CHAPTER-1
INTRODUCTION
Page No. 01-44
1.1 Indole
1.2 Recent trends in the synthesis of indole
1.3 Biologically active indoles
1.4 Indole research in this laboratory
1.5 Within the frame of the thesis
1.6 References
Chapter - 1
1
1. INTRODUCTION
It is well known that the indole ring is a privileged structural scaffold, which
has been found in a fascinating array of numerous natural products, such as alkaloids,
peptides and various synthetic compounds1,2. Indole and its derivatives have occupied
a unique place in the chemistry of nitrogen heterocyclic compounds because of their
varied biodynamic properties3. The derivatives of indole were known for their dyeing
properties. Many compounds having structural resemblance to the ancient dye indigo
are known. A large number of naturally occurring compounds, like alkaloids, were
found to possess indole nucleus. The recognition of the plant growth hormone,
heteroauxin4 and the essential amino acid tryptophan5 as derivatives of indole have
added stimulus to this research.
The significant contribution of many derivatives of indole in the development
of medicinal chemistry should be recognized. Serotonin or 5-Hydroxytryptamine
known for its vasoconstrictor principle6 plays a vital role as a neurotransmitter and
psychosis. The discoveries of psilocin and psilocybin7 as the important
psychotomimetic indoles have led to extensive research on derivatives of indole-3-
ethylamine (tryptamine). Several derivatives of tryptamine are reported to be central
nervous system (CNS) depressant. Antiinflammatory8 activity was found to be
associated with many derivatives of indole e.g., indomethacine.
The spectroscopic data collected9 on the newer derivatives of indoles, isolated
from various natural sources, have immensely helped in their structure elucidation.
Because of this, good number of minor alkaloids containing indole nucleus are
reported in the literature. Mukherjee et.al10., have isolated a new indole alkaloid,
trinervaine from the roots of S. trinervis. A great deal of chemistry of indole and its
derivatives have thus been accumulated and many monographs11-13 on indole have
Chapter - 1
2
already been published in the literature. Today the scope of indole research is
multifarious extending from rather simple parent molecule to highly complex
molecules.
1.1 Indole (1)
Indole or benzo[b]pyrrole (1) is a planar heteroaromatic molecule in which the
benzene ring is fused to position -2 and -3 of the pyrrole ring. This nucleus has ten π-
electrons which are free to circulate throughout the molecule. Two of these electrons
originate from nitrogen atom and each of the eight carbon atoms contributes one
electron to π-cloud. Since these ten electrons are distributed over nine ring atoms,
indole is an electron rich or -excessive system. Since the ring nitrogen atom
contributes two electrons to the overall system, it is a very weak base12.
(1)
The chemistry14-16 of indole (1) began in the mid of the 19th century with
extensive research on the natural dye indigo, a violet-blue dye, imported to Europe
mainly from India since the 16th century. This research resulted in the early
development of the German chemical industry, culminating in the development of a
viable industrial process for indigo, as well as the first preparation of indole in 186617
by zinc dust distillation of oxindole.
Indigo
Chapter - 1
3
Structure and reactivity of indoles
Indole is a planar heteroaromatic molecule, with a benzene ring fused to the b-
face of the pyrrole. The numbering of indole starts at the nitrogen as shown in
structure (1). Due to the delocalization of nitrogen lone-pair into the π-system, indole
is a very weak base with a pKa value of -3.5. This means, that you need a strongly
acidic solution (12 M H2SO4) to completely protonate indole. Of the three possible
cations, the 3-protonated (1b) is the thermodynamically most stable, since it retains
full benzene aromaticity (in contrast to the 2-protonated cation (1c)) with
delocalization over the nitrogen and the 2-carbon (in contrast to the N-protonated
cation (1a). Kinetically, however, the 1H-indolium cation is favoured.
Indole is highly reactive towards electrophilic substitution reactions, position-
3 being the most preferred place for substitution. The high reactivity of position-3 is
due to -electron density18 and localization energy19. In presence of acids, indole is
protonated at position-3, which seldom results in dimerization or polymerization
(Scheme-1). However, indole has appreciable stability in concentrated acids, where it
is completely protonated20. The NH group of indole is relatively acidic and forms
anion in presence of strong base21. The aromatic character12 of indole is explained on
the basis of ring current affect in PMR spectrum and its appreciable resonance energy
(47 K cal / mole).
Chapter - 1
4
Scheme-1
Indole dimerization is an example of a mannich reaction, where the protonated
indole (1b) is the mannich reagent, an immonium ion, which is fairly reactive
electrophile.
Indole is widely distributed in nature10 viz, in essential oils, coal tar, molassess
tar and also it is found along with the pus, in liver, pancreas, brain and bile. Human
and animal faeces are found to contain indole and skatole. This nucleus is present in a
number of physiologically significant compounds like serotonin, tryptophan, indole-3-
acetic acid, gramine, abrine, reserpine, yohimbine, physostigmine,
lysergicaciddiethyleamide and also in important antibiotics like mitomycin and
gliotoxin.
1.2 Recent trends in the synthesis of indole
Indole and its derivatives have been synthesized by various procedures, the
most prominent being Fischer indole synthesis. Two review articles have appeared on
the recent advances in Fischer indole synthesis22,23.
