Borde R.M. -Final PPT.pptx

Thesis entitled,
“DEVELOPMENT OF NEW AND IMPROVED SYNTHETIC
PROTOCOLS FOR BIOACTIVE HETEROCYCLIC COMPOUNDS”
Thesis Submitted to
DR. BABASAHEB AMBEDKAR MARATHWADA UNIVERSITY,
AURANGABAD
For the Degree of
D o
c
to
r o
f P h
ilo
so
p
h
y
In Chemistry
Submitted by
Ramesh M. Borde
(Research Scholar)
Under the guidance of
Dr. A. S. Munde
Professor & Head
Dept. of Chemistry, Milind College of Science,
Nagsenvana, Aurangabad (MS), 431001.
1

The present work is divided into Six chapters:-
Chapter I Literature Overview & Introduction
Chapter II: Synthesis of substituted Nitriles
(Precursor for heterocyclic synthesis)
Chapter III: Synthesis of substituted Bis-Thiazoles, Hydrazones
It isdivided into three sections
Chapter IV: Synthesis of substituted Thiazolyl-Thiazolidine-4-one
Chapter V: Synthesis of substituted Thiazolyl-1, 3, 4-Oxadiazoles
Chapter VI: Antimicrobial and Anti-inflammatory activity
It isdivided into two sections.
Section A: Anti-bacterial and anti-fungal Activity
Section B: Anti-inflammatory Activity.
2

Chapter-I
Literature Overview
3

Introduction
Heterocycles and medicines are both inter-related, human are
totally dependent on drugs and most of the drugs are derived
from heterocyclic compounds.
Heterocycles and their derivatives have attracted the attention of
chemist mainly because of broad spectrum biological and
pharmacological activities.
Most of heterocyclic compounds are naturally occurs and
playing a vital role in the metabolism of living cells.
The main objective of the medicinal chemistry is to synthesize
the compounds that show promising activity as therapeutic
agents with lower toxicity.
Introduction
4

Anti-inflammatory Antitubercular Analgesic
5
 Compounds containing more than one pharmacophore is present in
the single molecules, leads to increases the biological activities of
compounds.
 There are vast numbers of pharmacologically active heterocyclic
compounds, many of which are in regular clinical use.
 They have been found to possess biological activities viz.,
antiviral, anticonvulscent and Analgesic.

Anti-bacterial Anti-fungal
 Due to such important biological activity, heterocyclic
compounds and their derivatives occupy an important place in
medicinal chemistry.
 The most successful biologically active heterocyclic compounds
are Thiazole, Bis-Thiazole, Thiazolidin-4-one, 1,3,4-Oxadiazole,
Benzimidazole, Coumarine, 1,2-benzisoxazole, Flavone, Benzo
diazepine and Benzothiazepine etc.
6

Aim and objectives of the research work
 Keeping in view, the widespread applications of heterocyclic
classes of compounds in medicinal chemistry, we have decided to
synthesize a series of heterocyclic species substituted to thiazoles
ring core like Nitriles, Bis-Thiazole, acyl-hydrazone, Thiosemi-
carbazone, Thiazolidine-4-one, 1,3,4-Oxadiazole, Oxadiazole-2-
thione derivatives.
 In the present research program we intended to focus on.
 Design and synthesis of novel analogs of heterocyclic scaffolds.
 Purification and characterization of newly synthesized compounds
by using different spectroscopic (IR, 1HNMR, Mass) techniques.
Biological evaluation of these novel chemical entities.
7

 Thiazoles having potent biological applications, described by
Hantzsch and Weber for the first time in 1887.
 Thiazoles are organic five-membered aromatic compounds with the
general formula of C3H3NS, similar chemical and physical
properties to pyridine and pyrimidine.
 The most important naturally occurring thiazole derivatives is a
thiamine (Vitamin B1). Various natural food flavours and aroma
consisting of thiazole nucleus.
 Thiazole and bis-thiazoles derivatives are important research area
due to their interesting diverse pharmacological activities such as
antibacterial, antifungal, antiviral, anti-inflammatory and anticancer
properties.
 Resonating structure of Thiazole
8
N
S
N
S
+
N
S
+
_
N
S
_
+
N
S
+
_
N
S
_
+
_

9
 Synthesis of thiazole and bis-thiazoles derivatives by involves the
condensations of alpha-halocarbonyl compounds with various
reactant containing the N-C-S fragment. Such as, compounds
includes thiourea, thioamides and thiosemicarbazones.
 Various oldest methods of synthesis of thiazole derivatives such
as, Gabriel thiazole synthesis involves cyclization reactions of
acyl aminocarbonyl compounds and stoichiometric amount of
phosphorus pentasulfide at 170 0C.
 Cook-Heilbron synthesis of 2,4-disubstituted 5-aminothiazole
derivatives by the reaction of an α-aminonitrile and dithio acids or
esters of dithioacids , carbon disulfide, carbon oxysulfide or
isothiocyanates under mild reaction conditions, product obtained
in good yields
N
S
H2N R2
N
H2N
R1
HS R2
S
+ -H2S
R1

 some biologically active bis-thiazoles derivatives.
10
N
S
Br
H
N
H 3CO O CH 3
H
N
S
N
Br
N
S
H N
N
H 3C
H 3CO O CH 3
N
S
N
H N
CH 3
A nti-proliferative (I) A nti-tubercular (II)
N
S
CH 3
N
H
H 3C
N
S
N
H
N CH 3
A ntifungal (III) A ntibacterial (IV )
N
S
H 2N
O
R
O
N
S
N H 2

11
 Thiazole is an important pharmacophore in a number of useful
drugs such as, Febuxostat, Nizatidine, Vitamin B1 and Cobicistat.
 Febuxostat is a urate-lowering drugs and inhibitor of xanthine
oxidase used for the treatment of hyperuricemia and chronic gout.
 Nizatidine is a histamine H2 receptor antagonist that inhibit
stomach acid production, used for the treatment of peptic ulcers
and gastroesophageal reflux disease.
O
S
N CH3
COOH
NC
Febuxostat
S
N
H
O
H
3
C +
N
N
C
H
3
H
2
N
V
i
t
a
m
i
n
eB
1
N
S
H O
S
N H
H N
N O 2
H 3 C
N i z a t i d i n e

12
Thiazolidin-4-one
 Thiazolidin-4-one is the derivative of thiazolidine which belong to
an important group of heterocyclic compounds containing S and N
in a five member ring.
 Thiazolidin-4-one containing β-lactam ring stops the biosynthesis
of p-glycone moiety which is needed for cell wall of bacterial
organism.
 Thiazolidinone nucleus is present in acithiazic acid is an antibiotic
obtained from Streptomyces strains exhibits highly specific in-
vitro activity against mycobacterium tuberculosis.
 Thiazolidin-4-one derivatives are important research area due to
their interesting diverse pharmacological activities such as
antimicrobial, anti-inflammatory and antiviral properties.

13
 Thiazolidinones are the derivatives of thiazolidine derivatives and
have an atom of sulfur at position 1, an atom of nitrogen at
position 3 and a carbonyl group at position 2, 4 or 5 positions
responsible for enhancing the compounds pharmaceutical
importance.
NH
S
O
NH
S
O
HN
S O
2-Thiazolidinone 4-Thiazolidinone 5-Thiazolidinone
 Thiazolidinone isomeric structure.
 The main synthetic route to thiazolidin-4-ones comprising three
components such as, amine, carbonyl group and thioglycolic
acid. One pot synthesis of thiazolidin-4-ones derivatives by acid
catalyst beta-cyclodextrin-SO3H, substituted aldehydes and
thioglycolic acid.
N
R1
Cl
CHO
N
S
R2
O
N
Cl
NH2
R2
+ + HS COOH
beta-cyclodextrin-SO3H
R1

14
N
N
Br
O
S
N
Cl
H
N N S
O
Cl
N
S N
H
N S
O
OCH3
OH
N
H
H3C
H
N
S
N
N S
O
OH
N
N
N
S
CH3
N
H
O
N
S
O
Anti-inflammatory (I) Anticonvulsant (II)
Anti-diabetic (III) Anti-tubercular (IV)
 some biologically active thiazolyl-thiazolidine-4-one derivatives.

15
 Thiazolidine-4-one is an important pharmacophore in a number
of useful drugs such as, Epalrestat and Pioglitazone etc,.
 Epalrestat is a carboxylic acid derivatives and non-competitive
and reversible aldose reductase inhibitor used for the treatment of
diabetic neuropathy.
 Pioglitazone is a anti-dibetic drugs for the treatment of type 2
diabetes who have inadequate glycemic control.
N
S
O
C
O
O
H
S
C
H
3
E
p
a
l
r
e
s
t
a
t
H
N
S
O
O
O N
P
i
o
g
l
i
t
a
z
o
n
e

16
1,3,4-Oxadiazole
 The promising objects for discovery belong to quite a one oxygen
and two nitrogen-containing five-membered heterocyclic compounds
such as, oxadiazoles. The oxadiazoles exists in different isomeric
forms such as, 1,2,4-, 1,2,5-, 1,2,3-, and 1,3,4-oxadiazoles.
 Oxadiazoles have also attracted interest in medicinial chemistry as
bioisosteres for carboxylic acids, esters and carboxamides. it also
significant part of pharmacophore which is capable binding to a
ligand.
 2,5-substiuted-1,3,4-Oxadiazoles compounds with diversified types
of pharmacological activities such as, anti-inflammatory activity,
anti-oxidant, human NK1 antagonists, antiplatelet and antithrombotic
agents.
N
N
O
N
N
O
N
N
O
N
N
O
1,2,4-Oxadiazole 1,2,5-Oxadiazole 1,2,3-Oxadiazole 1,3,4-Oxadiazole
 Oxadiazole isomeric structures.

17
 The 1,3,4-oxadiazole undergoes number of reactions including
electrophilic substitution, nucleophilic substitution, thermal and
photochemical reactions.
 The common synthetic method for these compounds is cyclo-
dehydration of diacylhydrazines and their derivatives with
dehydrants such as, phosphorous oxychloride, trifluoroacetic
anhydride and thionyl chloride etc.
 2,5-substituted 1,3,4-oxadiazole derivatives by the condensation
of N-acyl hydrazone with aq. hydrogen peroxide as oxidant using
Iodine as catalyst in DMSO solvent at room temperature.
N
N
O R'
I2 (10 mol%), Aq.H2O2, K2CO3
DMSO, RT, 4-9 hr's
R
R N
H
N
O
R'

18
N
N
O OCH3
N
S
CH3
N
Anti-tubercular (I) Anti-tumor (II)
NC
O
N
N N
O
H
N
N
S
N
S
O
N N
O
HS
Anti-bacterial (III) Anti-fungal (IV)
S
N
CH3
O
N
N
F
Cl
Cl
 some biologically active thiazolyl-1,3,4-Oxadiazole derivatives.
 1,3,4-Oxadiazole containing drugs such as, Ataluren used for
the treatment of Duchenne muscular dystrophy, small molecule
compounds that targets nonsense mutation.
O N
N
F
COOH
Ataluren

19
Chapter-II
Synthesis of substituted Pyrimidines
Synthesis of substituted Nitriles
(Precursor for heterocyclic synthesis)
One flask synthesis of substituted nitriles by the reactions of
aldehydes and hydroxylamine hydrochloride in the presence of calcium
chloride as a catalyst.

