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. 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

1
 Chapter - 1
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

2
 Chapter - 1
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).

3
 Chapter - 1

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.

4
 Chapter - 1
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, CdSO425, CdS26-30, Cu-CuO431, CaSO432, 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.

5
 Chapter - 1

(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

6
 Chapter - 1
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.

7
 Chapter - 1
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).

8
 Chapter - 1

(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

9
 Chapter - 1
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

10
 Chapter - 1
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)

11
 Chapter - 1
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

12
 Chapter - 1
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.

13
 Chapter - 1

(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

14
 Chapter - 1
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)

15
 Chapter - 1
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.

16
 Chapter - 1
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

17
 Chapter - 1
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.

18
 Chapter - 1

(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.

19
 Chapter - 1

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.

20
 Chapter - 1

(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.

21
 Chapter - 1

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.

22
 Chapter - 1

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.

23
 Chapter - 1

(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.

24
 Chapter - 1

(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

25
 Chapter - 1
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.

26
 Chapter - 1
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)

27
 Chapter - 1
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.

28
 Chapter - 1
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

29
 Chapter - 1
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

30
 Chapter - 1
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.

31
 Chapter - 1
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

32
 Chapter - 1
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

33
 Chapter - 1
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

34
 Chapter - 1
1.6 References

1. K. Kerstin, V. Sylvia, B. Stefan, Beilstein J. Org. Chem., 8, 1191 (2012).

2. A. Pews-Davtyan, T. Annegret, S. Anne-Caroline, O. Stefanie, J. F. Moritz,

R. Arndt, B. Matthias, Org. Biomol. Chem., 8, 1149 (2010).

3. A. Baeyer, Chem. Ber., 13, 2254 (1880).

4. F. Kogl, A. J. Haagens-Smith, H. Erxleben, Z. Physiol.Chem., 214, 241

(1933).

5. W. C. Rose, Physiol. Rev., 18,109 (1938).

6. M. E. Specter, R. V. HeinZieman, P. I. Weisblat, J. Amer. Chem. Soc., 73,

5515 (1951).

7. A. Hoffman, A. Frey, H. Ott, T. H.Petrizika, F. Troxler, Experiments (Basel)

14, 397 (1958).

8. T. Y. Shen, International Symposium on Nonsteriodal Anti-inflammatory

Drugs, Milan, 63 (1964-65).

9. S. P. Hiremath, R. S. Hosamane, “Applications of Nuclear Magnetic

Resonance Spectroscopy to Heterocyclic Chemistry of Indole and its
Derivatives”. Advances in Heterocyclic Chemistry, A.K. Katrizky,
Academic press, New York, 15, 277 (1973).

10. R. Mukherjee, M. Melo, Heterocycles., 31(10), 1819 (1990).

11. W. C. Sumpter, F.M miller, “Heterocyclic Compounds with indole and

carbazole system”. Ed Interscience Publishers, Inc, New York (1954).

12. R. J. Sundberg, “The Chemistry of Indoles” Academic Press, New York

(1970).

13. W. A. Remars, R. E. Brown, Indoles, W. J. Hollihan, Ed. J. Wile’y, New

York, 1 (1972).

14. W. J. Houlin, Indoles; Wilry-Interscience: New York, Part I (1972).

15. J. A. Joule, K. Mills, G. F. Smith, Het. Chem., 3rd edit.; Chapman and Hall,
(1995).

16. R. J. Sundberg, The Chemistry of Indoles; Academic Press: New York,

(1970).