Chapter - 1
5
Several metal catalysts have been used in the synthesis of indoles on a
commercial scale by the cyclocondensation of anilines with ethylene glycol. The
catalyst used are CdCl224, CdSO4
25, CdS26-30, Cu-CuO431, CaSO4
32, Ag, metal oxides
like CdO, CaO, MgO, SrO, ZnO33, Cu-C34 etc.
TiCl3 has been used as a reductive cyclisation catalyst for the condensation of
o-nitrotoluenes with tripiperidinomethane leading to indole35.
KiKugawa36 has synthesized the substituted indoles (2) from indolines. High
pressure cyclisation of hydroxy alkyl anilines yield indoles in the presence of
catalyst37.
(2)
R1 =H, Alkyl, acylaminoethyl, R=H, CH3; R, R1= Alkenyl.
Vapour phase cyclisation of two moles of ethylaniline with molecular oxygen
in the presence of tungsten oxide or manganese oxide affords indole in 93% yield38.
TiCl4 mediated cyclisation of methane sulfonamides of N-(2,2-diethoxyethyl)
anilines leads to the corresponding indoles. Stereoelectronic effects of intramolecular
electrophilic aromatic substitution are also discussed39.
1.2.1 Alkyl/aryl indoles
Baccolini et.al40., have described a new method for the synthesis of
diastereoisomeric indoles (3) (R=Ph, CH2Ph, R1=Ph, R2=H, R3=H) through
diazophospholes with alkyl halides.
Chapter - 1
6
(3) (4) (5)
Hydrochloric acid catalyzed cyclisation of substituted phenylhydrazine
hydrochloride and methyl ketones in ethanol affords 2-methyl-3-ethylindoles (3) (R,
R1=CH3, CH2.CH2, [CH2 CH2 OH] Et, R3=H, R=ClC6H4CO)41.
Borane mediated reductive elimination of α-methylthio-α-hydroxide or α-
alkoxy-α'-substituted oxindoles affords 3-substituted indoles (4)42. Alkyl indoles are
obtained by gas phase catalysis of aniline and carbonyl compounds over aluminium
orthophosphates43.
Palladium catalyzed Fisher Indole synthesis (5) have described by Seble
wagaw et.al44., (R=CH3, C6H5; R1=H, COOC2H5; R2=Cl, CH3, OCH3, CF3).
Cobalt assisted synthesis of indole as 1:1 adducts from alkynes and diaryl
diazenes is described by Gstach et.al45., and CO(N2)(PPh3) gives 2:1 adducts.
Modification of the Reissert indole synthesis yields 4-(2-dipropylaminoethyl)-
7-methoxyindole via 2-nitro-3-methyl-4-cyanoanisole, followed by homologation of
the cyano group of the resulting indole46. Seniei et.al47., have developed a new
method to synthesize 4-aryl/heteroarylindoles using boronation-thallation technique.
1.2.2 Hydroxyindoles
The supra-suprafacial Wittig rearrangement of 1,2-dihydro-4H-3,1-
benzoxazines [R=CH3, OCH3, F, CF3, R1=H, R=CH3, R1=Cl] results in the synthesis
of 3-hydroxyindoles (6, 7) (R and R1 are same) in the presence of strong base. The
intermediate presumably involves close ion-pair48. Reduction of (E)-2-
O2NC6H4.CH=CHN(CH3)2 with Zn and NH4Cl in two phases (C2H5)2-H2O system for
Chapter - 1
7
25min gave 1-hydoxyindoles49. Nagao et.al50., synthesized 4-hydroxyindole by
treating phenyl acetaldehyde derivatives with H-donors in presence of bases and
metal catalysts.
(6) (7)
1.2.3 Indole -3- carboxylic acid (8)
A new synthesis of indole-3-carboxylic acid (8) by phototropic generation of
dipoles has been reported by Grigg et.al51. The cyclisation of 2-HOOCCH2C6H4-
N=CHR (R=Ph, C6H4OCH3-o, 2-pyridyl, CH=CHPh, COPh) in CH3CN at 25°C for
2-5 days or 1-4h under reflux yield the corresponding indole carboxylates.
(8)
A new route has been developed to prepare 4-, 5- and 6- indole carboxylic acids
by Kasahara et.al52.
1.2.4 Miscellaneous indole derivatives
Silica gel assisted reductive cyclisation of alkoxy-2,β-dinitrostyrenes yield
alkoxyindoles53. Polyfluorinated typical Fischer indole products (9) are reported by
reaction of RNHN=CCH3Ph (R=heptaflouro-2-napthyl, C6F4) in tetralin, surprising
loss of o-fluorine is observed54.
Chapter - 1
8
Nitrobenzenes (R=H, R'=Br) are converted to indoles (10) (R=H) by treatment
with HC=CSi(CH3)3 and the aniline analogues so obtained is treated with conc. HCl
and EtOH55.
(9) (10)
Kawasaki56 has prepared a tandem Wittig-Cope reaction sequence converts a
2-allylindoxyl to the corresponding indole (11) in excellent yield.
(11)
Several new routes to o-aminophenylacetaldehyde derivatives have provided
new indole ring synthesis by electrophilic cyclizations (12)57,58.
(12)
Ketcha et.al59., have utilized Mn(II) in the oxidation of 2-methyl-1 (phenyl
sulfonyl)indolines to the corresponding 2-acetoxymethylindoles (13).