20
 Nitriles have played a major role in the synthesis of a variety of
open chain and heterocyclic compounds. these nitrogen containing
compound possessing broad spectrum of biological activities.
 It has been found that the cyano functional group is presents in
HIV protease inhibitors, 5-lipoxygenase inhibitors. A number of
nitriles functional group are present in enzyme inhibitors and
receptor ligands.
 Nitriles are widely used for transformation into amides, amines,
ester and carboxylic acids. Hence they have been used as
intermediates for the synthesis of fine chemicals such as,
agricultural chemicals, dyes and medicines, chemical solvents.
 Cyano functional group can also prepared by via.Oxidation,
rearrangement, elimination, dehydration of primary amides or
aldoximes to nitriles.
 Traditional methods of synthesis of nitriles are Kolbe nitrile
synthesis, Rosenmund-Van Braun reaction and Sandmeyer
reaction etc.

21
 Transformation of Nitriles to heterocycles
N
i
t
r
i
l
e
s
C N
N
S
T
h
i
a
z
o
l
e
s
N
O
O
x
a
z
o
l
e
s
N
N
S
T
h
i
a
d
a
z
o
l
e
s
N
N
H
N
N
T
e
t
r
a
z
o
l
e
s
 Synthesis of substituted nitriles by using dehydrating agent
calcium chloride(CaCl2) without isolation of oximes. Cacl2 is a
homogeneous catalyst, is inexpensive, this catalyst better than
heterogeneous catalyst in this method synthesis of aryl/alkyl
nitriles in good yields.

22
 The nitriles functional group is present in a variety of leading
drugs such as, Milrinone, Citalopram, Letrozole and Fadrozole
etc.
 Milrinone is a phosphordiesterase 3(PDE3) inhibitor drugs used
as cardiac surgeries as an inotropic and pulmonary vasodilator
agents, for the treatment of heart failure. Citalopram is a selective
serotoniun reuptake inhibitor (SSRI) antidepressant, commonly
used in the treatment of major depressive disorder. Letrozole is an
aromatase inhibitor used for the treatment of breast cancer.
N
H
O
CN
H3C
N
Milrinone
O
N C
N C H 3
C H 3
F
C i t a l o p r a m
NC
N
CN
N
N
Letrozole

23
Present work
R-CHO NH2OH.HCl
CaCl2, DMF
Reflux, 1-3.30 hrs
[R-CH=N-OH] R-C N
1a-k 2 3a-k
(82-95%)
Scheme-I
[1] Borde Ramesh M., Waghmare Rahul A., Jadhav Satish B., *Munde Achut S., “One Pot
Synthesis of Nitriles from aldehydes and hydroxylamine hydrochloride using calcium chloride
in DMF solvent under reflux conditions”, Heterocyclic Letters., (2017), 7(3), 829-833.

24
Experimental
General procedure for the synthesis of 4-hydroxybenzonitrile (3c).
Taken in round bottom flask para-hydroxybenzaldehyde (1c) (0.02 mol) and
hydroxylamine hydrochloride (2) (0.024 mol) mixed with calcium chloride
(0.02 mol) and DMF (60 ml) was added. Whole mixture was reflux for 3
hrs. After completion of reaction, the mixture was poured in water (100 ml)
and extracted with ethyl acetate (100 mL) and dried over anhydrous
Na2SO4. Evaporated ethyl acetate layers to give residue which was purified
by column chromatography using benzene/ethyl acetate (8:2) as, eluent to
afford the desired nitriles (3c). Other compounds (3a-k) were prepared in
the similar way by using various substituted aldehydes and their percentage
yield and physical constants were recorded in Table I. Their structures have
been confirmed by the IR, 1HNMR and Mass spectra.
CHO
OH
+ NH2OH.HCl
CaCl2, DMF
reflux, 2.20 hrs
HC
OH
N-OH C
OH
N
1c 2 3c

25
Physical data of nitriles (3a-k)

26
Analytical data of the compounds 3(a-k)
Entry Calculated Observed
C% H% N% C% H% N%
3a 81.53 4.89 53.58 81.49 4.90 53.50
3b 61.12 2.93 10.18 61.07 2.89 10.10
3c 70.58 4.23 11.76 70.60 4.17 11.68
3d 72.16 5.30 10.52 72.10 5.17 10.48
3e 69.42 3.33 11.57 70.00 3.27 10.98
3f 56.76 2.72 18.91 56.80 2.73 19.01
3g 69.83 5.86 7.40 70.00 5.47 7.32
3h 82.01 6.02 11.96 81.60 5.96 11.90
3i 86.25 4.61 9.14 86.20 4.55 9.09
3j 69.52 10.21 20.27 69.58 10.19 20.30
3k 72.24 10.91 16.85 72.28 10.82 16.80

27
1H-NMR OF Butyronitrile (3j)
Chemical
Shift (δ)
ppm
Number of
protons
Multiplicity
0 Assignment
1.90 2H t -CH2-CH2-
1.22 2H m CH3-CH2-CH2-
0.62 3H t CH3-CH2-

28
MASS SPECTRA OF Butyronitrile (3j)

29
IR SPECTRA OF Butyronitrile (3j)
IR
cm-1
C-H CH2 , CH3
2973, 2941, 2881 2249 1464, 1427,
1385
C N

30
Chapter-III
Preparation of substituted Bis-thiazoles, Hydrazones
Section A:
Synthesis of substituted 2-(2-(4-benzyloxy)phenyl-4-methylthiazol-
5-yl)thiazoles
Section B:
Synthesis of substituted N-benzylidene-2-(4-benzyloxy)phenyl)-4-
methylthiazol-5-carbohydrazide
Section C:
Synthesis of substituted 2-benzyl-1-(4-methyl-2-phenylthiazol-5-yl)
methyleneamino)isothiourea

31
 Bis-thiazole, Thiazolyl-hydrazone, Thiazolyl-isothiourea
 Medicinal chemistry is the science that deals with the discovery
and design of new therapeutic chemicals.
 Bisthiazole-metal complexes are used in biological activities in
mammals. The developing organic electronics using bithiazole
based semiconductors such as, photovoltaic sensitizers and solar
cells.
 2,4’-bis-thiazole, 2,5’-bis-thiazole or 4,5’-bis-thiazole, 5,5’-bis-
thiazoles, and 2,2’-bis-thiazoles) are considered privileged
structural motifs and have application in various fields, such as
materials science, for the preparation of liquid crystals etc. Some
di- and tri-substituted 1, 3-thiazole derivatives with various
pharmacological properties.
 N-acylhydrazone moiety promising motif in drug design and
medicinal chemistry. Some hydrazones derivatives used as
nematocides, rodenticides, herbicides, insecticides and plant
growth regulator.

32
 These functional group of acyl-hydrazones possess diverse
biological and pharmacological properties such as, antiviral, anti-
malarial, anti-inflammatory, and anticonvulsant.
 The hydrazone moiety presents in drugs such as, Azumolene and
Nitrofurantoin and Carbazochrome etc.
 Combination of different pharmacophores in the same molecules
may lead to new compounds having higher biological activity due
to these properties associated with them. We thought worthwhile
to synthesis of linkage of –CONH-N=CH- with thiazole moieties.
 Thiosemicarbazones are a types of schiffs base formed by the
condensation of thiosemicarbazide and aldehyde or ketones.
 Thiosemicarbazones have been extensively studied due to their
ability to chelate several metal ions and to suppress tumor growth
by inhibiting ribonucleotide reductase a key enzyme required for
DNA synthesis.

33
 Metal complexes of thiosemicarbazone special attention due to
their activity against small poxvirus, and ptotozoa.
 The thiosemicarbazide and thiosemicarbazone possess diverse
biological and pharmacological properties such as, antiviral,
anticancer, antitumor, antibacterial, and antioxidant etc.
 Isothiourea derivatives possess cardiovascular properties such as,
nitric oxide synthase inhibitors and calcium channel blockers.
 Isothiourea derivatives display potent antimicrobial, anti-
anthelmintic activities. S-benzyl-isothiourea derivative to induce
spherical cells in Escherichia coli.
 The thiosemicarbazone moiety present in drugs such as, triapine
is a potent ribonucleotide reductase inhibitor with broad spectrum
antitumor activity by inhibiting DNA synthesis.
 Metisazone is an antiviral drugs that works by inhibiting m RNA
and protein synthesis, especially in pox viruses

34
Section-A
Synthesis of substituted 2-(2-(4-benzyloxy)phenyl-
4-methylthiazol-5-yl)thiazoles

35
Present work
Cl C
O C
P2S5
C2H5OH
Reflux, 3 hrs
Zn dust, PEG-400
O
S
N
CH3
S
N
R1
R2
K2CO3, DMF
Reflux
RT
2 hrs
NH2
S
O
Cl COOC2H5
H
CH3
O
O
S
N CH3
COOC2H5
isopropyl alcohol
O
S
N CH3 NH2OH.HCl O
S
N
CH3
C N
P2S5
C2H5OH
RT
2 hrs
O
S
N
CH3
NH2
S
Cl R2
H
R1
O
isopropyl alcohol,
HO
COOH
N
N
1 2 3
6 4 5
NaOH 10%
H2SO4
7 8
Reflux, 3- 4 hr's
10a-e 9
Scheme-II

36
Experimental
Step-I:-
General procedure for the synthesis of 4-(benzyloxy)benzo
nitrile (3).
Equimolar amount of benzyl chloride (1) (0.01 mol) and 4-hydroxy
benzonitrile (2) (0.01mol) was taken in N,N-dimethyl formamide (DMF)
(30 ml) as solvent and reaction is carried out in K2CO3 (0.005 mol) and
reflux for 2 hr’s. The reaction mixture was cooled to room temperature
and poured over ice-cold water. The precipitate was filtered, washed with
water and dried. The product was crystallized from ethanol.
Yield: 87%, M.P: 94-96 0C.
C l C
O C
K 2 C O 3 , D M F
r e f lu x , 2 h rs
H O
N
N
1 2 3

37
Experimental
Step-II:-
General procedure for the synthesis of 4-(benzyloxy)benzo
thioamide (4).
To a solution of 4-(benzyloxy)benzonitrile (3) (0.015 mol) in ethanol (50
ml), phosphorous pentasulfide (0.030 mol) was slowly added at room
temperature and stirred at RT for 2 hr’s. Reaction mass was poured on ice-
cold water. Obtained precipitate was filter, wash with water to give
product. The greenish colour impurity removed by benzene solvent.
Yield: 80%, M.P: 176-182 0C.
O C
P2S5, ethanol
RT, 2 hrs
NH2
S
O
N
3 4

