. Compound
[XXII] also demonstrated the greatest antioxidant activity based on results from the
DPPH radical scavenging assay.
[XXII]
A new series of 2-aryl-N-(4-phenylthiazolyl)-4-thiazolidinones were prepared
by Prabhu, Padmavathi P et.al [42]. The products were evaluated for in-vitro growth
inhibiting activity against several microbes. Some of the compounds showed
anthelmintic activity.
5-chloro-3-methyl-2-(2'-aminothiazole-4'-yl)benzofuran incorporate schiff's
base, thiazolidinone derivatives [XXIII] were synthesized by Basawaraj, Raga
et.al.[43]. The synthesized compounds were screened for antimicrobial and some
selected compounds were screened for their antitubercular activity.
[XXIII]
A series of 2-aryl, 3-benzyl-(1, 3-oxazolidine or 1, 3-thiazolidine)-4-ones,
possessing a methyl sulfonyl pharmacophore were synthesized by Zarghi, A.; et. al.
[44]. They evaluated their biological activities as selective cyclooxygenase-2 (COX-
2) inhibitors. Compound [XXIV] was identified as the most potent (IC50 =0.21 μM)
and selective (S. I. > 476) COX-2 inhibitor among the synthesized compoundsIt also
was a more selective COX-2 inhibitor than the parent reference compound celecoxib
(S. I. > 403).
SYNTHESIS AND CHARACTERISATION OF SOME NEW SULPHUR BASED HETEROCYCLES
Page : 39
[XXIV]
Verkman, Alan S. et al [45] have provides methods for identifying compounds
that are inhibitors of a calcium-activated chloride channel. Aminothiophene and
aminothiazole compounds [XXV] comprising these compounds are described that
inhibit efflux of chloride through a calcium-activated chloride channel and are useful
for treating diseases, disorders, and sequelae of diseases, disorders, and conditions
that are associated with aberrantly increased chloride and fluid secretion, e.g.
secretary diarrhea.
[XXV]
A range of benzothiazoles [XXVI], [XXVII] and [XXVIII] were synthesized
by Sonwane, S. K et.al [46]. The synthesized compounds were screened in vitro for
their antimicrobial activity against Bacillus subtilis, Escherichia coli, Klebsiella
pneumoniae and Streptococcus aureus bacteria and Aspergillus niger, Aspergillus
flavus, Fusarium oxisporum and Trichoderma viridefungi respectely. Some of the
compounds displayed pronounced biological activity.
[XXVI], [XXVII] and [XXVIII]
(R1 = 2-Cl, 3-Br, 4-MeO, 2-NO2, 4- N Me2, etc.)
SYNTHESIS AND CHARACTERISATION OF SOME NEW SULPHUR BASED HETEROCYCLES
Page : 40
REACTION MECHANISM:
..
R'
N
H
R
HOOC SH
..
.. HOOC
-
NH
R'H
R
S
O
O+
H HN H
R'H
R
S
O+
N
R'H
R
S
O
.. ..
N R'
H
R
S+ H
H+ Shift
-H2O
Protonation
-H+
SYNTHESIS AND CHARACTERISATION OF SOME NEW SULPHUR BASED HETEROCYCLES
Page : 41
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Page : 45
CHEMISTRY OF AZATIDINONE:
The azetidinone or β-lactums have been known as products of the reaction of
certain ketenes with anils. The discovery, during world war-II, that the important
antibiotics known as the penicillin contained a fused ring systems of which one part
was a β-lactums ring.
The systematic name assigned to the conjugated doubly unsaturated ring made
up of three carbon atoms and one nitrogen atom is azete [1], accordingly, the dihydro
derivatives is named azetine and the saturated ring system is name azetidine.
N NN
N
O1-azetine azetidine 2-azetidinoneazete
The 2-carbonyl derivative of azetidine is known as 2-azetidinones. The
development of the chemistry of the β-lactms was initiated by Staudinger and his co-
worker during his classical studies of ketenes [2]. For several years these researches
stood as only important contribution to this field of heterocyclic chemistry. However,
since 1940 a tremendous impetus has been given to the reactivity of these compounds
because of their relation to the structure of the naturally occurring penicillin.
S
O
NHO
RCH3
CH3
O
OH
General Structure of penicillin
A review of the earlier literature by Mogilaiah K. et al [3] describes the
synthetic procedure for 2-azetidenones. Various methods for the preparation of 2-
azetidinones have been described [4-6].