Chapter - 1
9
(13)
Similarly prepared are 6-azaindoles (14) from 4-iodo-3-nitro-2,6-
dimethylpyridine55. Wender et.al60., have described a facile and regio-controlled
synthesis of indoles (15) (R=CH3, CH3CO, F3C) based on organodimetallic reagents.
A new route to 4-substituted indoles is through Claisen rearrangement of
substituted-N-alkyl aniline followed by ozonolytic cleavage of the resulting 1,2,3-
trisubstituted aniline derivatives61. Indole halides useful as intermediates for
tryptophan derivatives are prepared by treating semicarbazone derivatives with TiCl3
over buffer solution62.
(14) (15)
1.3 Biologically active indoles
Synthesis and isolation of compounds having structural resemblance to the
important derivatives of indole, which are known for their varied biodynamic
properties, are the main objects of research in this field. The research work centers
mainly on seven indole derivatives namely serotonin, tryptophan, heteroauxin,
lysergicaciddiethyl amide, tryptamine, indole fused to other heterocyclic systems and
also biheterocycles containing indole nucleus.
1.3.1 Serotonin (16)
Serotonin or 5-hydroxytryptamine (16) was isolated for the first time from
blood serum by Rapport and coworkers63. Earlier, Erspamer64 had shown that there
Chapter - 1
10
was a substance responsible for characteristic staining reactions of organtaffin cells of
the gastrointestinal mucosa.
(16)
He also showed that an extract of cells containing the above substance was
responsible for contractions of smooth muscles. Later the active substance isolated by
Erspamer65 was identified as serotonin. Interest in the psychopharmacological activity
of serotonin was aroused where it was found to be antagonized66,67 by lysergic acid
diethylamide at low concentrations. Wooley and Shaw68,69 have reported that some
synthetic analogues of 5-hydroxytryptamine cause behavioral changes in man and
animals. Some naturally occurring alkaloids viz., ergot and harmala alkaloids,
possessing psychotomimetic properties, also exhibits antiserotonin activity similar to
lysergicaciddiethylamide. The compound, which possesses the psychotomimetic
activity, is due to the tryptamine moiety present in it. These discoveries have
prompted many research workers to isolate many more alkaloids of this type from the
natural source or to synthesize compounds having structural resemblance.
Serotonin was found to be present in mammalian brain70, its highest
concentration were found in the basal ganglia71,72 and pineal glands73. Basal ganglia
are thought to be the area of brain concerned with emotions. These observations
suggested that any change in concentration of serotonin in the brain either by drugs or
by mental disorderliness would result in psychosis70,74,75. Tryptophan was found to be
the precursor of serotonin in the body, thus when 5-hydroxytryptamine68, 76 was
injected, a marked increase in the serotonin level was observed. Tryptophan upon
Chapter - 1
11
hydroxylation at position-5 in presence of the enzyme hydroxylase gives 5-
hydroxytryptamine (16). This may be undergoing conversion into 5-
hydroxytryptamine by an enzyme 5-hydroxytryptophan decarboxylase77. This enzyme
and monoamino-oxidase are not uniformly distributed throughout the brain, but are
present in high concentration in the area of brain where 5-hydroxytryptamine (16) is
prevalent78.
Because of its psychopharmacological properties, analogues of serotonin have
been synthesized as potential agonists or antagonists. Wooley79 has suggested that 5-
methoxytryptamine and N-acetyl-5-methoxytryptamine may be involved in easing the
passage of 5-hydroxytryptamine into nerve cells.
Psilocin (17) is one of the active constituents of Mexican mushrooms which
have been used as early as 1500 BC in Aztec and Mayan culture as hallucinogens80.
Bufotenine (18) is another hallucinogen that occurs in toadstool81.
It has been suggested that affinity for 5-HTID receptors may be obtained by
combining the ethylamine and indole groups. Maintenance of the hydrogen bond
acceptor qualities of substituents in the 5-position should conserve affinity82.
Melatonin (19) is the principal hormone of the vertebrate pineal gland83. Recent
studies on the pharmacology of (19) and on the distribution of its binding sites suggest
that this neuro hormone has a variety of biological effects84,85.
(17) (18) (19)
Chapter - 1
12
Gessner and page86 have shown that 5-methoxy-N,N-dimethyltryptamine is
more active in conditioned avoidance response than bufotenine, N,N-
dimethyltryptamine and N,N-diethyltryptamine. Reserpine (20) has been shown to be
active in reducing the
(20)
concentration of serotonin in central tissues87. Hence the synthesis of compounds,
which are similar to the structure of serotonin or containing tryptamine residue or
aminoindole moiety, has gained much attention in recent years.
There are several indole alkaloids known and many of these have important
physiological activity88. Ergotamine (21) is a potent vasoconstrictor and is used, as its
tartrate salt, to treat migraine89.
(21)
Wooley and Shaw69,90 have synthesized various derivatives of indole
possessing amino group at different positions for the evaluation of antiserotonin and
serotonin like activity. Medamine (22) (2-methyl-3-ethyl-5-dimethylaminoindole) and
Chapter - 1
13
methylmedamine (23) (1,2-dimethyl-3-ethyl-5-dimethylaminoindole) have shown to
possess high degree of potency on isolated tissue. 5-Aminotryptamine showed the
serotonin like activity, but less than that of (23), whereas N,N-dimethyl-5-
aminotryptamine possesses both serotonin like and antiserotonin activity, depending
upon the concentrations used. Potency changes with change in the position of amino
group in the indole nucleus. It was found that 5-, 6-, 7-aminoindoles were more active
than 4-isomer. Schnieder et.al91., have prepared several 1-(aminoalkyl)-indoles as
serotoninergic S2 antagonists. The compounds showed an IC50 of 0.06μgm against
serotonin potentiated ADP-induced platelet aggregation in vitro.