38
Experimental
Step-III:-
General procedure for the synthesis of ethyl 2-(4-(benzyloxy)
phenyl-4-methylthiazole-5-carboxylate (6).
An equimolar quantity of 4-(benzyloxy)benzothioamide (4) (0.012 mol)
was dissolved in isopropyl alcohol (30 ml) and ethyl-2-chloroacetoacetate
(5) (0.012 mol) was added reflux for 3 hr’s. completion of the reaction
monitored by TLC. The mixture was cooled to room temperature.
Obtained solid compound was filtred and dried.
Yield: 82%, M.P: 106-108 0C.
r e f lu x , 3 h r s
N H 2
S
O
C l C O O C 2 H 5
H
C H 3
O
O
S
N C H 3
C O O C 2 H 5
i s o p r o p y l a l c o h o l
4 5 6

39
Experimental
Step-IV:-
General procedure for the synthesis of 2-(4-(benzyloxy)phenyl-
4-methylthiazole-5-carboxyllic acid (7).
To a solution of The hydrolysis of ethyl 2-(4-(benzyloxy)phenyl)-4-
methylthiazole-5-carboxylate (6) (0.02 mol) in ethanol (4 ml) was
refluxed with caustic lye solutions (5 ml, 2N) for 2 hr’s. The solution
cooled, neutralized by H2SO4 (10%) and filtered. The product obtained
wased with water and crystallized fom ethanol.
Yield-70%, M.P: 218-223 0C.
O
S
N C H 3
C O O C 2 H 5
1 0 %
H 2 S O 4
N a O H , e th a n o l O
S
N C H 3
C O O H
6 7

40
Experimental
Step-V:-
4-methylthiazole-5-carbonitrile (8).
A mixture of the 2-(4-(benzyloxy)phenyl)-4-methyl thiazole-5-carboxylic
acid (7) (0.01 mol), hydroxylamine hydrochloride (0.02 mol) and zinc
dust (0.02 mol) was taken in polyethylene glycol (50 ml) and stirred at 85
0C for 3 hr’s. the reaction mass was extracted with ethyl acetate and
separated PEG. The ethyl acetate layer evaporated, crude product was
purified by column chromatography.
Yield-74%, M.P: 150-155 0C.
Z
n
d
u
s
t
,P
E
G
-
4
0
0
O
S
N C
H
3 N
H
2
O
H
.
H
C
l O
S
N
C
H
3
C
N
C
O
O
H
7 8

41
Experimental
Step-VI:-
4-methylthiazole-5-carbothioamide (9).
A mixture of 2-(4-(benzyloxy)phenyl)-4-methylthiazole-5-carbonitrile (8)
(0.015 mol) in ethanol (50 ml) and then phosphorous pentasulfide (0.030
mol) was slowly added at room temperature and stirred at RT for 2 hr’s.
reaction mass was poured into ice-cold water, precipitated solid was
filtered, wased with water to pure compound.
The greenish colour impurity removed by benzene solvent.
Yield-78%, M.P: 160-165 0C.
R
T
,2
h
r
'
s
P
2
S
5
,e
t
h
a
n
o
l
O
S
N
C
H
3
C
N
O
S
N
C
H
3
N
H
2
S
8 9

42
Experimental
Step-VII:-
General procedure for the synthesis of 2,5’-bis-thiazole i.e
2-(4-(benzyloxy)phenyl)-5-(4-(4-methoxyphenyl)thiazol-2-yl)-4-
methylthiazole (10e).
A mixture of 2-(4-(benzyloxy)phenyl)-4-methylthiazole-5-carbothioamide
(9) (0.010 mol) in isopropyl alcohol (30 ml), an equimolar quantity of the
corresponding 2-chloro-1-(4-methoxyphenyl)ethanone (0.010 mol) was
added and it was reflux for 3 hrs. On completion of the reaction,
monitored by TLC, the mixture was cooled to room temperature. Solid
compound obtained, filtered dried and recrystallized from ethanol.
O
S
N
C
H
3
S
N
O
S
N
C
H
3
N
H
2
S
i
s
o
p
r
o
p
y
l
a
l
c
o
h
o
l
,
r
e
f
l
u
x
,
3
h
r
'
s
O
C
H
3
H
C
l
O
O
C
H
3
9 1
0
e

43
Physical data of the compounds 10(a-e)
Compound
no.
R1 R2 Yield % M.P. OC
10a CH3 COOC2H5 78 145-150
10b H 75 220-222
10c H 82 250-255
10d CH3 84 238-244
10e H 80 140-145
Cl
NO2
OCH3

44
Analytical data of the compounds 10(a-e)
C% H% N% C% H% N%
10a 63.98 4.92 6.22 63.95 4.90 6.18
10b 65.74 4.03 5.90 65.69 4.01 5.86
10c 64.31 3.94 8.65 64.30 3.90 8.62
10d 71.33 4.88 6.16 71.28 4.85 6.13
10e 68.91 4.71 5.95 68.88 4.65 5.91

45
1H-NMR OF COMPOUND (10e)
Chemical
Shift (δ) ppm
Number of
protons
Multiplicity 0
Assignment
7.94 1H s thiazolic-CH
7.47 2H d Ar-H (Aromatic hydrogen)
7.41 2H t Ar-H (Aromatic hydrogen)
7.20-7.05 5H m Ar-H (Aromatic hydrogen)
6.79 2H dd Ar-H (Aromatic hydrogen)
5.20 2H s ether-OCH2
3.78 3H s OCH3
2.65 3H s thiazolic-CH3

46
MASS SPECTRA OF COMPOUND (10e)

47
IR SPECTRA OF COMPOUND (10e)
IR
cm-1
Ar-CH CH3 C=C in Ar C=N OCH3 C-O C-S-C
3071 2935, 2836 1603, 1559 1432, 1378 1173 1026 736

48
Section-B
Synthesis of substituted N-benzylidene-2-(4-benzy
loxy)phenyl)-4-methylthiazol-5-carbohydrazide

49
Present work
S
N CH3
OC2H5
O
O H
O
R
Reflux
H2SO4
EtOH
S
N
CH3
H
N
O
N
R
O
4-5 hrs
+
NH2-NH2.H2O
S
N CH3
H
N
O
O
NH2
EtOH, Reflux
1 2 3
4a-h
Scheme-III

50
Experimental
Step-I:-
General procedure for the synthesis of 2-(4-(benzyloxy)phenyl)-
4-methylthiazole-5-carbohydrazide (2).
To a solution of ethyl 2-(4-(benzyloxy)phenyl)-4-methylthiazole-5-
carboxylate (1) (0.01 mol) in ethanol (50 ml) and then hydrazine hydrate-
80% (0.042 mol) was added dropwise and the mixture was reflux for 12
hr’s. After completion of the reaction the mixture was cooled down and
poured into ice-cold water, precipitated obtained was filtered off, washed
with water and recrystallized from ethanol.
Yield-88%, M.P: 152-154 0C.
S
N C H 3
O C 2 H 5
O
O
N H 2 - N H 2 .H 2 O
S
N C H 3
H
N
O
O
N H 2
E t O H , r e f l u x , 1 2 h r s
1 2

51
Experimental
Step-II:-
General procedure for the synthesis of N-(4-chlorobenzylidene)-
2-(4-(benzyloxy)phenyl)-4-methylthiazole-5-carbohydrazide (4c).
A mixture of 2-(4-(benzyloxy)phenyl)-4-methylthiazole-5-carbohydrazide
(2) (0.01 mol), 4-chlorobenzaldehydes (3) (0.012 mol) in ethanol solvent
(50 ml) and catalytic amount of sulfuric acid (0.2 ml) added and the mixture
was heated at reflux for 5 hr’s. After completion of the reaction, monitored
by TLC, the mixture cooled down, solid formed filtered off and
recrystallized from ethanol.
H
O
H 2 S O 4 , E tO H
S
N
C H 3
H
N
O
N
O
+
S
N
C H 3
H
N
O
O
N H 2
re flu x , 5 h r's
2 3 4 c
C l
C l

52
Physical data of the compounds 4(a-h).
Compound no. R Yield % M.P. OC
4a H 65 228-229
4b CH3 84 170-171
4c Cl 75 158-160
4d OCH3 88 199-200
4e 3,4-di-OCH3 76 210-211
4f F 64 178-180
4g NO2 65 202-203
4h OH 73 188-189

53
Analytical data of the compounds 4(a-h)
C% H% N% C% H% N%
4a 70.24 4.95 9.83 70.20 4.88 9.78
4b 70.72 5.25 9.52 70.70 5.22 9.47
4c 65.00 4.36 9.10 64.90 4.32 9.00
4d 68.25 5.07 9.18 68.20 5.00 9.10
4e 66.51 5.17 8.62 66.46 5.10 8.58
4f 67.40 4.52 9.93 67.38 4.48 9.88
4g 63.55 4.27 11.86 63.49 4.23 11.80
4h 67.70 4.77 9.47 67.66 4.73 9.42

54
1H-NMR OF COMPOUND (4c)
Chemical Shift
(δ) ppm
Number of
protons
Multiplicity 0
Assignment
11.68 1H s NH
8.12 1H s CH=N
7.49 2H m Ar-H (Aromatic hydrogen)
5.22 2H s OCH2
2.75 3H s Thiazolic-CH3

55
MASS SPECTRA OF COMPOUND (4c)

56
IR SPECTRA OF COMPOUND (4c)
IR
cm-1
NH Ar-CH CH3 CONH CH=N C=C in Ar C-O C-Cl
3433 3041 2936,
2858
1641 1603 1512 1168,
1032
875

57
Section-C
Synthesis of Substituted 2-benzyl-1-(4-methyl-2-
phenylthiazol-5-yl)methyleneamino)isothiourea

58
Present work
S
N CH3
COOC2H5
R
diethyl ether, 0 o
C S
N CH3
OH
S
N CH3
R
H
O
LiAlH4
S
N
CH3
R
N
H
NH2
S
EtOH
Reflux, 3 hr's
Cl
K2CO3, DMF
Reflux, 2hrs
R
PCC
MS
DCM
RT
H2N
N
N
H NH2
H
S
S
N
CH3
R
N
N NH2
H
S
1a-f 2a-f
5a-f 3a-f 4
6a-f
Scheme-IV