The four member 2-azetidinone rings appears to be smallest cyclic system that
is of accommodating the amide function as a consistent which is also known as β-
lactum ring.
SYNTHESIS AND CHARACTERISATION OF SOME NEW SULPHUR BASED HETEROCYCLES
Page : 46
BIOLOGICAL SIGNIFICANCE: Over the years it has been of great practical significance because of their good
pharmacological and biological activities such as antidepressants, antidegenerative,
sedative [7], Fungicidal [8], anti-inflammatory [9], antibacterial[10-13].
A novel, practical and stereo selective synthesis of (3R, 4R)-4-acetoxy-3-
[(R)-1-(t-butyldimethyl silyloxy) ethyl] -2-azetidinone, a key intermediate in the
prepn. of β-lactum antibiotics is reported by Grzeszczyk, Barbara; et.al. [14]
Mccomas, Casey Cameron; et.al [15] have prepared 2-azetidinone
derivativesand their pharmaceutically acceptable salts, are prepd. and disclosed as
antiviral agents. Some compounds were evaluated in HCV replicon inhibition assays
Gomathy, S.; Gowramma, B et.al [16] have synthesized naphthalene bearing 2-
azetidinone derivatives. The synthesized compounds are evaluated for their
antiparkinson's activity by 6-Hydroxydopamine lesioned rat's model (6-OHDA).
Among evaluated 2-azetidinone derivatives, compound with nitro Ph group at 2nd
position exhibited max. anti parkinson's activity.
4-aryl-3-chloro-1-(thieno [2, 3-d] pyrimidin-4-ylamino)azetidin-2-ones were
synthesized by Akbari, Vikunjana K et.al [17]. The final compounds were screened
for antibacterial activity against from Gram positive and Gram negative bacteria as
well as for antifungal activity.
Antre, R. V.; et.al [18] have described development of new chemical entities
of Edaravone (3-methyl-1-phenyl-1H-pyrazol-5(4H)-one) for their antibacterial
activity. Various N-(substituted benzylidenyl)-[2-(4, 5-dihydro-3-methyl-5-oxo-1-
phenyl-1H-pyrazol-4-yl)acetohydrazide] and 2-(4, 5-dihydro-3-methyl-5-oxo-1-
phenyl-1H-pyrazol-4-yl)-acetamide- (3-chloro-4-substituted phenylazetidin-2-one)
(DTa-DTe) screened for their antibacterial activity against Escherichia coli and
Bacillus subtilis.
A series of [1-(2-aryl-5-mercapto-1, 2, 4-triazol-1-yl)-3-(2-chlorophenoxy) -4-
(3-indolyl)] azetidin-2-ones were synthesized for anticonvulsant activity by Garg,
Neha;et.al. [19.] All compounds were screened in vivo for their anticonvulsant
activity and acute toxicity studies.
An efficient and extremely fast procedure for the synthesis of 3-chloro-4-[4-
(diethyl amino)-2-hydroxyphenyl] -N-phenyl-2-azetidinone derivatives were reported
by Raval, Jignesh P et.al. [20] under microwave irradiations. All synthesized target
SYNTHESIS AND CHARACTERISATION OF SOME NEW SULPHUR BASED HETEROCYCLES
Page : 47
compounds were screened for their antifungal activity and their antibacterial activity
against various Gram-positive and Gram-negative bacteria (Bacillus subtilis,
Staphylococcus aureus, Escherichia coli, Shigella flexneri, Pseudomonas aeruginosa,
Candida albicans, Aspergillus niger.
A series of 2-azetidinones and 4-thiazolidinones of 4, 4’-sulfonyldianiline, e.
g. [I and II] have been synthesized under microwave irradiation and conventional
heating by Bhusnure et.al. [21].All the synthesized products were screened for their in
vitro antibacterial, antifungal and anti-tubercular activity. The results indicated that
the synthesized compounds have moderate to potent activities.
[I]
[II]
Several 2-aminomethylene-[2-(3-chloro-2-oxo-4-aryl-1-azetidinyl)-1, 3, 4-
thiadiazol-5-yl] pyridine derivatives, 2-aminomethylene-[2-(2-aryl-4-thiazolidinyl)-1,
3, 4-thiadiazol-5-yl] pyridine derivatives were designed by Rajput et.al. [22] for a
study of their biological activity. They evaluated for their activity as antifungal agents
and they discovered that one compound displayed activity greater than Fluconazole
and Griseofulvin.