(22) and (23)
R R1 R2 R3
22 H CH3 C2H5 N(CH3)2
23 CH3 CH3 C2H5 N(CH3)2
1.3.2 Tryptophan (24)
Tryptophan (24) is one of the naturally occurring amino acids and is a protein
structural unit. It is not synthesized in the animal body and hence must be supplied
through diet. Deficiency of tryptophan causes characteristic syndrome in animals.
This amino acid plays a vital role in the biosynthesis of cellular proteins and
porphyrins in animals. The metabolic pathway of tryptophan indicates that, it can
substitute for nicotinic acid in higher animals92.
Chapter - 1
14
(24)
A large number of methyl substituted tryptophans have been synthesized and
screened for their biological activity. Anderson93 has synthesized and demonstrated
that, 5-methyltryptophan inhibits the growth of E.coli. Fields and Rydon94 have
synthesized several derivatives of 2-methyltryptophan, which had little inhibition
against the growth of B. typhosum.
1.3.3 Heteroauxin (25)
Indole-3-acetic acid, also known as heteroauxin (25) is a naturally occurring
plant growth hormone and is an important derivative of indole.
(25) (26)
Various structural analogues of this hormone, such as indole-3-propionic acid,
indole-3-butyric acid and indole-3-pyruvic acid, have been synthesized and tested for
their phytohormonal activity. 4-chloroindole-3-acetic acid95 was found to have
considerable activity against A. coleoptile. Schindler96 observed that the 2-isomer of
indole-3-acetic acid exhibited much lower phytohormonal activity than the 3-isomer.
Lot of interest has been centered on 1-(p-chlorobenzoyl)-5-methoxy-2-methylindole-
3-acetic acid (indomethacin) (26), which is used in the treatment of rheumatoid and
Chapter - 1
15
related conditions97.
Indomethacine (26) and tenidap (27) are non-steroidal anti-inflammatory
drugs (NSAIDs) and have been shown to exert anti-inflammatory effects98,99. Tenidap
is an inhibitor of prostaglandin100 and interleukin-I101 production in the body used for
the treatment of rheumatoid arthritis and osteoarthritis. It also inhibits both enzymes
cyclooxygenase and 5-lipoxygenase102, which convert arachidonic acid into
prostaglandin and leukotrienes83 and exhibit superior activity compared to
indomethacine.
(27)
1.3.4 Lysergic acid diethylamide (28)
Ergot alkaloids and related compounds were recognized earlier having
antiserotonin activity, particularly on smooth muscles. In this group lysergic acid
derivatives, such as diethylamide, 2-bromodiethylamide and 1-methyllysergic acid
diethylamide (28) are specially quoted. The action of LSD is selective103. It prevents
the antidiuretic104 action of serotonin and is also a very potent hallucinogenic drug.
(28)
Chapter - 1
16
1.3.5 Indole Esters (29)
Indole carboxylic acids/esters are biologically important systems. These have
been found to inhibit a number of copper enzymes, which are important in the
biological
(29)
systems. Ethyl-5,6-dimethoxy-3-methylindole-2-carboxylate (29) was found to be a
inhibitor of tyrosinase105 and showed good activity against M. leprae106. Indole 2-
carboxylic acid was found to be a competitive antagonist of potentiation by glycine at
NMDA receptor107.
It is also, selectively and competitively inhibits the potentiating action of
glycine on current elicited by NMDA. These studies have indicated that NMDA
receptors in the control of synaptic plasticity and in excitotoxic cell death.
Investigations of antagonists of the glycine potentiation site such as indole-2-
carboxylate/acid should lead to better understanding of the role of glycine in these
processes. These antagonists may have therapeutic value for the treatment of stroke,
epilepsy and other neurodegenerative disorders108. 5-methoxyindole-2-carboxylic acid
was found to be associated with antitumour109 activity. Gray et.al110., have reported
that indole-2-carboxylates and its derivatives are therapeutically effective in the
treatment of CNS disorders resulting from neurotoxic damage or neurodegenerative
diseases, especially those disorders resulting from ischaemic events. Some of the 3-
alkenyl-6-(alkoxycarbonyl)indol-1-yl-alkane caboxylates are found to be potential
agents for the treatment of allergic or inflammatory diseases111.
Chapter - 1
17
Nenitzescu indole synthesis and this classic sequence were used to construct
methyl 5-hydroxy-2-ethyl-N-benzylindole-3-carboxylate (30), the key intermediate in
a synthesis of the antitumor indolequinone EO9112. This reaction has also been used to
prepare a series of N-aryl-5-hydroxyindole113 and it was utilized in the synthesis of a
key indole used to prepare potent and selective s-PLA2 inhibitor114.
(30)
Many heterocyclic systems in which indole nucleus is fused or linked with
other heterocyclic systems are reported to be biologically more potent molecules.