59
Experimental
Step-I:-
General procedure for the synthesis of (4-methyl-2-p-tolyl
thiazol-5-yl)methanol (2b).
A mixture of ethyl 4-methyl-2-p-tolylthiazole-5-carboxylate (1b) (0.01 mol)
in diethyl ether (50 ml) solvent was added dropwise in a cold solution of
lithium aluminium hydride (0.02 mol) in dry diethyl ether (50 ml), the
reaction mixture was stirred for 2 hr’s at 0 oC. After completion of the
reaction, checked by TLC, the reaction mixture was quenched by satuarated
solution of sodium sulphate. The reaction mixture filtered and the aqueous
layer was extracted with diethyl ether (2×50 ml), the combined organic
layer was washed with water and dried over sodium sulphate. The product
obtained by removing the solvent by distillation.
Yield-80%, M.P: 120-122 0C.
S
N CH3
COOC2H5
diethyl ether, 0 o
C
2 hrs
S
N CH3
OH
LiAlH4
1b 2b
H3C
H3C

60
Experimental
Step-II:-
General procedure for the synthesis of 4-methyl-2-p-tolyl
thiazole-5-carbaldehyde (3b).
To a solution of (4-methyl-2-p-tolylthiazol-5-yl)methanol (2b) (0.01 mol) in
DCM (50 ml), PCC (0.003 mol) and molecular sieves 4A0 (0.5 gm) was
added, the reaction mixture stirred at room temperature for 8 hr’s. after
completion of the reaction, residue filtered and washed with DCM. Solvent
removed by distillation to afford pure product.
Yield-82%, M.P: 134-136 0C.
S
N CH3
OH
S
N CH3
H
O
PCC, MS
DCM, RT, 8 hrs
2b 3b
H3C H3C

61
Experimental
Step-III:-
General procedure for the synthesis of 1-((4-methyl-2-p-tolyl
thiazol-5-yl)methylene)thiosemicarbazide (5b).
A mixture of 4-methyl-2-p-tolylthiazole-5-carbaldehyde (3b) (0.01 mol) in
ethanol (50 ml), thiosemicarbazide (4) (0.014 mol) was added and the
mixture was reflux for 3 hr’s. after completion of the reaction, solids
filtered off, washed with water and crude product recrystallized from
ethanol solvent to afford pure product.
Yield-74%, M.P: 226-228 0C.
S
N C H 3
H
O
S
N
C H 3
N
H
N H 2
S
E tO H
reflux, 3 hr's
H 2N N
N
H N H 2
H
S
H 3C
H 3C
3b 4 5b

62
Experimental
Step-IV:-
General procedure for the synthesis of 2-benzyl-1-((4-methyl-2-
p-tolylthiazol-5-yl)methyleneamino)isothiourea (6b).
A mixture of equimolar amount of 1-((4-methyl-2-p-tolylthiazol-5-
yl)methylene)thiosemicarbazide (5b) (0.01 mol) and benzyl chloride (0.01
mol) was taken in DMF (50 ml), potassium carbonate (0.004 mol) was
added. The reaction mixture was reflux for 2 hr’s. after completion of
reaction, cooled to room temperature, ice-cold water added, filtered, dried.
The crude product recrystallized by ethanol + DMF solvent.
S
N
C H 3
C l
K 2 C O 3 , D M F
r e f l u x , 2 h r s
N
N
H N H 2
H
S
S
N
C H 3
N
N N H 2
H
S
H 3 C H 3 C
5 b 6 b

63
Physical data of the compounds 6(a-f)
6a H 68 160-162
6b CH3 72 137-138
6c Cl 74 150-152
6d OCH3 76 130-132
6e 3,4-di-OCH3 65 170-171
6f F 60 158-159

64
Analytical data of the compounds 6(a-f)
C% H% N% C% H% N%
6a 62.27 4.95 15.29 62.20 4.88 15.21
6b 63.13 5.30 14.72 63.10 5.20 14.70
6c 56.92 4.27 13.97 56.90 4.20 13.92
6d 60.58 5.08 14.13 60.50 5.00 14.07
6e 59.13 5.20 13.13 59.07 5.10 13.00
6f 59.35 4.46 14.57 59.27 4.38 14.35

65
1H-NMR OF COMPOUND (6b)
Chemical Shift
(δ) ppm
Number of
protons
Multiplicity 0
Assignment
8.24 1H s CH=N
5.43 2H s SCH2
4.25 2H s NH2
2.69 3H s Thiazolic-CH3
2.36 3H s -CH3

66
MASS SPECTRA OF COMPOUND (6b)

67
IR SPECTRA OF COMPOUND (6b)
IR
cm-1
NH Ar-CH CH3 CH=N C=C in Ar C-S
3436 3079, 3040 2987, 2931 1596 1572, 1498 728, 650

68
Chapter-IV
Preparation of substituted Thiazolidine-4-one
Section A:
One pot three-component synthesis of substituted 2-
(4-methyl-2-phenylthiazol-5-yl)-3-phenylthiazolidin-4-
one
Section B:
Synthesis of Substituted 4-methyl-N-(2-(4-methyl-2-
phenyl thiazol-5-yl)-4-oxothiazolidin-3-yl)-2-
phenylthiazole-5-carboxamide
Section C:
Synthesis of Substituted (2,5)-5-benzylidene-2-(2-((2-
(3,4-dimethoxyphenyl)-4-methylthiazol-5-yl)methylene)
hydrazinyl)thiazol-4(5H)-one

69
 Thiazolyl-thiazolidine-4-one, Thiazolyl-5-arylidene-thiazolidinone
 The nitrogen, sulfur containing hetrocycles are an important class
of compounds in pharmaceuticals and of many physiologically
active natural products, industrial point which helps to improve
life processes.
 The thiazolyl-thiazolidin-4-one derivatives have motif pharma-
cological activity. The presence of certain groups such as,
hydroxy, methoxy, thio and chloro in the phenyl ring has been
reported to increases the activity of parent compounds.
 5-arylidene-4-thiazolidinone derivatives are known to possess
diverse biological activity such as, fungicidal activity, anti-
convulsant activity, antiviral, and anti-inflammatory activity.
 The better conventional is Knoevenagel condensation midway
aromatic aldehydes and 4-thiazolidinones carry through glacial
acetic acid included anhydrous sodium acetate, Ethylenediamine
Diacetate catalyst, isopropanol and potassium tert-butylate and
soluble polymer-supported synthesis.

70
 Thiazolidinone ring core present in drugs such as, Teneligliptin is
drugs for the treatment of type 2 diabetes mellitus and third
generation dipeptidyl peptidase-4 (DPP-4) inhibitor.
 Balaglitazone is a second generation peroxisome proliferator-
activated receptor gamma agonist with only partial agonistic
properties.
 The base of 5-arylidene-4-thiazolidinones is Darbufelone drugs
i.e. (5-(3,5-ditert butyl-4-hydroxybenzylidene)-thiazol-4-one that
has broad attention as dual inhibitor of cellular prostaglandin and
leukotriene production via. Cyclooxygenase activity inhibition
including inhibition of prostaglandin endoperoxide synthase-1
(PGHS-1) and PGHS-2.
N
N
N H
N
O
S
N
N
H 3 C
N
N
O
C H 3
O N H
S
O
O
T e n e lig lip t in B a la g lita z o n e D a r b u fe lo n e
H O
S
N H
H
O
H N

71
Section-A
One pot three-component synthesis of substituted 2-(4-
methyl-2-phenylthiazol-5-yl)-3-phenylthiazolidin-4-one

72
Present work
S
N
H 3 C
P T S A , T o lu e n e
D & S , R e flu x , 1 3 -1 5 h rs
H S
H O O
R
S
N
H 3 C N
S
O
R
R 1
N H 2
R 1
H
O
1 2 3 4 a -h
Scheme-V

73
Experimental
Step-I:-
General procedure for the synthesis of 3-(4-fluorophenyl)-2-(4-
methyl-2-phenylthiazol-5-yl)thiazolidin-4-one (4d).
A mixture of 4-methyl-2-phenylthiazole-5-carbaldehyde (1) (0.01 mol) in
a dry toluene (50 mL), 4-fluoroaniline (2) (0.015 mol), (10 mol %) p-
toluenesulfonic acid (p-TsOH) and mercapto acetic acid (3) (0.016 mol)
was added. The reaction mixture was refluxed (110-118 ºC) for 15 hr’s
with azeotropic separation of water using Dean and Stark apparatus.
Completion of reaction was determined by TLC analysis. Toluene was
removed under vacuum to give viscous oil, which was treated with a
saturated aqueous NaHCO3 solution to remove any unreacted
mercaptoacetic acid. The product was extracted with ethyl acetate, washed
with water, brine and dried over Na2SO4. The solvent was removed under
reduced vacuum. The crude product was purified by column
chromatography using benzene:ethyl acetate (8:2) solvent system.
S
N
H 3 C
P T S A , T o l u e n e
D & S , r e f l u x , 1 5 h r s
H S
H O O
S
N
H 3 C N
S
O
F
N H 2
F
H
O
1 2 3 4 d

74
Physical data of the compounds 4(a-h)
Compound no. R R1 Yield % M.P. OC
4a H H 62 184-188
4b H CH3 70 100-104
4c H OCH3 60 130-134
4d H F 58 128-134
4e Cl H 72 108-112
4f Cl CH3 76 138-145
4g Cl OCH3 60 106-110
4h Cl F 62 92-96

75
C% H% N% C% H% N%
4a 64.74 4.58 7.95 64.70 4.56 7.90
4b 65.54 4.95 7.64 66.50 4.89 7.62
4c 62.80 4.74 7.32 62.78 4.70 7.33
4d 61.60 4.08 7.56 61.54 4.00 7.55
4e 58.98 3.91 7.24 58.90 3.84 7.20
4f 59.91 4.27 6.99 59.88 4.24 6.97
4g 57.61 4.11 6.72 57.60 4.09 6.67
4h 56.36 3.49 6.92 56.33 3.47 6.89

76
1H-NMR OF COMPOUND (4d)
Chemical Shift
(δ) ppm
Number of
protons
Multiplicity 0
Assignment
6.39 1H s SCH
3.97 1H d Thiazolidinone-CH2
3.83 1H d Thiazolidinone-CH2

77
MASS SPECTRA OF COMPOUND (4d)

78
IR SPECTRA OF COMPOUND (4d)
IR
cm-1
Ar-CH CH3 CO C-S C=C in Ar C-N C-F
3062, 3029 2964, 2862 1694 1610 1578, 1521 1257 1172

79
Section-B
Synthesis of Substituted 4-methyl-N-(2-(4-methyl -2-
phenylthiazol-5-yl)-4-oxothiazolidin-3-yl)-2-
phenylthiazole-5-carboxamide

80
Present work
S
N
H3C
+
H
O
R1
S
N
CH3
H
N
O
N
R
S
N
H3C
R1
S
N
CH3
N
O
N
R
S
N
H3C
R1
S
O
SH-CH2-COOH
ZnCl2
DMF
Reflux
8-10 hrs
S
N CH3
OC2H5
O
NH2-NH2.H2O
S
N CH3
H
N
O
NH2
EtOH, Reflux
R R
1 2 3
H2SO4
EtOH
Reflux
5 hr's
H
4a-h
5a-h
Scheme-VI