Smith Elizabeth M et. al [23] have prepared series of spiro-azetidines and
azetidinones and evaluated as novel blockers of the T-type calcium channel
(Ca(V)3.2) which is a new therapeutic target for the potential treatment of both
inflammatory and neuropathic pain.
Sayyed, M. A.; et.al [24] have synthesized 2-azetidinones were screened for
their antibacterial activity against E. coli, S. aureus, X. citri and E. carotovora. Some
of the compounds showed better activity than slandered antibiotic Tetracycline.
3-chloro 4-Aryl N-Pyridine 2-yl 2-Azetidinone derivatives were prepared by
Ramalakshmishmi, Natarajan et.al . [25]. All the compounds were subjected to
leptospirocidal study. Among the synthesized compounds some showed significant
SYNTHESIS AND CHARACTERISATION OF SOME NEW SULPHUR BASED HETEROCYCLES
Page : 48
activity and the compounds few showed moderate activity. From the above summary
they reported that forming azetidinone nucleus at the side chain of 2-amino pyridine
showed significant leptospirocidal activity.
Bhusare S. R. et al have synthesized [26] 2-azetidinones having structure [III].
All the synthesized compounds are screened for their antimicrobial activity.
S
NOCH3
N
O
Cl
CH3
Cl
I
BrN
N
N
N
SH
N
ClOR
[III] [IV]
Priyadarsani, Vijyaraj, Ravi T. K. and Prabha [27] have synthesized some
azetidinones [IV] for their antitubecular, antibacterial, antifungal activities.
Z. Huibin et al [28] have synthesis of a series 2-azetidinones with ester or amide
group in C-3 side chain. Their cholesterol absorption inhibition activity was assessed
in orally dosed, cholesterol fed hamsters. It was demonstrated that compound with
amide group in C-3 side chain exhibited high cholesterol absorption inhibition
activity.
Padam Kant and Saxena R. K. [29] synthesized 2-azetidinone derivatives [V, VI]
containing quinazoline scaffold as an antibacterial and antifungal agents.
N
N
O
C6H5
N
HC
CH3
NO
OO
N
NN
S
NN
N
O
Ar
H
ClR
Ar = 3-OCH3-C6H5,2-Cl-C6H5
[V] [VI]
Azetidiones [VII a, b] and thiazolidinones II (R1-R3 as above) were
synthesized by Shanmugapandiyan et.al. [30]. The synthesized compounds were
screened for antibacterial (Bacillus cereus, Escherichia coli, Micrococcus luteus,
Klebssiela pneumoniae, Staphylococcus aureus and Salmonella epidermidis),
antifungal (Aspergillus niger and Candida albicans), analgesic activity by writhing
reflex method and anti-inflammatory activity by carrageen an induced paw edema
method. The synthesized compounds showed significant activity of antibacterial,
antifungal, analgesic and anti-inflammatory activity comparable to that of standard.
SYNTHESIS AND CHARACTERISATION OF SOME NEW SULPHUR BASED HETEROCYCLES
Page : 49
[VII a, b] R1, R3 = H, OMe; R2 = H, Cl, OH, Me, NMe2, OMe
Triazoles [VIII a, b] which were prepared by Deeb, A.;et.al, [31] showed that
they are potential bactericides.
[VIII a, b]
(R1 = H, Cl, OMe, NMe2, NO2; R2 = Cl, phthalimido)
Abdel-Rahman, A. E et.al.[32] have synthesized [IX a, b, c] for bactericidal
activity. Thus, II (R = H, R1 = OMe) and III (R = H, R1 =Cl, NMe2, R2 = Cl) are
effective against Salmonella and III (R = H, R1 = NMe2, R2 = phthalimido) against
Proteus.
[IX a, b, c]
The azetidinones [X] were obtained by Abdel-Rahman, A. E et.al. [33] have
showed variable bactericidal activity.
[X]
SYNTHESIS AND CHARACTERISATION OF SOME NEW SULPHUR BASED HETEROCYCLES
Page : 50
S. K. Srivastava [34] have synthesized several 1-[5’-N’-1, 2, 4-
triazolomethyl)-1’, 3’, 4’-thiadiazole-2’-yl] -4-(substituted phenyl)-3-chloro-2-
oxaazetidines [XI] and evaluated for their antibacterial, antifungal, anticonvulsant and
anti-inflammatory activities.