Dipyrido[4,3-b][3,4-f]indoles115 are useful for the preparation of medicaments in the
treatment of AIDS, e.g.[(γ-diethylaminopropyl)amino]-5-methyldipyrido[4,3-b][4,3-
f]indole-3-hydrochloride inhibited production of human immunodeficiency virus-1
(HIV-1) by PHA-stimulated peripheral lymphocytes treated with HIV-1, also
inhibited HIV-1 replication in macrophages Williams et.al116., have reported that
indole-2-carboxyamides and analogues are HIV reverse transcriptase inhibitors and
claimed for treatment of AIDS and ARC. Indolyl benzimidazole-2-carbamates117 have
shown anthelmintic activity against Brugia malayi infection in Mastomyl natalensis.
Several piperazinyl indole derivatives118 are used in the treatment of CNS disorders
including anxiety, depression and aggression or in diseases related to cardiovascular,
renal and gastrointestinal systems. Biheterocycles like indolyl oxadiazoles119 and
indolyl pyrrolidines120 have been found to be novel 5-HT3 antagonists and 5-HT1
agonists, respectively. Girard et.al121., have reported that 2,3-dihydro-1-
hydroxyamino-1H-pyrrolo[1,2-a]indole inhibit synthesis, action and release of SRS-A
Chapter - 1
18
or leukotrienes in mammals and are useful for treating asthma and inflammatory
disease. Furanyl indole-3-methanamines122 are found to be useful as antidiabetic,
antiobesity and antiartheroscleroytic agents.
The synthesis of indole, have attracted enormous attention towards synthetic
organic chemists and a number of methods have been developed for the preparation of
indoles123. Simone et.al124., have synthesized 5,6,11,12,17,18,23,24-
Octahydrocyclododeca[1,2-b-4,5-b'-7,8-b''-10,11-b''']tetraindole CTet, although a
mixture of CTet and cyclic indole trimer CTr is formed which possess potential
anticancer agent.
In recent years there has been increasing interest for the synthesis of organic
compounds using green and rapid method which is used ‘Grindstone Chemistry’.
These reactions were usually carried out on a very small scale in an agate mortar and
grinding with a pestle. Ramin Ghahremanzadeh et.al125., have synthesized
spiro(diindenopyridine-indoline) triones (31) with the help of grinding using a mortar
and pestle of appropriate size.
Chapter - 1
19
(31)
The analogues of indole play an important role in the making of dyes 5, 7, 5',
7'-tetrabromo derivative (Vat Blue 4B) and the 5, 5'-bis-sulfonic acid analog (Blue
Saxon). Indole-7-carboxaldehyde has cytotoxic effect on cancer cells. Complexes
formed with the indole-7-carboxaldehydes are used as chemotherapeutic agents126
(32). Yingchun Gu et.al127., have synthesized trimethine indole quinoline dyes (33).
(32) (33)
Cyclohepta[b]indole represents a significant part of naturally occurring
alkaloids, such as ervatamine, 20-epiervatamine, methuenine, 16-episilicine, ervitsine,
caulersine and homoarcyriaflavin. Cyclohepta[b]indoles possess a wide range of
biological activities such as antitumour, antibiotic and anti inflammatory activities128.
Chapter - 1
20
Bisindole alkaloids are known to possess various biological activities such as
Nortopsentins A-C which exhibit in vitro cytotoxicity against P388 cells and
Hamacanthin B which possess cytotoxic activities against a wide range of human
tumor cell lines with GI50 values at micromolar concentration129. 3,3'-
Bisindolylmethane have been found to inhibit the development of tumors in breast,
uterus and liver. The 5,5'-dimethoxy-3,3'-methanediyl-bis-indole (34) was found to
inhibit the growth of cancer cell lines HOP-92 (lung), A498 (renal) and MDA-MB-
231/1TCC (breast)130.
Chapter - 1
21
(34)
Suresh Kumar et.al131., have described the synthesis of 3,3'-
bis(indolyl)methanes (35) which showed efficient antimicrobial activity against
human pathogens and DPPH radical scavenging effect.
(35)
Atul Kumar et.al132., 3-substituted indoles represents an important
pharmacophore in the drug discovery as well as found in various natural products
such as 5-HT1 B/1D receptor agonist activities used in the treatment of migraine,
Gramine, Ergine and Sumatriptan.
Chapter - 1
22
Kameshwara et.al133., have synthesized 3-substitued indoles (36) and
synthesized compounds were screened for inhibition of cell proliferation of human
colon carcinoma (HT-29), human ovarian adenocarcinoma (SK-OV-3) and c-Src
kinase activity.
(36)
Analogues of indole derivatives are found in important alkaloids such as
murrayanine, which was isolated from Murraya koenigii134. These plants are used as
folk medicines in Southern Asia for the analgesia, local anaesthesia and the treatment
of eczema, rheumatism and dropsy135. Nortoseptins possess antitumor activity136.
Chapter - 1
23
Xue Li et.al137., have synthesized a series of novel indolylquinones and were
screened for antiproliferative activity against human MDA-MB-231 and MCF-7
breast cancer cell lines. All the tested compounds showed potent cytotoxicity activity
in breast cancer cell lines. 2,5-dichloro-3-(2-methyl-1H-indol-3-yl)-6-(2-phenyl-1H-
indol-3-yl)cyclohexa-2,5-diene-1,4-dione (37) and 2,5-dibromo-3-(5-methoxy-2-
methyl-1H-indol-3-yl)-6-(2-p-tolyl-1H-indol-3-yl)cyclohexa-2,5-diene-1,4-dione (38)
have shown most potent antiproliferative activity.