81
Experimental
Step-I:-
General procedure for the synthesis of 2-(4-fluorophenyl)-4-
methyl-N-((4-methyl-2-phenylthiazol-5-yl)methylene)thiazole-5-
carbohydrazide (4a).
To a solution of 2-(4-fluorophenyl)-4-methylthiazole-5-carbohydrazide (2a)
(0.01 mol) in absolute ethanol (50 ml), 4-methyl-2-phenylthiazole-5-
carbaldehyde (3a) (0.01 mol) and two-three drops of concentrated sulfuric
acid were added. The mixture was heated for 5 hr’s. After completion of the
reaction, monitored by TLC, the mixture was cooled down and the
precipitated obtained was filtered off, washed with water and recrystallized
from ethanol.
S
N
H3C
+
H
O
S
N
CH3
H
N
O
N S
N
H3C
S
N CH3
H
N
O
NH2
H2SO4, EtOH
reflux, 5 hrs
F F
2a 3a 4a

82
Experimental
Step-II:-
General procedure for the synthesis of 2-(4-fluorophenyl)-4-
methyl-N-(2-(4-meth yl-2-phenylthiazol-5-yl)-4-oxothiazolidin-3-
yl)thiazole-5-carboxamide (5a).
To a solution of 2-(4-fluorophenyl)-4-methyl-N-((4-methyl-2-phenyl
thiazol-5-yl)methylene)thiazole-5-carbohydrazide (4a) (0.01 mol) in N,N-
Dimethylformamide (50 ml) and mercaptoacetic acid (0.02 mol) with a
pinch of anhydrous zinc chloride catalyst was added reflux the mixture for
10 hr’s. After completion of the reaction, monitored by TLC, the mixture
was cooled down and poured it in to an crushed ice, the precipitated
obtained was filtered off, washed with water and recrystallized from
ethanol.
S
N
C H 3
H
N
O
N S
N
H 3 C
S
N
C H 3
N
O
N S
N
H 3 C
S
O
S H - C H 2 - C O O H , Z n C l 2
D M F , r e f l u x , 1 0 h r s H
F
F
4 a 5 a

83
Physical data of the compounds 5(a-h)
Compound no. R R1 Yield % M.P. OC
5a F H 78 186-190
5b NO2 H 87 210-214
5c OCH3 H 74 167-170
5d Cl H 80 188-192
5e F Cl 88 220-224
5f NO2 Cl 82 260-265
5g OCH3 Cl 90 222-226
5h Cl Cl 75 136-140

84
C% H% N% C% H% N%
5a 56.45 3.75 10.97 56.40 3.74 11.01
5b 53.62 3.56 13.03 53.58 3.48 12.90
5c 57.45 4.24 10.72 57.40 4.18 10.60
5d 54.69 3.63 10.63 54.60 3.58 10.58
5e 52.88 3.33 10.28 52.80 3.30 10.30
5f 50.39 3.17 12.24 50.25 3.10 12.20
5g 53.90 3.80 10.06 53.85 3.84 9.90
5h 51.33 3.23 9.98 51.30 3.18 9.90

85
1H-NMR OF COMPOUND (5a)
Chemical Shift
(δ) ppm
Number of
protons
Multiplicity 0
Assignment
11.50 1H s NH
6.23 1H s SCH
3.60 1H d thiazolidinone-CH2
3.42 1H d thiazolidinone-CH2

86
MASS SPECTRA OF COMPOUND (5a)

87
IR SPECTRA OF COMPOUND (5a)
IR
cm-1
NH Ar-CH CH3 CO CONH C-S C=C in Ar C-N C-F
3264 3035 2930, 2860 1739 1645 1605 1514, 1500 1251 1171

88
Section-C
Synthesis of Substituted (2,5)-5-benzylidene-2-(2-((2-
(3,4-dimethoxyphenyl)-4-methylthiazol-5-yl)methylene
)hydrazinyl)thiazol-4(5H)-one.

89
Present work
+
H3CO
S
N
CH3
N
N
H
S
N
CH3
N
N
H
NH2
S
S
N
O
H3CO
S
N
CH3
N
N
H
S
N
O
H3CO
H3CO
H3CO
H3CO
Cl
HO O
AcONa, EtOH
Reflux, 8 hrs
R
Reflux, 10 hr's
4a-g
H
O
R
1 2 3
AcONa, CH3COOH
Scheme-VII

90
Experimental
Step-I:-
General procedure for the synthesis of 2-(2-((2-(3,4-dimethoxy
phenyl)-4-methylthiazol-5-yl)methylene)hydrazinyl)thiazol-4(5H
)-one (3).
A mixture of 1-((2-(3,4-dimethoxyphenyl)-4-methylthiazol-5-yl)methylene)
thiosemicarbazide (1) (0.01 mol) in ethanol solvent (50 ml), chloroacetic
acid (2) (0.01 mol) was slowly added and anhydrous sodium acetate (0.02
mol), the reaction mixture was reflux for 8 hr’s. After completion of the
reaction, checked by TLC, cooled the reaction mass solid of product
obtained, filtered off, washed with water and recrystallized from ethanol
solvent to afford pure product.
Yield-72%, M.P: 189-190 0C.
+
H 3C O
S
N
C H 3
N
N
H
S
N
C H 3
N
N
H
N H 2
S
S
N
O
H 3C O
H 3C O
H 3C O
C l
H O O
A cO N a, E tO H
reflux, 8 hrs
1 2 3

91
Experimental
Step-II:-
General procedure for the synthesis of 5-(4-fluorobenzylidene-
2-(2-((2-((3,4-dimethoxyphenyl)-4-methylthiazol-5-yl)methylene
)hydrazinyl)thiazol-4(5H)-one (4f).
A mixture of equimolar amount of 2-(2-((2-(3,4-dimethoxyphenyl)-4-
methyl thiazol-5-yl)methylene)hydrazinyl)thiazol-4(5H)-one (3) (0.01 mol)
in glacial acetic acid (50 ml), 4-Fluorobenzaldehyde (0.01 mol) and
anhydrous sodium acetate (0.04 mol) was added and the mixture was reflux
for 10 hr’s. After completion of the reaction, checked by TLC, cooled the
reaction mass solid of product obtained, filtered off, washed with water and
recrystallized from DMF-Ethanol solvent to afford pure product.
H 3C O
S
N
C H 3
N
N
H
S
N
O
H 3C O
S
N
C H 3
N
N
H
S
N
O
H 3C O
H 3C O
reflux, 10 hr's
A cO N a, C H 3C O O H
F
F
H
O
3 4f

92
Physical data of the compounds 4(a-g)
4a H 74 122-123
4b CH3 75 160-162
4c Cl 60 130-132
4d OCH3 63 147-148
4e NO2 62 170-172
4f F 63 139-140
4g OH 64 180-181

93
Analytical data of the compounds 4(a-g)
C% H% N% C% H% N%
4a 59.46 4.34 12.06 59.41 4.28 12.00
4b 60.23 4.63 11.71 60.19 4.58 11.65
4c 55.36 3.84 11.23 55.29 3.80 11.00
4d 58.28 4.48 11.33 58.19 4.31 11.26
4e 54.21 3.76 13.74 54.16 3.68 13.66
4f 57.25 3.97 11.61 57.16 3.91 11.57
4g 57.48 4.19 11.66 57.41 4.10 11.60

94
1H-NMR OF COMPOUND (4f)
Chemical Shift
(δ) ppm
Number of
protons
Multiplicity 0
Assignment
12.09 1H s NH
8.30 1H s CH=N
7.89-7.80 3H m Ar-H (Aromatic hydrogen) & C=CH-Ar
3.80 3H s OCH3
3.74 3H s OCH3

95
MASS SPECTRA OF COMPOUND (4f)

96
IR SPECTRA OF COMPOUND (4f)
IR
cm-1
NH Ar-CH CH3 CO CH=N C=C in Ar OCH3 C-F
3435 3085, 2992 2943, 2847 1693 1600 1552, 1457 1268 1148

97
Chapter-V
Preparation of substituted 1,3,4-Oxadiazole
Section A:
Synthesis of substituted 1-(5-(2-(4-(benzyloxy)phenyl)-
4-methylthiazol-5-yl)-2-phenyl-1,3,4-oxadiazol-3(2H)-yl)
ethanone
Section B:
Synthesis of substituted 5-(2-(4-(benzyloxy)phenyl)-4-
methylthiazol-5-yl)-3-((phenylamino)methyl)-1,3,4-
oxadiazole-2-(3H)-thione
Section C:
Synthesis of Substituted 2-(benzylthio)-5-(4-methyl-2-
phenylthiazol-5-yl)-1,3,4-oxadiazole

98
 Thiazolyl-1,3,4-Oxadiazole, Thiazolyl-Oxadiazole-2-thione
 Medicinal chemistry concern with organic, analytical, biological
aspect of new drugs and involes synthesize, development of new
chemical entities suitable for therapeutic uses, biological
properties and their quantitative structure activity relationship.
 Mannich-reaction is also used for the synthesis of natural
compounds such as, peptide, nucleotides, antibiotics and
alkaloids.
 1,3,4-oxadiazole-2-thiones, which has exocyclic sulfur at C-2 of
1,3,4-oxadiazole skeleton it is the important for coordination
chemistry because of their multifunctional donor sites, i.e. sulfur
or nitrogen.
 Mannich bases have various application the production of
synthetic polymers, resins, as additives used by the petroleum
industry, as products used in water treatment, analytical reagents,
cosmetic, dyes, etc

99
 1,3,4-Oxadiazoles and their Mannich bases possess diverse
biological and pharmacological properties such as, anti-
inflammatory activity, antitumor activity, anti-proliferative agent
and Tubulin polymerization inhibitory activity.
 Mannich bases and Benzylthio-1,3,4-Oxadiazole derivatives are
biologically and pharmaceutically important compounds shown
below.
H3CO
HO
N
CH3
CH3
N
CH3
CH3
O
HO
O
N
H
C6H5
O
N
N
S
NH CH3
Tramadol (Anti-inflammatory)) Tolmetin (Anti-inflammatory) anticancer agent
O
O
O
N
N
S
Antiproliferative activity Antimycobacterial activity Phospholipase-A2-Inhibitor
O2N
NO2
O
N
N
S
Br
O2N
O
O
N
N
S
Cl

100
Section-A
Synthesis of substituted 1-(5-(2-(4-(benzyloxy)phenyl)-
4-methylthiazol-5-yl)-2-phenyl-1,3,4-oxadiazol-3(2H)-yl
)ethanone.