O
N
S
R2
N
R1
NH
O
ClO
Where R1= H, CH3; R2= H,Br,OH
[XI]
N. R. Pai and J. P. Suryavanshi [35] have synthesized N-{naphtha-[1, 2-b] -
pyrano-[3, 4-d] -thiazol-8-yl} spirondoloazetidin-2-one and evaluated for their
antibacterial activities.
Various 4 – aryl – 1 - (aryl amino benzothiazolyl carbamoylphenyl) – 3 -
chloroazetidin-2-ones have been synthesized by Kumar, M. M. et.al. [36]. The
compounds were tested for anti-inflammatory activity (in-vitro) by protein
denaturation method and showed significant activity at low and high concentration
compared to standard drugs.
A novel series of new isonicotinyl hydrazide derivatives containing 2-
azetidinone nucleus were synthesized by Jaju, Sandip; Palkar et.al. [37]. All the
synthesized compounds were tested for their in-vitro anti mycobacterial activity
against Mycobacterium tuberculosis H37Rv using Alamar-Blue susceptibility test,
and the activity is expressed as the min. inhibitory concn. (MIC) in μg/mL. Among
the series, few compounds displayed an encouraging anti mycobacterial activity
profile as compared to that of the reference drugs isoniazid / rifampicin.
Galletti, Paola et.al [38] have described the synthesis and biological evaluation
of a series of novel β-lactums. In vitro inhibition assays against HDAC isoforms
showed an interesting isoform-selectivity of these compounds towards HDAC6 and
HDAC8. The isoform selectivity changed in response to modification of the
azetidinone-ring nitrogen atom substituent. The presence of an N-thiomethyl group is
a prerequisite for the activity of these compounds in the micromolar range towards
HDAC8.
A five and six membered heterocyclic systems containing nitrogen, oxygen
and sulfur of fused β-lactums incorporating thienopyridazine [XII] were found to
possess interesting biological properties were successfully synthesized by Solieman
SYNTHESIS AND CHARACTERISATION OF SOME NEW SULPHUR BASED HETEROCYCLES
Page : 51
H. A, Abd El. Latif F. M Khalil M. A. and Elazab I. H [39] thereby enhancing the
activity of β-lactum ring systems.
NN
SO
H5C2O
Ph
O
NHCO NAr
OCl
[XII]
P. S. Reddy and co workers [40] have synthesized novel bisquinazoline β-
lactum derivatives [XIII] having following structure.
N
N
O
CH3
N Z N
N
O
CH3
N
O O [XIII]
Moreover, 2-Azetidinone derivatives have been reported to possess Anti-
HCMV activity, [41]. Antiviral activity [42] and cholesterol absorption inhibition
activity [43].
3-Benzylazetidine-2-one derivatives were designed and evaluated as a novel
series of chymase inhibitors by Aoyama Y et.al [44]. Structure-activity relationship
studies of 3-benzylazetidine-2-ones, which exhibited 3.1 nM inhibition of human
chymase and enhancement of stability in human plasma (t(1/2) 6h).
The design and synthesis of a biotin-tagged photo reactive analogue C-4 of the
cholesterol absorption inhibitor Ezetimibe is described by Frick Wendelin et.al. [45].
Photo affinity labeling of intestinal brush border membrane vesicles with C-4 and
subsequent streptavidin-biotin chromatography leads to selective extraction of a 145
kDa integral membrane protein as the molecular target for cholesterol absorption
inhibitors.
Hassan, Khairy M et al [46] have synthesized new sulfa drugs [XIV, XV] (R=
aryl and R1 = heterocycle) contg. both β--lactum moieties is described. Biological.
screening of these compounds on some strains of pathogenic bacteria indicated they
have a different mechanism of action from that already known for the sulfa drugs.
[XIV, XV]
SYNTHESIS AND CHARACTERISATION OF SOME NEW SULPHUR BASED HETEROCYCLES
Page : 52
REACTION MECHANISM:
R
R'
N
H
R
..
N R'HR
O
Cl Cl
O+
H3CH2C
N CH2CH3
H3CH2C
H3CH2C
N+
CH2CH3
H3CH2C
Cl Cl
O-
ClO +
Chloro acetyl chloride
Step‐1
Step‐2
ClO O
-
Cl
R'
N+
HR
Ketene
(C2H5)3 N+.HCl
-
SYNTHESIS AND CHARACTERISATION OF SOME NEW SULPHUR BASED HETEROCYCLES
Page : 53
References: 1. Patterson and Cappel; The Ring Index, Reinhold Publishing Corp., N.Y., P4
(1940).