(37) (38)
Shikha et.al138., have reported a series of indolylglyoxylamide (39) analogues
and evaluated in vitro antileishmanial.
Chapter - 1
24
(39)
Tarunkumar et.al139., have synthesized 5-substituted-3-[{5-(6-methyl-2-
oxo/thioxo-4-phenyl-1,2,3,4 tetrahydro pyrimidin-5-yl)-1,3,4-thiadiazol-2-yl}imino]-
1,3-dihydro-2H-indol-2-one (40) derivatives and were screened for in vitro anti-
tubercular activity against Mycobacterium tuberculosis H37Rv and in vitro
antibacterial activity against selected human pathogens viz. E. coli, P. aeruginosa, K.
pneumoniae, S. typhi, S. aureus, S. pyogenus, B. subtilis and antifungal activity
against C. albicans, A. niger, A. clavatus strains.
(40)
Subba Reddy et.al140., have synthesized 3-(1-(1H-indol-3-yl)-2-oxo-2-
phenylethyl)indolin-2-ones (41) using molecular iodine as a novel and evaluated for
antibacterial and antifungal agents. All the synthesized compounds have shown
moderate to potent activity.
Chapter - 1
25
(41)
Maria et.al141., have synthesized 3,4-dihydroxy-N-[1-[2-(5-hydroxy-1H-indol-
3-yl)-2-oxoethyl]piperidin-4-yl]benzamide (42) and it was the most effective
antioxidant agent.
(42)
Cigdem et.al142., have synthesized substituted 2-phenyl-1H-indoles and
evaluated for antioxidant activity. Among the tested compounds, 2-(4-Aminophenyl)-
6-fluoro-1H-indole (43) have shown potent antioxidant activity in the DPPH and
superoxide radical scavenging assays (80% and 81% inhibition at 1 mM
concentration) compared with the reference standard melatonin (98%and 75% at 1
mM).
(43)
Thirupathi Reddy et.al143 have reported the synthesis of (Z)-5-((N-benzyl-1H-
indol-3-yl)methylene)imidazolidine-2,4-diones (44) and 5-((N-benzyl-1H-indol-3-
yl)methylene) pyrimidine-2,4,6(1H,3H,5H)triones (45). These analogues were
Chapter - 1
26
evaluated for their radiosensitization activity against the HT-29 cell line, electron
withdrawing substituent such as –CN,–NO2, or –COOCH3 at the 4-position of the N-
benzyl group, exhibit potent radiosensitizing properties.
(44) (45)
1.4 Research on indole in this laboratory
Indole has been the major field of research in this laboratory for several years,
efforts in our laboratory centers mainly around the following derivatives of indole,
namely serotonin, tryptophan, heteroauxin, carboline, carbazole, pyrimidoindoles,
fused heterocyclic systems and biheterocycles containing indole.
1.4.1 Serotonin
Synthesis and biological activity of a large number of tryptamines, which are
structurally same to serotonin, have been reported from this laboratory.
Hiremath and Siddappa144,145 have synthesised a few Bz-substituted indole for
the evaluation of antiserotonin activity. Several methyl substituted indole-2-(2'-
ylethylamines) have been synthesized and shown to have greater antiserotonin activity
than BAS146,147. Hiremath and Siddappa148 reported some Bz-substituted tryptamines
for the evaluation of biological activity. Hiremath and Kaddargi149 have reported the
synthesis and evaluation of antiserotonin activity of several 3-methyl and 3-phenyl
substituted benzindole-2-(2'-ylethylamines). These workers have also reported the
synthesis of some benztryptamines150.
Chapter - 1
27
1.4.2 Tryptophan
Hiremath and Siddappa151 have reported the synthesis of Bz-nitro, methyl
nitro, methoxy nitro tryptaphans. Ambekar and Siddappa152 have synthesised some
Bz-haloalkyl substituted tryptophans for the assessment of their biological activity.
1.4.3 Heteroauxin
Some Bz-nitro substituted indole-3-acetic acid was prepared by Hiremath and
Siddappa153. Amongest them 7-nitroindole-3-acetic acid was reported to be the
mutagenic and its activity154 was found to be more than heteroauxin itself.
1.4.4 Carbazole
The synthesis of a good number of carbazole derivatives have been reported
Hiremath and coworkers155 by Diels-Alder reaction between 2-(2'-nitrovinyl)indoles
and various dienophiles. Same authors155 have synthesised benzo[a,i]carbazole-1,4-
quinones and naphtho[3,2-i]carbazole-5,13-quinones. Synthesis of
dibenzo[a,i]carbazole-1,4-quinones benzonaphtho[2,3-i] carbazole-5,13-quinones
have been reported by Hiremath et.al156. In these reactions, nitrovinylindoles were
found to be better dienes than corresponding vinyl derivatives reported by Noland
et.al157.
1.4.5 Carboline
The synthesis of several γ-carboline derivatives have been reported from this
laboratory. Hiremath and Purohit146 have synthesised several alkyl substituted-3,4-
dihydropyrido[4,3-b]indoles from their corresponding indole-2-(2'-ylethylamines).