101
Present work
S
N
CH3
H
N
O
O H
O
H2SO4, EtOH
Reflux
S
N
CH3
H
N
O
N
O
S
N
CH3
O
N
N
COCH3
1 2 3a-g
Reflux
4a-g
8 hrs
CH3
O
H3C
O
O
NH2 O
R
R
R
Scheme-VIII

102
Experimental
Step-I:-
General procedure for the synthesis of 1-(5-(2-(4-(benzyloxy)
phenyl)-4-methylthiazol-5-yl)-2-(4-methylphenyl)-1,3,4-oxadiazol
-3(2H)-yl)ethanone (4b).
A mixture of Thiazolyl acyl hydrazone i.e N’-(4-methylbenzylidene)-2-(4-
(benzyloxy) phenyl)-4-methylthiazole-5-carbohydrazide (3b) (0.01 mol) was
dissolved in acetic anhydride (40 ml) and it was reflux for 8 hr’s. On
completion of the reaction, monitored by TLC, excess of acetic anhydride
removed by under reduce pressure. The hot mixture was poured onto the
crushed ice, the product which separated was filtered off, washed with water
and recrystallized from ethanol and dried.
S
N
CH3
H
N
O
N O
S
N
CH3
O
N
N
COCH3
reflux, 8 hrs
CH3
O
H3C
O
O
O
CH3
CH3
3b 4b

103
4a H 57 214-216
4b CH3 63 198-199
4c Cl 60 223-224
4d OCH3 65 188-190
4e NO2 56 220-222
4f F 58 160-162
4g OH 66 110-112

104
C% H% N% C% H% N%
4a 69.06 4.94 8.95 69.00 4.88 8.89
4b 69.54 5.21 8.69 69.40 5.18 8.64
4c 64.34 4.40 8.34 64.30 4.32 8.28
4d 67.32 5.04 8.41 67.28 5.00 8.34
4e 67.02 4.31 10.89 67.00 4.26 10.78
4f 66.51 4.55 8.62 66.43 4.49 8.57
4g 66.79 4.77 8.65 66.71 4.70 8.58

105
Chemical Shift
(δ) ppm
Number of
protons
Multiplicity 0
Assignment
8.09 1H s Oxadiazoline-H
5.20 2H s OCH2
2.36 3H s Ar-CH3
1.24 3H s CH3CO

106

107
IR
cm-1
Ar-CH CH3 CO C=N C=C in Ar N-N=C C-O-C C-O
3035 2929, 2862 1718 1605 1579, 1500 1294 1250, 1172 1112, 1002

108
Section-B
Synthesis of substituted 5-(2-(4-(benzyloxy)phenyl)-4-
methylthiazol-5-yl)-3-((phenylamino)methyl)-1,3,4-
oxadiazole-2-(3H)-thione

109
Present work
S
N
CH3
H
N
O
O
CS2, KOH, EtOH
Reflux, 12 hrs
1 2 3
Reflux
4a-g
O
S
N
CH3
O
NH
N
S
H H
O
O
S
N
CH3
O
N
N
S
R
prim, sec-ammines
EtOH 3-4 hrs
NH2
Scheme-IX

110
Experimental
Step-I:-
General procedure for the synthesis of 5-(2-(4-benzyloxy) phenyl)-
4-methylthiazol-5 -yl)-1,3,4-oxadiazole-2(3H)-thione (2).
To a solution of 2-(4-(benzyloxy)phenyl)-4-methylthiazole-5-carbohydrazide
(1) (0.01 mol) in ethanol (50 ml), potassium hydroxide (0.01 mol), then
carbon disulfide (3.0 mol) was added slowly to the reaction mixture was
heated to reflux for 12 hr’s. after the completion of reaction, checked by TLC,
the residue was dissolved in water and then acidified with dilute hydrochloric
acid (10%). The precipitate was filtered, washed with water and recrystallized
from ethanol, to obtained pure product.
Yield-87%, M.P: 218-219 0C
S
N
C H 3
H
N
O
O
C S 2, K O H , E tO H
R eflux, 12 hrs
1 2
O
S
N
C H 3
O
N H
N
S
N H 2

111
Experimental
Step-II:-
Step-I:-
General procedure for the synthesis of 5-(2-(4-benzyloxy)phenyl)-
4-methylthiazol-5-yl)-3-((phenylamino)methyl)-1,3,4-oxadiazole-2
(3H)-thione (4b).
A mixture of 5-(2-(4-benzyloxy)phenyl-4-methylthiazol-5-yl)-1,3,4-oxadiazol
-2(3H)-thione (2) (0.01 mol), paraformaldehyde (3) (0.015 mol) in ethanol (50
ml) and aniline (0.01 mol) was added slowly, the reaction mixture stirred for 4
hr’s at room temperature and kept overnight in a refrigerator. The precipitate
formed was filtered, washed with ice water and recrystallized from ethanol to
obtained pure product.
O
S
N
C H 3
O
N H
N
S
H H
O
O
S
N
C H 3
O
N
N
S
R
E t O H , r e f l u x , 4 h r s
N H 2
2 3 4 b

112
4a p-NO2-C6H4-NH 66 190-192
4b C6H5-NH 72 167-168
4c N(C2H5)2 62 173-174
4d p-CH3-C6H4-NH 73 149-151
4e N(Ph)2 66 201-202
4f (Naphthyl)-NH 62 119-121
4g o-Cl-C6H4-NH 74 177-179

113
C% H% N% C% H% N%
4a 58.74 3.98 13.17 58.68 3.90 13.00
4b 64.17 4.56 11.51 64.10 4.50 11.48
4c 61.78 5.62 12.01 61.48 5.58 11.94
4d 64.78 4.83 11.19 64.72 4.78 11.10
4e 68.30 4.66 9.96 68.24 4.61 9.89
4f 67.14 4.51 10.44 67.10 4.49 10.24
4g 59.93 4.06 10.75 59.88 4.00 10.72

114
Chemical Shift
(δ) ppm
Number of
protons
Multiplicity 0
Assignment
5.87 1H s NH
5.72 2H s N-CH2-N
5.11 2H s CH2O

115

116
IR
cm-1
NH Ar-CH CH3 C=N C=C in Ar C=S N-N=C C-O-C C-O
3410 3063, 3032 2917, 2847 1602 1557, 1520 1422 1316 1258 1189, 1079

117
Section-C
Synthesis of Substituted 2-(benzylthio)-5-(4-methyl-2-
phenylthiazol-5-yl)-1,3,4-oxadiazole

118
Present work
Scheme-X
S
N
CH3
H
N
CS2, KOH, EtOH
reflux, 12 hrs
1a-g 2a-g 3
Reflux
4a-g
S
N
CH3
O
N
N
S
R
R
H
S
N
CH3
O
N
N
R
SH
Cl
S
N
CH3
O
N
N
R
S
K2CO3
DMF 2-3 hrs
NH2
O

119
Experimental
Step-I:-
General procedure for the synthesis of 2-(2-(4-(benzyloxy)phenyl)-
4-methylthiazol-5-yl)-5-(benzylthio)-1,3,4-oxadiazole (4d).
A equimolar quantity of 5-(2-(4-benzyloxy)phenyl)-4-methylthiazol-5-yl)-
1,3,4-oxadiazole-2(3H)-thione (2d) (0.01 mol), benzyl chloride (3) (0.01 mol)
in DMF (50 ml) and potassium carbonate (1.40 mol) was added the reaction
mixture was reflux for 3 hr’s. after completion of the reaction, checked by
TLC, cooled the reaction mixture, solids filtered off, washed with water and
crude product recrystallized from ethanol + DMF solvent systems to afford
pure product.
reflux, 3 hrs
S
N
CH3
O
N
N
S
H
Cl
S
N
CH3
O
N
N
S
K2CO3, DM F
O
O
2d 3 4d

120
4a H 66 110-112
4b CH3 68 148-149
4c Cl 64 136-138
4d Ph-CH2-O 72 130-131
4e OCH3 60 140-142
4f NO2 58 170-172
4g 3,4-di-OCH3 62 158-159

121
C% H% N% C% H% N%
4a 62.44 4.14 11.50 62.38 4.09 11.42
4b 63.30 4.52 11.07 63.28 4.38 10.97
4c 57.06 3.53 10.51 57.00 3.48 10.39
4d 66.22 4.49 8.91 66.19 4.38 8.87
4e 60.74 4.33 10.62 60.67 4.27 10.54
4f 55.60 3.44 13.65 55.54 3.34 13.56
4g 59.27 4.50 9.87 59.22 4.45 9.80

122
1H-NMR OF COMPOUND (4d)
Chemical Shift
(δ) ppm
Number of
protons
Multiplicity 0
Assignment
7.39 2H t Ar-H (Aromatic hydrogen)
5.13 2H s CH2O
4.51 2H s S-CH2

123
MASS SPECTRA OF COMPOUND (4d)

124
IR SPECTRA OF COMPOUND (4d)
IR
cm-1
Ar-CH CH3 C=N C=C in Ar N-N=C C-O-C C-O
3071, 2995 2966, 2831 1637 1586, 1517 1289 1264 1182, 1066

125
Chapter VI: Antimicrobial Screening
Section A: Antibacterial & Antifungal activity
Section B: Anti-inflammatory activity

126
Antibacterial & Antifungal Activity
 Synthesized compounds were screened for their antibacterial
activity against gram(-ve) bacteria Escherichia coli (E. coli),
Pseudomonas aeruginosa as well as gram(+ve) bacteria
Staphylococcus aureus, Bacillus subtilis and antifungal activity
against Aspergillus niger (Asp. Niger), Aspergillus flavus (Asp.
Flavus), Penicillium chrysogenum (Pen. Chrysogenum) and
Fusarium moneliforme .
 Antibacterial activities determined by paper disc diffusion method.
 Antifungal activity was carried out by using poison plate method
 Ciprofloxacin, and Griseofulvin used as a standard.

