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ABSTRACT OF THE THESIS
“DESIGN AND SYNTHESIS OF NOVEL HETEROCYCLIC COMPOUNDS
FROM ANACARIDIUM OCCIDENTALE AND THEIR BIOLOGICAL
EVALUATION”
The thesis is consists of five chapters
The first chapter deals with the survey of literature with particular
reference to the
i. The introductory aspects of anacardic acid derivatives
ii. Isolation of anacardic acid
iii. Biological activity of various anacardic acid analogs.
In Chapter II, Synthesis and anti-bacterial activity of some substituted
amino anacardic acids derivatives have been described.
In Chapter III, Synthesis and anti-bacterial activity of some sulphonamido
analogues of anacardic acid have been described.
In Chapter IV, Synthesis and anti-bacterial activity of some urea analogues
of anacardic acid have been described.
In Chapter V, Synthesis and anti-bacterial activity of some thiourea
analogues of anacardic acid have been described.
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Chapter-1: Introduction
The cashew tree (Anacardium occidentale) a species originally native to
Brazil where it is still cultivated, also grown in a large number of other
tropical and sub-tropical countries. It is now commonly found along the
coastal regions of India. Cashew nut shell liquid (CNSL) is a by-product of
cashew nut industry and anacardic acid ene mixture (Figure 1.1) is isolated
from CNSL which are salicylic acid derivatives with a nonisoprenoid alk(en)yl
side chain.
Figure 1.1: Ene mixture of anacardic acid
Each consists of a salicylic acid substituted with an alkyl chain that
has 15 carbon atoms. Anacardic acid is a mixture of saturated and
unsaturated molecules. The exact mixture depends on the species of the
plant of which the 15 carbon unsaturated side chain found in the cashew
plant is very lethal to Gram positive bacteria.
It is primarily used for tooth abscesses, it is also active against acne,
some insects, tuberculosis, and MRSA. It is primarily found in foods such as
cashew nuts, cashew apples, and cashew nutshell oil, but also in mangos
and Pelargonium geraniums.
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Chapter-2: Synthesis and anti-bacterial activity of some
substituted amino anacardic acid derivatives
Owing to the extensive biological properties of anacardic acid
derivatives, we were also prompted to develop several such analogues of
anacardic acid and screen them for their potential anti-microbial properties.
The present chapter deals with our efforts to make diversely functionalized
anacardic acid derivatives. The synthesis of all the new compounds 6a–6u
and 10a-10s is depicted in Scheme 2.1. The above new compounds were
screened for their anti-bacterial activity screenings against Escherichia coli,
Pseudomonas aeruginosa, Streptococcus pyogenes and Staphylococcus
aureus bacterial strains using agar well diffusion method. The anti-bacterial
activity of the analogues was compared with standard drug Ampicillin.
Scheme 2.1
Reagents and Conditions: a) 10 % Pd/C, EtOH, H2 (50 psi), RT, 2 h;
b) (CH3)2SO4, K2CO3, CH3CN, 90 °C, 24 h; c) LiAlH4, THF, 0 °C-RT, 18 h; d)
Methane sulphonyl chloride, Et3N, DCM, 0°C-RT, 3 h; e) different amines,
Et3N, CH3CN, 85 °C, 3-18 h;
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Having synthesized the 2-substituted amine analogues of anacardic
acids, we then turned our attention to synthesize 6-substituted amino
derivatives (10a-10s) as depicted in Scheme 2.2. The bromo compound 9
thus obtained was treated with different substituted aliphatic or aromatic
amines resulted compounds 10a-s respectively (Scheme 2.2). All the
synthesized compounds (6a-6u, 10a-10s) were characterized by 1H NMR,
FT-IR, and Mass analysis. Some of the derivatives and intermediates were
characterized by 13C NMR also.
Scheme 2.2
Reagents and Conditions: a) (CH3)2SO4, K2CO3, CH3CN, 90 °C, 24 h;
b) O3, MeOH, DCM, -78 °C; c) MeOH, NaBH4, 18 h, 0 °C-RT; d) CBr4,
Pyridine, Ph3P, DCM, 0 °C-RT, 6 h; e) different amines, K2CO3, CH3CN, 90
°C, 4-12 h.
Compounds 6a-6u & 10a-10s were tested against two Gram negative
strains viz., i) Escherichia coli and ii) Pseudomonas aeruginosa and two
Gram positive strains viz., i). Streptococcus pyogenes and ii) Staphylococcus
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aureus using agar well diffusion method. The anti-bacterial activity of the
analogues was compared with standard drug Ampicillin.