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Krajewska, Olga; Chmielewski, Marek; Furman, Bartlomiej ; J. Antibiotics,
66(3), 161-163 (2013).
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Bulletin of the Faculty of Science, Assiut University, 11(1), 41-8 (1982). 34. Srivastava, S. K.; Ind. J. Chem., 41B, 2357, (2002). 35. Rai, N. R. and Suryavasani, J. P.; Ind. J. Chem., 45B, 1227, (2006). 36. Kumar, M. M. J. Vijay; Nagaraja, T. S.; Shameer, H.; Jayachandran, E.;
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40. Reddy, P. S., Reddy, P. P. and T. Vasantha; Ind. J. Chem., 41B, 1946, (2002). 41. Guillermo, G. N., Teresa, G. L., Graciela, A., Robert, S., Jan, B., Erik, D. C.
and G. M. Rosario, Bioorg. Med. Chem. Lett., 14, 2253, (2004). 42. Grigoris, Z., Christos, F., Ioannis, P., George, B. F., F. George, P. Elizaveta,
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SYNTHESIS AND CHARACTERISATION OF SOME NEW SULPHUR BASED HETEROCYCLES
Page : 56
CHEMISTRY OF PYRIMIDINES: Pyrimidine is a six membered heterocyclic compound consisting of two
nitrogen atoms at 1 and 3 position of heterocyclic ring.
N
N
Pyrimidine
Generally pyrimidine derivatives such as 2-hydroxy pyrimidine, 2-mercapto
pyrimidine and 2-aminopyrimidine are studied. Pyrimidines have been isolated from
the nucleic acid hydrolysates.
Pyrimidines are among those molecules that make life possible has being
some of the building blocks of DNA and RNA. Several analogs of pyrimidines have
been used as compounds that interfere with the synthesis and functioning of nucleic
acids e.g. fluorouracil, which has been used in cancer treatment, Also there are some
thiouracil derivatives, which produce adverse reduction in susceptible patients and
found more potent and less likely to produce side effects and is being widely used[1].
There are several other important groups of pyrimidines with medicinal uses.
Pyrimidine ring carrying various substituent may be built up from two or three
aliphatic fragments by the principle synthesis or by a variety of other synthesis, which
are complimentary rather than alternative to it. A second type of synthesis is the
isomerisation or break down of another heterocycles such as a hydration of purine but
such roots are frequently used.
The first primary synthesis from aliphatic fragments was carried out by
Frankland et al., in 1848, since then a many distinct primary synthetic method have
been devised [2-11]. It is also possible to prepare pyrimidines from other heterocyclic
compounds such as pyrole [12], imidazole[13] and oxazoles[14-15], pyridines[16],
pyrazines[17], 1, 3, 5-triazines[18], oxazines[19], thiazines[20] by variety of
processes. Pyrimidine derivatives occurs in natural products [21]like nucleic acids and
vitamin-B have remarkable pharmaceutical importance [22-23]because of their
biological activities[24].The biological significance of the pyrimidine derivatives has
led us to the synthesis of substituted pyrimidines. As pyrimidine is a basic nucleus in
DNA & RNA, it has been found to be associated with diverse biological activities.
SYNTHESIS AND CHARACTERISATION OF SOME NEW SULPHUR BASED HETEROCYCLES
Page : 57
[25]The synthesis of substituted pyrimidine and many detailed reviews have been
appeared. [26-27].
GENERAL METHODS OF PREPARATION OF PYRIMIDINES:
Synthetic strategies involved four main routes based on the condensation of
two fragments, as illustrated by (I) to (IV). Of these strategies, the one illustrated by
(I) i.e. the condensation of a three carbon unit with an N – C – N fragment, appears to
be the most widely used, offering direct entry in to the pyrimidine nucleus.
N
CN
CC
C
CC
C
N
N
CC
C
N
CN
C
CC
C
N
CN
( I ) ( II ) ( III ) ( IV ) This approach has been called ‘the common synthesis because of its general
applicability to the synthesis of a whole range of pyrimidine derivatives.