127
Table-I: Antibacterial screening of Chapter-3: Section-A (10a-e):
Antibacterial zone of inhibition (mm)
Microorganisms
Entry R1 R2 E.
Coli
P.
aeruginoa
S.
aureus
B.
Subtilis
10a CH3 COOC2H5 08 -ve 09 08
10b 4-Cl-Ph H 15 13 09 14
10c 4-NO2-Ph H 14 13 11 10
10d C6H5 CH3 13 15 10 16
10e 4-OCH3-Ph H 09 16 -ve 15
Ciprofloxacin - 27 24 22 30
DMSO - -ve -ve -ve -ve
-ve no antibacterial activity
O
S
N
CH3
S
N
R1
R2
Antibacterial zone of inhibition (in mm)
Microorganisms
Entry R E. coli P.aeruginosa S.aureus B.subtilis
4a H 15 13 12 17
4b CH3 14 13 15 20
4c Cl 19 17 16 23
4d OCH3 16 12 14 18
4e 3,4-OCH3 15 18 13 20
4f F 20 13 15 16
4g NO2 16 15 14 21
4h OH 18 19 17 24
S
N
CH3
H
N
O
N
R
O
Table-II: Antibacterial screening of Chapter-3: Section-B (4a-h):

128
Table-III: Antibacterial screening of Chapter-3: Section-C (6a-f):
Microorganisms
6a H 14 11 15 18
6b CH3 21 10 18 19
6c Cl 22 18 17 20
6d OCH3 10 15 18 18
6e 3,4-OCH3 12 17 17 16
6f F 18 13 16 17
S
N
CH3
R
N
N NH2
H
S
Table-IV: Antibacterial screening of Chapter-4: Section-A (4a-h):
Microorganisms
Entry R R1 E. coli P.aeruginosa S.aureus B.subtilis
4a H H 15 12 14 15
4b H CH3 14 09 10 13
4c H OCH3 11 11 09 10
4d H F 17 14 15 23
4e Cl H 19 10 16 12
4f Cl CH3 18 11 17 18
4g Cl OCH3 17 08 15 17
4h Cl F 22 15 16 19
S
N
H3C N
S
O
R
R1

129
Table-V: Antibacterial screening of Chapter-4: Section-B (5a-h):
Microorganisms
Entry R R1 E. coli P.aeruginosa S.aureus B.subtilis
5a F H 23 20 19 24
5b F Cl 21 19 18 22
5c NO2 H 15 16 14 17
5d NO2 Cl 17 16 15 18
5e OCH3 H 16 14 11 15
5f OCH3 Cl 14 15 12 16
5g Cl H 20 18 17 20
5h Cl Cl 21 18 16 20
S
N
CH3
N
O
N
R
S
N
H3C
R1
S
O
H
Table-VI: Antibacterial screening of Chapter-4: Section-C (4a-g):
Microorganisms
4a H 09 16 18 15
4b CH3 16 17 15 19
4c Cl 21 19 18 23
4d OCH3 17 16 17 20
4e NO2 10 12 13 16
4f F 19 16 11 19
4g OH 10 17 16 13
H3CO
S
N CH3
N
N
H
S
N
O
H3CO
R

130
Table-VII: Antibacterial screening of Chapter-5: Section-A (4a-g):
Microorganisms
4a H 18 16 08 19
4b CH3 15 10 17 21
4c Cl 19 16 18 19
4d OCH3 22 17 16 24
4e NO2 15 19 12 18
4f F 12 18 16 14
4g OH 09 16 15 17
O
S
N
CH3
O
N
N
COCH3
R
Table-VIII: Antibacterial screening of Chapter-5: Section-B (4a-g):
Microorganisms
4a NHC6H4 -NO2 19 16 18 17
4b NHC6H5 18 12 19 20
4c N(C2H5)2 20 15 16 18
4d NHC6H4 -CH3 14 13 16 18
4e N(C6H5)2 17 09 11 16
4f NHNaphthyl 08 14 16 13
4g NHC6H4-Cl 21 17 15 22
O
S
N
CH3
O
N
N
S
R

131
Table-IX: Antibacterial screening of Chapter-5: Section-C (4a-g):
Microorganisms
4a H 15 16 18 13
4b CH3 19 18 17 22
4c Cl 16 13 09 19
4d Ph-CH2O 18 16 13 17
4e OCH3 08 14 16 18
4f NO2 16 13 15 19
4g 3,4-OCH3 19 12 16 18
S
N
O
N
N
R
S
CH3
Table-X: Antifungal screening of Chapter-3: Section-A (10a-e):
Microorganisms
Entry R1 R2 Asp.
niger
Asp.
flavus
Penicillium
chrysogenum
Fusarium
Moneliforme
10a CH3 COOC2H5 -ve -ve +ve -ve
10b 4-Cl-Ph H -ve -ve -ve -ve
10c 4-NO2-Ph H +ve -ve -ve -ve
10d C6H5 CH3 -ve +ve -ve -ve
10e 4-OCH3-Ph H +ve RG +ve +ve
Griseofulvin - -ve -ve -ve -ve
DMSO - +ve +ve +ve +ve
-ve: No growth Antifungal activity present, +ve: Growth Antifungal activity absent
RG: Reduce growth
O
S
N
CH3
S
N
R1
R2

132
Table-XI: Antifungal screening of Chapter-3: Section-B (4a-h):
Microorganisms
Entry R Asp. niger Asp.
flavus
Penicillium
chrysogenum
Fusarium
Moneliforme
4a H -ve -ve -ve +ve
4b CH3 -ve -ve -ve -ve
4c Cl -ve -ve RG -ve
4d OCH3 RG -ve +ve +ve
4e 3,4-OCH3 -ve RG +ve RG
4f F -ve -ve RG -ve
4g NO2 RG RG -ve +ve
4h OH -ve -ve RG -ve
RG: Reduce growth
S
N
CH3
H
N
O
N
R
O
Table-XII: Antifungal screening of Chapter-3: Section-C (6a-f):
Microorganisms
flavus
Penicillium
chrysogenum
Fusarium
moneliforme
6a H +ve -ve RG -ve
6b CH3 -ve +ve -ve -ve
6c Cl -ve -ve -ve -ve
6d OCH3 RG +ve -ve -ve
6e 3,4-OCH3 -ve RG -ve RG
6f F -ve -ve +ve -ve
RG: Reduce growth
S
N
CH3
R
N
N NH2
H
S

133
Table-XIII: Antifungal screening of Chapter-4: Section-A (4a-h):
Microorganisms
Entry R R1 Asp. niger Asp.
flavus
Penicillium
chrysogenum
Fusarium
Moneliforme
4a H H RG RG +ve RG
4b H CH3 -ve -ve RG -ve
4c H OCH3 RG RG +ve -ve
4d H F -ve -ve -ve RG
4e Cl H RG RG -ve +ve
4f Cl CH3 -ve RG -ve -ve
4g Cl OCH3 RG -ve RG +ve
4h Cl F -ve -ve RG -ve
RG: Reduce growth
S
N
H3C N
S
O
R
R1
Table-XIV: Antifungal screening of Chapter-4: Section-B (5a-h):
Microorganisms
Entry R R1 Asp. niger Asp.
flavus
Penicillium
chrysogenum
Fusarium
moneliforme
5a F H -ve -ve -ve -ve
5b F Cl -ve -ve -ve -ve
5c NO2 H -ve RG +ve -ve
5d NO2 Cl +ve -ve RG -ve
5e OCH3 H RG -ve RG +ve
5f OCH3 Cl RG +ve -ve RG
5g Cl H -ve RG -ve -ve
5h Cl Cl -ve -ve RG -ve
RG: Reduce growth
S
N
CH3
N
O
N
R
S
N
H3C
R1
S
O
H

134
Table-XV: Antifungal screening of Chapter-4: Section-C (4a-g):
Microorganisms
flavus
Penicillium
chrysogenum
Fusarium
moneliforme
4a H -ve RG -ve -ve
4d OCH3 +ve RG -ve -ve
4e NO2 -ve +ve -ve RG
4f F -ve RG +ve -ve
4g OH +ve -ve RG -ve
RG: Reduce growth
H3CO
S
N CH3
N
N
H
S
N
O
H3CO
R
Table-XVI: Antifungal screening of Chapter-5: Section-A (4a-g):
Microorganisms
flavus
Penicillium
chrysogenum
Fusarium
moneliforme
4a H -ve -ve RG +ve
4c Cl -ve -ve -ve RG
4d OCH3 RG -ve RG -ve
4e NO2 -ve -ve +ve -ve
4f F +ve -ve -ve +ve
4g OH -ve -ve RG +ve
RG: Reduce growth
O
S
N
CH3
O
N
N
COCH3
R

135
Table-XVII: Antifungal screening of Chapter-5: Section-B (4a-g):
Microorganisms
Entry R Asp.
niger
Asp.
flavus
Penicillium
chrysogenum
Fusarium
moneliforme
4a NHC6H4 -NO2 -ve -ve -ve RG
4b NHC6H5 -ve -ve +ve +ve
4c N(C2H5)2 -ve RG -ve -ve
4d NHC6H4 -CH3 -ve -ve RG +ve
4e N(C6H5)2 -ve -ve -ve RG
4f NHNaphthyl RG +ve RG -ve
4g NHC6H4-Cl -ve -ve -ve RG
RG: Reduce growth
O
S
N
CH3
O
N
N
S
R
Table-XVIII: Antifungal screening of Chapter-5: Section-C (4a-g):
Microorganisms
flavus
Penicillium
chrysogenum
Fusarium
moneliforme
4a H RG -ve +ve -ve
4d Ph-CH2O -ve -ve -ve RG
4e OCH3 +ve RG -ve -ve
4f NO2 -ve +ve RG -ve
4g 3,4-OCH3 -ve RG +ve RG
RG: Reduce growth
S
N
O
N
N
R
S
CH3

136
Conclusion:
All the synthesized compounds in Chapter-3, 4 and 5 were screened for
Antimicrobial activity.
Among the screened compounds
 Chapter-3
Section-A:-
compounds 10b, 10c and 10d showed moderate activity against E. coli, S.
aureus and B. subtilis but did not exhibit activity against P. aeruginosa
strains. Compound 10e showed moderate activity against E. coli, P.
aeruginosa, and B. subtilis but not exhibit activity against S. aureus.
The investigation of antifungal activity data revealed that compounds 10a,
10b, 10d show inhibitory effect against A. niger and compounds 10a, 10b,
10c show inhibitory effect against A. flavus. Similarly, most of the
compounds are active against F. moniliforme.
Section-B:-
compounds 4c, 4f exhibit activity against E.coli, compound 4b, 4c are
significantly active against all strains.
compounds 6b and 6c were significantly active against E. coli strains.
Section-C:-

137
 Chapter-4
Section-A:-
compounds 4e, 4f, 4g, and 4h shows good activity against both E. coli and
S. aureus bacteria. compounds 4a, 4b, 4c showed moderate activity against
both gram-positive and gram-negative bacteria.
Section-B:-
compounds 5a, 5d, 5e.5h electron withdrawing (Fluro, chloro) group on
phenyl rings shows significant activity against both gram-positive and
gram-negative bacteria. compound 5b, 5c, 5f, 5g showed moderate
activity.
Section-C:-
compounds 4c & 4d were significantly active against all strains.
Compounds 4a, 4b, 4e, 4f and 4g showed moderate activity against all
bacterial strains.
The investigation of antifungal activity data revealed that compounds 4a,
4b, 4c show inhibitory effect against all fungal strains. The Cl, H, and CH3
substituents on phenyl ring increases the antifungal activity.

138
 Chapter-5
Section-A:-
compounds 4c, 4d, and 4e shows good activity against all strains.
compounds 4b, 4c, and 4d were significantly active against all fungal
strains.
Section-B:-
all compounds showed good to moderate antibacterial activity. compounds
4b, 4c and 4g were significantly active against E. coli and B. subtilis
strains.
The investigation of antifungal activity data revealed that compounds 4b,
4c, 4e and 4g show inhibitory effect against all fungal strains.
Section-C:-
compounds 4b, 4c, 4d, 4e, 4f & 4g were significantly active against B.
subtilis strains except 4a.
The investigation of antifungal activity data revealed that compounds 4b,
4c, 4d show inhibitory effect against all fungal strains.
compounds with electron withdrawing fluoro, chloro and electron donating
methyl groups these pharmacophores exhibited good antimicrobial activity.