These workers have made use of polyphosphate ester158 for the first time in the
synthesis of 3,4-dihydropyrido[4,3-b]indoles from acyl/aryl derivatives of indole-2-
(2'-ylethylamines). Hiremath and Kaddargi159 have reported the synthesis of 3,4-
dihydropyrido[4,3-b]benz(g) and benz(e) indoles from their corresponding benz(g)
Chapter - 1
28
and benz(e) indole-2-(2'-ylethylamines). Same workers have reported the preparation
of some pyridoindoles which have been found to possess antiserotonin activity160.
1.4.6 Heterocyclic ring systems containing indole nucleus
A large number of alkaloids are known to possess indole nucleus. In addition
to alkaloids some antibiotics derived from microbial sources are also known to
possess indole nucleus. To isolate a compound, which can exhibit either like or
antagonistic property with respect to alkaloids or antibiotics, a large number of their
structural analogues have been synthesized and screened to know their biological
properties. The acetyl indol-2-(2'-ylethylamines) prepared by Hiremath and
Purohitl161, were subjected to Bischler-Napieralski cyclisation with polyphosphate
ester to get 3,4-dihydropyrido [4,3-b]indoles. Hiremath and Kaddargi162 prepared
various 3-phenyl and 3-methyl substituted benz(e) and benz(g) indol-2-(2'-
ylethylamines) for the synthesis of dihydropyrimido[3,4-a] indoles. These compounds
were screened for antiserotonin and antihistaminic activity. Siddappa et.al., have
reported the synthesis and biological evaluation of various substituted 3,4-
dihydropyrimido[3,4-a]indoles. Hiremath et.al162., have synthesised pyrrolo[3,2-b]
indoles, which is novel and previously unknown heterocyclic system and isosteroic
with that present in the alkaloid Physostigmine. This work is extended to synthesize
many physostigmine analogues.
A novel synthetic route has been developed by Biradar et.al163., for the
synthesis of -carboline from 2-phenylindole-3-aldoxime under acidic conditions.
This compound has been formed by the dehydration of Beckmann transformation
product of aldoxime. This has been confirmed by a unambigious synthetic method.
Hiremath et.al164., have developed another interesting method for the synthesis of
diazepinoindole where in diazepine nucleus is fused across c and d sides of indole.
Chapter - 1
29
These diazepinoindoles were obtained by converting ethyl-2-methyl-5-hydroxyindole-
3-carboxylate into its carboxyhydrazides, which on subsequent acylation and
cyclodehydration produced the above heterocyclic system. In all these cases free
hydroxyl group is present at 5-positions of indole nucleus and tertiary nitrogen of
diazepine moiety is present at β to indole-3-position, which are the characteristic
features of serotonin. Further, this work is extended by the above workers165 to obtain
the same heterocyclic system by an alternate route, where in ethyl-2-methyl-5-
hydroxy-6-substituted indole-3-carboxylate was subjected to Vilsmier-Haack
formylation to obtain 4-formyl derivative, which on reaction with hydrazine hydrate
produced the required compound. These compounds have showed significant
pharmacological properties. These workers165 have also synthesized 5-substituted-1-
carbethoxy-3,7-dihydro-2-methylpyrano[3,2-e]indol-7-ones [coumarinoindoles] from
the above formyl derivative.
Biradar et.al166-168., have developed an improved method for the synthesis of
some pyrazolines under microwave irradiation166, a one pot synthesis of substituted
imidazoles containing indole and evaluated for antimicrobial activity167 and also
synthesized solvent-free, microwave assisted Knoevenagel condensation of novel 2,5-
disubstituted indole analogues145. The coworkers also synthesized novel 2,5-
disubstituted-3[3'-(pyridine-2''-yl)-1'-substituted pyrazole-5'-yl and isoxazol-5'-yl)-
1H-indole in triethyl amine medium169, 5-((E)-3-(2,5-disubstituted-1H-indol-3-yl)-1-
phenylallylidene)pyrimidine-2,4,6(1H,3H,5H)-trione and evaluated these compounds
for their antioxidant and DNA cleavage activities170.
1.4.7 Biheterocycles containing indole nucleus
The synthesis of biheterocycles containing indole and oxadiazoles, linked
through an amino bridge, have been reportd by Hiremath et.al171. These compounds
Chapter - 1
30
have exhibited appreciable antibacterial and fungicidal properties. The substituted 2-
aminoindoles synthesized as intermediates in the above reaction by these workers,
have shown high degree of antibacterial properties.
Hiremath et.al172., have developed a convenient method to synthesize 2-(1', 3',
4'-oxadiazolyl) indoles from their corresponding ethylindole-2-carboxylates. This
work173 has been extended to the synthesis of biheterocycles containing thiadiazoles
and triazoles.
In all the above cases indole is linked to another heterocyclic system at
position-3. Sinnur et.al174., have also synthesized the biheterocycles containing
benzimidazole and indole moieties. Benzimidazole moiety was synthesized on a
preformed indole at position-2. These workers174 have also prepared 2-(benzopyran-
2'-one-3'-yl) indoles and various indolylpyrimidinediones and
indolylthiazolidinones175.
Renuka devi Patil et.al176., have synthesized some 1,2-disubstituted-4-[5'-
substituted-2'-phenylindol-3'-yl-methyl-one]imidazole-5-(4H)-ones and 3,5-
disubstituted-2-(5'-thioxo-1'-3'-4'-oxadiazol-4'-ethylacetate-2'-yl) indoles and
evaluated them for antimicrobial activity are the recent developments. Biradar
et.al177., have synthesized some bisindolyl analogs for in vitro cytotoxic and DNA
cleavage studies.