1. The great versatility in this synthesis rests with the fact that one or both of the
groups of the three carbon fragment may be present as an aldehyde, ketone, ester
or nitrile group. β-Dialdehydes (or their equivalent), β-keto aldehyde, β-keto
esters, malonicester, β-aldehyde or β-keto nitriles and many other combinations of
these groups or their marked derivatives may be used. The nitrogen containing
fragment may be an amidines, urea, thiourea or guanidine and acetylacetone
serves as an excellent illustrative example in that it readily undergoes reaction
with formamidine, [28]guanidine, [29]urea, [30]thiourea[31]to produce the
correspond- ding 4, 6-dimethyl pyrimidine. (Scheme –I)
CH3 CO CH2 COCH3
NH2 C NH2
O
NH2 C NH2
S
NH CH NH2C NHNH2
CH3
N
N
Me
Me
N
N
Me
SHMe
N
N
Me
Me OH
N
N
Me
Me NH2
(Scheme –I)
SYNTHESIS AND CHARACTERISATION OF SOME NEW SULPHUR BASED HETEROCYCLES
Page : 58
The limitation of this reaction is that, in practice not all possible combinations of
reactants produce the expected products, as typified by the failure of malondialdehyde
to undergo condensation with formamidine to produce pyrimidine. It is often possible
however; to achieve transformations of this type by modification of the reaction
conditions and/or reactants. Thus 1, 1, 3, 3-tetraethoxy propane, a readily available
precursor of malondialdehyde, reacts with formamide over an alumina catalyst at
200°C to produce pyrimidine in 70% yield.
2. Hussain et al [32] have prepared pyrimidine derivatives by the condensation
between chalcone and guanidine nitrate. (Scheme-II)
O
F
ClCl+ NH2 C NH2
NH
HNO3
EtOH / OH
F
ClCl
N N
NH2 (Scheme – II)
3. 3, 5-dibromo-4-hydroxy substituted chalcones react with SBT in presence of
piperidine / pyrrolidine in DMF to give pyrimidines [33] (Scheme-III)
OH
Br
Br
C CH3
O
+
R2
CH
O
R1
OH
OH
Br
Br
C CH
O
CH
R2
R1
SBT/DMF - piperidine/
pyrrolidineexcess base
[O]
3,5-Dibromo-4-hydroxy acetophenone
SYNTHESIS AND CHARACTERISATION OF SOME NEW SULPHUR BASED HETEROCYCLES
Page : 59
OH
Br
BrN
NS
R2
CH2 Ph
R1
OH
Br
BrN
NR3
R2
R1
(Scheme – III) Where R1, R2, R3 = H
4. 4-(2-Amino phenyl)-6-(2, 4-dichloro-5-fluoro phenyl) pyrimidine is obtained by
condensing compound (I) and guanidine hydrochloride in presence of sodium
hydroxide in ethanol. [34] (Scheme-IV)
O
Ar Ar'+ NH2 C NH2
NH
HCl
EtOH / OH
N N
NH2
Ar' Ar
( I )
Ar = 2,4-(Cl)2-5-F-C6H5
Ar' = C6H5
(Scheme-IV)
5. The reaction of chalcone with guanidine hydrochloride in presence of potassium-t-
butoxide in t-butanol yielded corresponding 2-amino pyrimidine derivatives [35]
6. Abd-El-galil E. Amr et.al [36] synthesized aminopyrimidines by the reaction of
chalcones with guanidine hydrochloride in the presence of NaOH.
7. Rasaki [37] synthesised 2-aminopyrimidine by the reaction of chalcone epoxides
with guanidine carbonate in xylene.
SYNTHESIS AND CHARACTERISATION OF SOME NEW SULPHUR BASED HETEROCYCLES
Page : 60
BIOLOGICAL SIGNIFICANCE:
Pyrimidines are an important class of drugs science they possess a wide range
of biological activities. A large number of derivatives are reported to exhibit
antitumor [38-41], antiviral [42], antifungal, anticancer [43], antibcteria [44], anti-
inflammatory [45-48], analgesic [49], Antagonist [50-51], antifolate [52],
antimicrobial [53], anti-HIV [54], antiproliferative [55], antiplatelet [56],
antithrombotic [57], antifilarial [58] activities, etc.