Chapter-3: Synthesis and antibacterial activity of some
sulphonamido analogues of anacardic acid
As discussed in the Chapter-1 and Chapter-2 about biological
significance of various anacardic acid derivatives, we now turned our
attention towards the synthesis of some amide analogues of anacardic acids.
Literature survey revealed that functionalized amide derivative of
anacardic acid such as N-(4-chloro-3-trifluoromethyl-phenyl)-2-ethoxy-6-
pentadecyl-benzamide (CTPB, Figure 3.1) was found to be the first specific
activator of histone acetyltransferase (HAT) activity of p300.
In view of the immense potential of anacardic acid and its derivatives
as selective and specific biological agents, the aim of the present work is to
make use of abundantly and cheaply available anacardic acid and to make
synthons for generating novel class of bioactive compounds such as
functionlised sulfonamido analogues of anacardic acids and screen them for
potential anti-bacterial properties.
The synthesis of all the new compounds 13a–13l is depicted in
Scheme 3.1. The crude products were purified by column chromatography
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to yield the title compounds 13a-13l (Scheme 3.1).
Scheme 3.1
Reagents and Conditions: a) NaN3, DMF, 100 oC, 2 h; b) 10 % Pd/C, H2
(50 psi), 2 h; c) different sulphonyl chlorides, Et3N, DCM, 0 oC-RT.
Having synthesized the sulfonamide analogues of the anacardic acid
with the methyl amine ortho to the methoxy group on the phenyl ring, we
have synthesized sulfonamide analogues (16a-16l) on side chain 15 to as
depicted in Scheme 3.2 tested for their biological activity.
The amino compound 15 was reacted with various substituted
sulfonyl chlorides in DCM using Et3N as a base and isolated sulfonamido
analogues of anacardic acid 16a-16l (Scheme 3.2). All the intermediates
and synthesized analogues (13a-13l, 16a-16l) were characterized by 1H
NMR, FT-IR, and Mass analysis. Some of the derivatives and intermediates
were characterized by 13C NMR also.
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Scheme 3.2
Reagents and Conditions: a) O3, MeOH, DCM, -78 oC, 6 h; b) MeOH,
NaBH4, 18 h, 0 oC-RT; c) CBr4, Pyridine, PPh3, DCM, 0 oC-RT, 8 h; d) NaN3,
DMF, 100 oC, 3 h; e)10% Pd/C, EtOH, H2 (50 psi), RT, 2 h; f) different
sulfonyl chlorides, Et3N, DCM, 0°C-RT, 3 h.
Compounds 13a–13l and 16a-16l were tested against two Gram
negative strains viz., i) Escherichia coli and ii) Pseudomonas aeruginosa and
two Gram positive strains viz., i).Staphylococcus aureus and ii) Streptococcus
pyogenes using agar well diffusion method. The anti-bacterial activity of the
analogues was compared with standard drug Ampicillin.
Chapter-4: Synthesis and Antibacterial Activity of some urea
analogues of anacardic acid
As discussed earlier in the previous chapters about the biological
significance of various analogues of anacardic acids, in the present chapter
we intended to synthesize some highly substituted urea and thiourea
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analogues of anacardic acid and screen them for their potential biological
activities.
In this regard, the amino compound 12 was synthesized following the
procedure outlined in Chapter-3 via its azido analogue. Compound 12 was
then reacted with substituted isocyanates derivatives in chloroform at room
temperature to afford the corresponding urea analogues of anacardic acid
ie., 17a-17k (Scheme 4.1)
Scheme 4.1:
Reagents and Conditions: a) different isocynates, CHCl3, RT
Following the similar lines of synthesis in Scheme 4.1, we have
synthesized the urea analogues (18a-k) on side chain of anacardic acid from
the amino compound 15 (scheme 4.2). The required amino compound 15
was synthesized following the protocol presented in Chapter-3. The amino
compound 15 was then reacted with substituted isocyanates derivatives in
CHCl3 at RT to afford the corresponding urea analogues of anacardic acid
i.e., 18a-18k. All the synthesized analogues (17a-17k, 18a-18k) were
characterized by 1H NMR, FT-IR, and Mass analysis. Some of the derivatives
and intermediates were characterized by 13C NMR also.
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Scheme 4.2:
Reagents and Conditions: a) different isocynates, CHCl3, RT
Compounds 17a–17k, 18a-18k were tested against two Gram
negative strains viz., i) Escherichia coli and ii) Pseudomonas aeruginosa and
two Gram positive strains viz., i). Streptococcus pyogenes and ii)
Staphylococcus aureus using agar well diffusion method. The anti-bacterial
activity of the analogues was compared with standard drug Ampicillin.