1.4.8 Triheterocycles containing indole nucleus
In continuation of research work on indoles in our laboratory same workers
have reported the synthesis of triheterocycles containing indole nucleus. Hiremath
et.al178., have reported the synthesis of 2-phenyl (indole-3-yl)isothiocynates, 1-
substituted-3-(substituted-2'-phenylindole-3'-yl)thiosemicarbazide and their reactions.
Manjunath179 have done the synthesis of some triheterocyclic moieties, which are
Chapter - 1
31
linked with indoles. These compounds 2-(5'-chloro-2'-phenylindole-3-yl)-5-
(coumarin-3''-yl)-1,3,4-oxadiazole, azetidin-2-one and diazepines and screening them
for various biological activities. Biradar et.al180., have synthesized MK-10 clay
catalyzed, one pot, three component and efficient synthesis of novel 4-(2',5'-
disubstituted-1'H-indol-3'-yl)-2,6-bis(2',5''-disubstituted-1''H-indol-3''-yl)pyridine-3,5-
dicarbonitrile under conventional and microwave methods.
1.5 Within the frame of the thesis.
The above discussion is still insufficient to describe the importance of the
chemistry of indole and its derivatives. It is just impossible to cite the pharmacology
of indole derivatives in a few pages. Good numbers of indole derivatives have found
wide range of application in chemotherapy.
The present investigation mainly describes the synthesis of various
heterocycles such as thiazolidinones, imidazopyridines, triazolothiadiazepines,
pyrazoloquinoline and oxadiazoles attached to the substituted indole of biological
interest and electrochemical study of various indole analogues. The synthesized
compounds have been screened for various biological activities.
The thesis is divided into six chapters.
CHAPTER-1: INTRODUCTION
This chapter has the biological importance of indole and its number of
derivatives have been described. Synthesis of indole fused with other heterocycles
also been described. Whenever a biologically active molecule is substituted with
different groups and molecules which are also biologically active may results into a
more potent molecule. Hence synthesis of several indole substituted with other
heterocycles have been synthesized. In this chapter, the detailed discussion about the
research going on in indole field in this laboratory has also been presented.
Chapter - 1
32
CHAPTER-2: DESIGN AND SYNTHESIS OF
INDOLYLCARBOHYDRAZIDES AND THIOPHENO-4-
THIAZOLIDINYLINDOLES
a) 3,5-disubstituted-N'-(1-(2,5-dichlorothiophen-3-yl)ethylidene)-1H-indole-2
carbohydrazide.
R= Cl, Br & CH3; R'= Ph & CH3
b) 3,5-disubstituted-N-(2-(2,5-dichlorothiophen-3-yl)-2-methyl-4-oxothiazolidin-3-
yl)-1H-indole-2-carboxamide.
R= Cl, Br & CH3; R'= Ph & CH3
c) 5-substituted-N-(2-(2,5-dichlorothiophen-3-yl)-2,5-dimethyl-4-oxothiazolidin-3-
yl)-3-phenyl-1H-indole-2-carboxamide.
R= Cl, Br & CH3; R'=Ph
Chapter - 1
33
CHAPTER-3: MICROWAVE ASSISTED SYNTHESIS OF NOVEL INDOLE
ANALOGUES
PART-I: Synthesis of 2-(3,5-disubstituted-1H-indol-2-yl)-3H-imidazo[4,5-
b]pyridine.
R=Cl, Br, CH3, OCH3 & H; R'= Ph, CH3 & H
PART-II: Synthesis of 8-(2,5-disubstituted-1H-indol-3-yl)-3-(5-substituted-
3-phenyl-1H-indol-2-yl)-6-(4-substitutedphenyl)-
[1,2,4]triazolo[3,4-b][1,3,4]thiadiazepine.
R= Cl, Br & CH3; R'= Cl, CH3 & H; R''= Cl, H & CH3; R'''= Ph & H
PART-III: Synthesis of 8-substituted-4-(2,5-disubstituted-1H-indol-3-yl)-1-
methyl-3H-pyrazolo[3,4-c]quinoline.
R= Cl, CH3 & H; R'= Cl, Br & CH3, H; R''= Ph & H
Chapter - 1
34
CHAPTER-4: SYNTHESIS OF NOVEL BISINDOLYLOXADIAZOLE
ANALOGUES
R= Cl, Br & CH3; R'= Cl, Br, CH3 & H; R''= Ph & H
CHAPTER-5: CYCLIC VOLTAMETRIC STUDIES OF NOVEL INDOLE
ANALOGUES PREPARED IN THE PRESENT STUDY
CHAPTER-6: BIOLOGICAL ACTIVITY
1) Antimicrobial Activity
Antibacterial Activity
Antifungal Activity
2) Antioxidant Activity
Free Radical Scavenging Activity
Total Antioxidant Capacity
Ferric Reducing Activity
3) DNA Cleavage Activity
SUMMARY AND CONCLUSION
LIST OF PUBLICATIONS
LIST OF PRESENTATIONS
LIST OF CONFERENCES / SEMINARS / WORKSHOPS ATTENDED
Chapter - 1
35
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