Khadse et. al. [59] prepared following type [V] of thiourea derivatives
possessing antituberculosis activity at 1.56 μg/ml against M.tuberculosis. N
N
NH2
NH2
NH C NH R
S [V]
6-Cyclopropyl-4-methyl-N-phenyl-2-pyrimidine [VI] synergistically
controlled pyrenophora terse on barley. [60]
NN
NH
Me
Ph N
N
N
NH2
NH2
CH3
N
R
[VI] [VII] Where R= H, Me
A series of pyrimidine derivatives of type [VII] have been synthesized as
potential Pneumocystis carrinii, Toxoplasma gondii and Dihydrofolate reductase
inhibitors as antitumor agents. [61]
6-Chloro-2-[(1-fuloro[2, 3-c]pyridine-5-ylethyl)thio]-4-pyrimidinamine and its
derivatives have been synthesized as broad spectrum of HIV-1 non-nucleoside reverse
transcriptase inhibitors. [62]
N
NX
NH2
NH2
R
Where R= 3,4,5-(OCH3)3,H,2-Cl
NN
F
O RR'
F
X
Where X = NH; R, R' = Me
[VIII] [IX]
L. Naesens et al [63] showed that some of the pyrimidine derivatives of type
[VIII] exhibited antiviral activity against DNA viruses or RNA viruses tested invitro.
SYNTHESIS AND CHARACTERISATION OF SOME NEW SULPHUR BASED HETEROCYCLES
Page : 61
R. Ragno [64]has synthesized a series of pyrimidine derivatives. Amongst
these, 2-cyclo pentyl amino-6-[1-(2, 6-difluoro phenyl)ethyl-3, 4-dihydro-5-methyl
pyrimidine-4(3H)-one [IX] was active against the Y181C HIV-1 mutant strain at
submicromolar concentration, with a resistance value similar to that of efavirenz, the
last FDA approved NNRTI for AIDS therapy.
Several novel 2, 4-diamino pyrimidines were synthesized and tested as
inhibitors of dihydrofolate reductase (DHFR) and compared with their activity against
DHFR derived from Mycobacteria and Escherichia coli. [65]
Highly potent dihydroalkoxybenzyloxopyrimidine (DABO) [X] derivatives
targeting the nonnucleoside inhibitors (NNI) binding site of Human
Immunodeficiency Virus (HIV), Reverse Transcriptase (RT) have been designed
based on the structure of the NNI binding pocket and tested for their anti-HIV
activity. [66]
NN
NH2
NNR
RR
R
N
NH
O
R2
R1
R1S S
Me
Where R1 = H,Me; R2 = Me,Ethyl, Isopropyl
[X] [XI]
Liu et al [67] synthesized three new two-photon absorption chromophores
based on a pyrimidine core [XI]. They were synthesized by aldol condensation in the
absence of any organic solvents. Their single-photon spectroscopic characterization as
well as their two-photon absorption properties is reported. In addition, strong
modulation of single-photon and two-photon fluorescent spectra of these molecules
by protonation is also discussed.
Many scientists have synthesized 2, 4, 6-trisubstituted pyrimidines. They have
been shown to possess diversely biological activities. As examples, compound [XII]
shows in vitro antimalarial activity against Plasmodium falciparum[68], with an MIC
value of 0.25 μg/ml. Compound [XIII] is a selective adenosine A1 receptor
antagonist[69], with high A1 affinity and selectivity. Compound [XIV] is a
phosphotidyli- nositol kinase inhibitor and can be used for the treatment of cancer
[70]. Compound [XV] shows antitubercular activity against Mycobacterium
tuberculosis at a concentration of 12.5 μg/ml[71].
SYNTHESIS AND CHARACTERISATION OF SOME NEW SULPHUR BASED HETEROCYCLES
Page : 62
NN
CH3N
NN
NHCH3
O [XII] [XIII]
NN
N
O
NN
NH
CH3
N
CH3
CH3
OOHCH3
[XIV] [XV]
Chikhliya et al [72] have studied and synthesized of pyrimidine derivatives
and their biological properties. Where R = aryl substituted [XVI].
NN
NH
R
S
O
O
N N
NN
O [XVI]
Thore synthesized [73]3, 5-bis-1, 4-dihydro-4-phenyl 2, 6-dimethyl pyridine-
2`-amino-6` phenyl pyrimidines [XVII].
NH
CH3CH3
R
N
N
NH2
R1
N
N NH2
R2
[XVII]
SYNTHESIS AND CHARACTERISATION OF SOME NEW SULPHUR BASED HETEROCYCLES
Page : 63
S. S. Bahekar and D. B. Shinde[74] have synthesized [2-amino-6-(4-
substituted aryl)-4-(4-substituted phenyl)-1, 6-dihydropyrimidine-5-yl]-acetic acid
derivatives [XVIII]. Synthesized compounds have shown good anti-inflammatory
activity against standard drugs.