139
Section B: Anti-inflammatory activity
 In-vitro Anti-inflammatory activities of synthesizing compounds
by using the inhibition of protein denaturation in percentage
technique which was studied according to K. Ishizaka (1965) with
slight modifications.
 Positive control used standard drugs Ibuprofen. The standard drug
and synthesized compounds were dissolving in minimum amount of
dimethyl formamide (DMF) and diluted with phosphate buffer (0.2
M, pH 7.4). Final concentration of DMF in all solutions was less
than 2.0%. Test solution (1ml) containing different concentration of
drugs was mixed with 1 ml of 1% mM albumin solution in
phosphate buffer and incubated at 27±1 0C in BOD incubator for 15
min.
 The turbidity was measured at 660nm (UV-Visible Shimadzu
Spectrophotometer). Percentage of inhibition of denaturation was
calculated from control where no drug was added. Each experiment
was done in triplicate and average was taken.
% of Inhibition = ( Vt / Vc ) – 1 × 100
Where, Vt = Mean absorbance value of test group.
Vc = Mean absorbance value of control group.

140
Table-XIX: Anti-inflammatory activity of Chapter-3: Section-B (4a-h):
Mean absorbance value ± SEM Inhibition of denaturation
(in %)
Control 0.195 ± 0.04 -
Ibuprofen 0.372 ± 0.02 90.76
4a 0.319 ± 0.04 63.59
4b 0.323 ± 0.06 65.64
4c 0.268 ± 0.01 37.43
4d 0.285 ± 0.08 46.15
4e 0.310 ± 0.03 58.97
4f 0.326 ± 0.07 67.18
4g 0.290 ± 0.02 48.72
4h 0.349 ± 0.03 78.97
S
N
CH3
H
N
O
N
R
O
Table-XX: Anti-inflammatory activity of Chapter-4: Section-A (4a-h):
(in %)
Control 0.195 ± 0.04 -
Ibuprofen 0.372 ± 0.02 90.76
4a 0.317 ± 0.03 62.56
4b 0.350 ± 0.01 79.49
4c 0.324 ± 0.07 66.15
4d 0.361 ± 0.02 85.12
4e 0.313 ± 0.01 60.51
4f 0.318 ± 0.03 63.07
4g 0.300 ± 0.04 53.84
4h 0.325 ± 0.05 66.66
S
N
H3C N
S
O
R
R1

141
Table-XXI: Anti-inflammatory activity of Chapter-4: Section-B (5a-h):
(in %)
Control 0.195 ± 0.04 -
Ibuprofen 0.372 ± 0.02 90.76
5a 0.359 ± 0.06 84.10
5b 0.340 ± 0.03 74.36
5c 0.302 ± 0.08 54.87
5d 0.294 ± 0.01 50.76
5e 0.290 ± 0.01 48.71
5f 0.280 ± 0.04 43.48
5g 0.332 ± 0.05 70.26
5h 0.326 ± 0.07 67.18
S
N
CH3
N
O
N
R
S
N
H3C
R1
S
O
H
Table-XXII: Anti-inflammatory activity of Chapter-5: Section-A (4a-g):
(in %)
Control 0.195 ± 0.04 -
Ibuprofen 0.372 ± 0.02 90.76
4a 0.348 ± 0.08 78.46
4b 0.327 ± 0.03 67.69
4c 0.305 ± 0.07 56.41
4d 0.291 ± 0.01 49.23
4e 0.318 ± 0.05 63.08
4f 0.337 ± 0.01 72.82
4g 0.274 ± 0.06 40.51
O
S
N
CH3
O
N
N
COCH3
R

142
Table-XXIII: Anti-inflammatory activity of Chapter-5: Section-B (4a-g):
(in %)
Control 0.195 ± 0.04 -
Ibuprofen 0.372 ± 0.02 90.76
4a 0.339 ± 0.03 73.85
4b 0.297 ± 0.01 52.31
4c 0.327 ± 0.05 67.69
4d 0.318 ± 0.01 63.08
4e 0.290 ± 0.04 48.72
4f 0.302 ± 0.09 54.87
4g 0.332 ± 0.06 70.26
O
S
N
CH3
O
N
N
S
R

143
Conclusion:
 Some of the synthesized compounds from the Chapter-3, Section-B,
Chapter-4, Section-A & B, and Chapter-5 Section-A & B was screened
for Anti-inflammatory activity.
 Among the screened compounds of Chapter-3 Section-B (4b, 4f &
4h) shows significant activity.
 In the screened compounds of Chapter-4 Section-A (4b & 4d) shows
significant activity, compaired to that of standard drugs Ibuprofen,
phenyl and fluro-substituents increases the antinflammatory activities.
 Simillarly, compounds of Chapter-4 Section-B (5a & 5b) shows
significant activity. Compound of 5a having fluoro substituent in 4-
position of phenyl enhancing the anti-inflammatory activity.
 compounds of Chapter-5 Section-A (4a) shows significant activities,
other compounds shows moderate anti-inflammatory activities.
Compounds of Chapter-5 Section-B (4a) shows significant
antinflammatory activity against standard drug Ibuprofen and (4b), (4e)
& (4f) shows moderate anti-inflammatory activities.

144
List of Publication
Research paper Published
[1] Borde Ramesh M., Waghmare Rahul A., Jadhav Satish B., *Munde
Achut S., “One Pot Synthesis of Nitriles from aldehydes and hydroxylamine
hydrochloride using calcium chloride in DMF solvent under reflux
conditions”, Heterocyclic Letters., (2017), 7(3), 829-833.
[2] Borde Ramesh M., Jadhav Satish B., Dhavse Rahul R., *Munde Achut
S., “Design, Synthesis, and Pharmacological evaluation of some novel bis-
thiazoles derivatives”, Asian Journal of Pharmaceutical & Clinical
Research., (2018), 11(4), 164-168.
[3] Borde Ramesh M., Gaikwad Mahendra A., Waghmare Rahul A., *Munde
Achut S., “Design, Synthesis and In-vitro Anti-inflammatoy, Antimicrobial
activities of some novel 2,3-disubstituted-1,3-Thiazolidin-4-one derivatives
containing thiazole moiety”, Journal of Ultra Chemistry., (2018), 14(3),
104-114.
[4] Borde Ramesh M., Jadhav Satish B., Gaikwad Mahendra A., *Munde
Achut S., “One Pot three-component synthesis of Thiazolidinone derivatives
of 4-methyl-5-carbaldehyde and its Biological evaluation”, Asian Journal of
Organic & Medicinal Chemisty., (2018), 3(4), 159-163.

145
Acknowledgement
 I am thankful to my research guide Dr. A. S. Munde, Professor & Head, Dept.
of Chemistry, Milind College of Science, Nagsenvana, Aurangabad.
 I express my sincere thanks to Dr. S. D. Rathod, Principal, Milind College of
Science, Aurangabad, for providing laboratory with all necessary facilities.
 I am thankful to Dr. R. A. Waghmare, Dr. K. N. Vidhate, Mr. S. R. Annapure,
Mr. S. D. Sarkate, Dr. S. B. Jadhav, Dr. R. P. Dongre and other teaching and
non-teaching staff of the department of Chemistry, Milind College of Science.
 I express my sincere thanks to Dr. S.T.Gaikawad, Prof. and Head Dept. of
Chemistry, Dr. B.A.M.U., Aurangabad for his consistent co-operation.
 My special thanks to all of my teachers & friends, Department of Chemistry,
Dr. Babasaheb Ambedkar Marathwada University, Aurangabad, for his valuable
advice & support .
 I am forever grateful to my Friend Rahul Dhavase & Mahendra Gaikwad for his
continuous inspiration and suggestions during the course of my work.
 I thankful to The Director, S.A.I.F., C.I.L., Punjab University, Chandigarh for
Spectral analysis.

147
Mechanism…
R C
O
H
+ N
H
2
-
O
H
:
C
a
C
l
2
R C H
N
H
H
O
:
C
a
C
l
2
O
H
+
H
-
H
2
O
R C N
H
H
O
H
C
a
C
l
2
-
H
-
H
2
O
R C N
The Proposed mechanism for the conversion of aldehydes via. aldoximine
into nitriles.
 Nitriles
 Thioamide
Hypothetical mechanism for conversion of nitriles to thioamide mediated by
phosphorus pentasulfide.
P
S P S
P
S
S S
P
S S
S
S
S
N C R
P
S P S
P
S
S S
P
S S
S
S
S
N C R
P
S P S
P
S
S S
P
S
S
S
S
S
N C R
H 2 O
R C
S
N H 2

148
 Thiazolidinones
Probable reaction mechanism of Hantzsch thiazole synthesis by the
reaction of α-haloketones and thioamide.
R
C l
O
+ H 2 N R '
S
:
R N
H
C l
R '
S
- H 2 O
R N
C l
R '
S
H
N
S
R
R '
- H C l
 Thiazoles
Initial imine formation followed by the attack of sulfur moiety of the
thioglycolic acid on the imine carbon followed by intramolecular
cyclization to thiazolidinone.
R H
O
+ R ' N H 2
- H 2 O
R N
R '
S
O H
O
H
:
R N H
R '
S
O H
O
:
- H 2 O
S
N
R
R '
O

149
 Reduction using Lithium Aluminium Hydride
The mechanism of oxidation of primary alcohols to aldehydes by using
Pyridinium chlorochromate.
R-CH2-OH
:
:
Cr
O
Cl
O
O
N
H
R C
O
H
H
Cr
H
O
O
O Cl
N
H
-Cl
R C
O
H
H
Cr
H
O
O
O
N
H
Cl
B
:
R C
O
H
H
Cr O
O
O
N
H
Cl
B
:
Chromate ester
oxidation step
R C
O
H + Cr
O
O
O
 Oxidation with PCC
A r O
O
C H 3
L iA lH 4
H - A lH 3
A r O
O
C H 3
H
A r H
O
H - A lH 3
A r H
O
H
H 3 O
A r H
O H
H
The mechanism of reduction using LiAlH4 of ester to aldehydes to
alcohols.

150
 Oxadiazoles
The mechanism of 1,3,4-oxadiazoles synthesis by the cylisation of acyl
hydrazone with acetic anhydride as a oxidant.
O
N
R
N
R '
H
+
O
O
O
:
O x i d a n t
N
N
O
R R '
C H 3
O
C H 3 C O O
 Oxadiazoles-2-thione
A r N
H
N H 2
O
C S 2
K O H
A r N
H
H
N
O
S
S K
K O H
N
N
O S K
S H
H
A r
- H 2 S
N
N
O S K
A r
H
N
N
O S
A r H
N H
N
O S
A r
The cyclisation of unstable dithiocarbamate salt to oxadiazole-2-thione
with the loss of H2S gas.

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