Chapter-5: Synthesis and Antibacterial Activity of some thiourea
analogues of anacardic acid
As discussed earlier in the previous chapters about the biological
significance of various analogues of anacardic acids, in the present chapter
we intended to synthesize some highly substituted urea and thiourea
analogues of anacardic acid and screen them for their potential biological
activities.
In this regard, the amino compound 12 was synthesized following the
procedure outlined in Chapter-3 via its azido analogue. Compound 12 was
then reacted with substituted isothiocyanates derivatives in chloroform at
room temperature to afford the corresponding urea analogues of anacardic
acid ie., 19a-19k (Scheme 5.1)
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Scheme 5.1
Reagents and Conditions: a) different isothiocynates, CHCl3, RT
Following the similar lines of synthesis as mentioned in Scheme 5.1,
we have synthesised the thiourea analogues (20a-20f) on side chain of
anacardic acid from the amino compound 15 (scheme 5.2). The required
amino compound 15 was synthesized following the protocol presented in
Chapter- 3. The amino compound 15 was then reacted with substituted
isothiocynate derivatives in CHCl3 at RT to afford the corresponding thiourea
analogues of anacardic acid (20a-20f) (Scheme 5.2). All the synthesized
analogues (19a-19f, 20a-20f) were characterized by 1H NMR, FT-IR, and
Mass analysis. Some of the derivatives and intermediates were characterized
by 13C NMR also.
Scheme 5.2
Reagents and Conditions: a) different isothiocynates, CHCl3, RT.
Compounds 19a-19f and 20a-20f were tested against two Gram
negative strains viz., i) Escherichia coli and ii) Pseudomonas aeruginosa and
two Gram positive strains viz., i). Streptococcus pyogenes and ii)
Staphylococcus aureus using agar well diffusion method. The anti-bacterial
activity of the analogues were compared with standard drug Ampicillin.
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TABLE OF CONTENTS
Acknowledgements i-ii
Abstract of the Thesis iii-xiii
Table of Contents xiv-xv
General Remarks xvi-xvii
Abbreviations xviii-xx
CHAPTER 1: Introduction 1
References 12
Aim and objectives 21
CHAPTER 2: Synthesis and Anti-bacterial Activity of Some substituted
amino Anacardic Acid Derivatives
Introduction 23
Present work 24
Experimental 43
References 73
Spectra 74
CHAPTER 3: Synthesis and Antibacterial Activity of some sulphonamide
analogues of anacardic acid
Introduction 101
Present work 102
Experimental 117
References 137
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Spectra 138
CHAPTER 4: Synthesis and Antibacterial Activity of some urea analogues of
anacardic acid
Introduction 157
Present work 157
Experimental 169
Spectra 185
CHAPTER 5: Synthesis and Antibacterial Activity of some thiourea
analogues of anacardic acid
Introduction 203
Present work 203
Experimental 214
Spectra 223
List of publications 231
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GENERAL REMARKS
All melting points were recorded on a superfit (India) capillary melting
point apparatus and are uncorrected.
Infrared spectra were recorded on a Perkin Elmer FT-IR spectrometer.
Samples were recorded either in neat, KBr wafers or in DCM as a thin
film.
1H NMR and 13C NMR Spectra were recorded on a Varian EM-360
spectrometer 400MHz. The samples were made in CDCl3 and DMSO-
d6 using TMS (δ = 0 ppm) as internal standard. Spectral assignments
are as follows: (1) chemical shifts on the δ scale, (2) standard
abbreviation for multiplicity, that is, s = singlet, d = doublet, t= triplet,
q = quartet, m = multiplet, brs = broad singlet. (3) Coupling constant J
in Hertz.
The mass spectra were recorded on Agilent ion trap MS.
Thin layer chromatography (TLC) was performed using silica gel 60-
F254 (0.5-mm) glass plates. Visualization of the spots on TLC plates
was achieved either by exposure to iodine vapour or UV light or
nihydrin solution and heating the plates to 100 oC.
Column chromatography was performed using silica gel (60-120
mesh/100-200 mesh) and executed under nitrogen pressure (flash
chromatography) conditions, the column was usually eluted with ethyl
acetate-petroleum ether or MeOH-CHCl3.
All solvents and reagents were purified by standard techniques.
Evaporation of solvents were carried out under reduced pressure on
Buchi rotary evaporator below 45 oC.