NH
N NH2
R1
ROH O
R = Aryl, R1 = H,Cl,CH3
N
NN
N
N N
Ar
Ar
Ar = Substituted phenyl [XVIII] [XIX]
Om Prakash [75]and his co-worker reported the synthesis of 3, 9-diaryl and 3,
9-difuryl-bis-1, 2, 4-triazolo[4, 3-a][4, 3-c]-pyrimidines [XIX] as antibacterial agents.
Aldo Andreani [76]and his co-worker reported the new heterocyclic system
diimidazo-(1, 2-a:1, 2-c)-pyrimidine [XX] which is a key intermediate for the
synthesis of antitumour derivatives.
S
N N
NN
RR
N
NH
NH
NH2
N
NH
NH
NH2
[XX]
Nigel J. Liverton et.al. [77] have synthesized 4-methylbenzyl 4-[ (pyrimidin-2-
ylamino) methyl]piperidine-1-carboxylate (XXI), an orally bioavailable, brain
penetrant NR2B selective N-methyl-D-aspartate receptor antagonist. Demonstrated
efficacy in vivo rodent models of antinociception, allodynia, and Parkinson's disease.
[XXI]
Prasenjit Mondal et al. [78] have synthesized the novel mercapto-pyrimidine
and amino-pyrimidine derivatives of indoline-2-one as potential antioxidant and
antibaterial agents, 1- (2-mercapto-6- (substituted phenyl) pyrimidine-4-yl) -3- (2-
substituted phenyl imino) indolin-2-one and 1- (2 amino-6- (substituted phenyl)
pyrimidine-4-yl) -3- (2-substituted phenyl imino) indolin-2-one were synthesized
from different substituted chalconised indole 2, 3 dione.
O N
O
HN
N
N
SYNTHESIS AND CHARACTERISATION OF SOME NEW SULPHUR BASED HETEROCYCLES
Page : 64
H. M. Hassan and A. A. Farrag [79], have synthesized 2-[glycyl or Dl-valyl-
p-substituted phenylmethyleneamino] -pyrimdine derivatives [XXII, XXIII]. The
resulting novel amino acid derivatives were screened for their antimicrobial activity
and application against plant pathogenic fungus Botrytis cinerea, the causal agent of
cucumber plant (Cucmis. sativa L) gray mold disease.
[XXII] [XXIII]
Rajesh Vyas et al., [80], have synthesized 4- (4-chlorophenyl) -6- (3, 4, 5-
trimethoxyphenyl) -pyrimidin-2-amine (XXIV), which showed the antibacterial and
herbicidal activity.
(XXIV)
Naik et. al., [81] have synthesized 2-[{2 (Morpholino) -3-pyridinyl- 5- thio} -
2 oxoethyl oxadiazolyl]- amino- 4- (2, 4 dichloro- 5- fluorophenyl) - 6- (aryl)
pyrimidine (XXV), which showed antimicrobial activity.
(XXV)
Stephane pedeboscq et al., have [82] synthesized 4- (2-Methylanilino)
benzo[b] thieno [2, 3-d] pyrimidine (XXVI) and 4- (2-Methoxyanilino) benzo [b]
N
O
NH2
N N
.HCl N
O
NH2
N N
C3H7
.HCl
XXI XXII
N N
Cl
OCH3
OCH3
OCH3
NH2
Cl
F
Cl
N N
NHO
S
N
N
O
N
N
O
CH3
SYNTHESIS AND CHARACTERISATION OF SOME NEW SULPHUR BASED HETEROCYCLES
Page : 65
thieno[2, 3-d]pyrimidine (XXVII) and demonstrated positive results on anti cancer
activity.
(XXVI, XXVII)
It was thought interesting to prepare some new oxo pyrimidine, thio
pyrimidine, substituted pyrimidine-2-thione derivatives from substituted chalcones.
N
N
NH
S
H2N
CH3N
N
NH
S
H2N
OCH3
SYNTHESIS AND CHARACTERISATION OF SOME NEW SULPHUR BASED HETEROCYCLES
Page : 66
Reaction Mechanism :
CR'
O
R CH
OH
NH
NH2
X
R ..
..NH NH
X
N N
NH2-H
-+, -H
-
OH-
-H2O
NH N
X
R'
NNH2
X
R R'R R'
R R' R R'
X = O, S, NH
SYNTHESIS AND CHARACTERISATION OF SOME NEW SULPHUR BASED HETEROCYCLES
Page : 67
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