17. A. Baeyer, Ann. Chem., 140, 295 (1896).

18. R. D. Brown, B. A. Coller, Aust. J. Chem., 12,152 (1959).

35
 Chapter - 1
19. J. M. Bruce, J. Chem. Soc., 15, 14 (1962).

20. R. L. Himman, E. V. Whipple, J. Amer. Chem. Soc., 84, 2534 (1962).

21. C. Yagil, Tetrahedron., 23, 2855 (1967).

22. B. Robinson, “The Fischer Indole Synthesis”, Wiley, New York (1982).

23. S. Y. Ambaker, Curr. Sci., 52 (12), 578 (1983).

24. Ube Industries Ltd., Jap. Patent, JP 58, 109471 (1983); Chem. Abstr.,
99,122302q (1983).

25. F. Matsuda and T. Kato, Can. Patent, CAI, 149, 396 (1983); Chem. Abstr.,
100, 6334s (1984).

26. Mitsui Toatsu Chemical Inc. Jap. Patent. JP. 5846, 067 (1983); Chem.
Abstr., 99, 139767 (1983).

27. A. Kudoh, T. Honda, M. Kontani, K. Terada, T. Tsuda, S. Kiyonono, Ger.

Patent, DE3, 332,152 (1983); Chem. Abstr., 100, 174657 (1984).

28. T. Honda, K. Kazuriho, PCT Int. Appl. WO 8300,691 (1983); Chem. Abstr.,
99, 5537W (1983).

29. Mitsui Toastu Chemicals Inc., Jap. Patent, JP 58, 29762 (1983); Chem.
Abstr., 99, 55373y (1983).

30. Mitsui Toatsu Chemical Inc., Jap. Patent, Jp 58, 32, 683 (1983); Chem.
Abstr, 99, 55378d (1983).

31. F. Matsuda, T. Kato, Can. Patent, CAI, 150, 729 (1983); Chem. Abstr., 100,
6336 (1984).

32. Ube Industries Ltd., Jap. Patent, JP58, 121,270 (1983); Chem. Abstr., 99,
139768u (1983).

33. T. Honda, F. Matsuda, T. Kiyoura, K. Terada Eur. Patent, EP 69, 242 (1983);
Chem. Abstr., 98, 179218a (1983).

34. Mitsui Toatsu Chemicals Inc. Jap. Patent, JP 5946, 267 (1984); Chem.
Abstr., 100, 212090n (1984).

35. D. H. Lloyd, D. E. Nichols, Tetrahedron Lett., 24 (42), 4561 (1983).

36. Y. Kikugawa, Jap. Patent, JP 58, 55, 458 (1983); Chem. Abstr., 99, 33596z.
(1983).

37. A. Kudoh, T. Honda, M. Kotani, K. Terada, T. Tsuda, S. Kiyono, Ger,

Patent, DE 3, 324, 092 (1984); Chem. Abstr., 100, 17465u (1984).

36
 Chapter - 1
38. K. K. Showa Denko, Jap. Patent, JP57, 139, 064 (1982); Chem. Abstr, 98,
125867 (1983).

39. R. J. Sundberg, J. P. Laurino, J. Org. Chem, 49 (2), 249 (1984).

40. G. Baccolini, P.E. Todesco, J. Chem. Soc. Perkin. Trans., 1 (3), 535 (1983).

41. C. Sarbu, N. Radulescu, M. lonsecu, M. R. Simionorici, N. Boesteanu, L.

Babes, Y. Cristescu, C. I. Lonescu, 1. Cornelio, S. Negitescu, Rom. RO77,
049 (1981); Chem. Abstr., 99, 21246j (1983).

42. W. Wierenga, J .Griffin, H. A. Warkehoski. Tetrahedron Lett., 24 (24), 2437

(1983).

43. S. Estelean, J. M. Marinas, M. P. Martinez-Alcazar, M. Martinez, A. R.

Agarrabeittia, Bull. Soc. Chem. 92 (8), 715 (1983).

44. S. Wagaw, B. Yang, S. L. Buchward, J. Am. Chem. Soc. 120, (1998).

45. H. Gstach, H. Z. Kisch, B. Naturforsch, Anorg. Chem., Org. Chem., 38B(2),

251 (1983).

46. J. G. Cannon, J. Lukszo, G. A. Max., J. Het. Chem., 20 (1), 149 (1983).

47. M. Somei, H. Amari, Y. Makita, Chem. Pharm. Bull., 34 (9), 3971 (1986).

48. R. R. Schmidt, B. Beitzke, Chem. Ber., 116 (6), 2115 (1983).

49. R. M. Acheson, G. N. Aldrige, C. K. Michael Choi, J. O. Nwankno, M.

Ruscoe, J. P. Wallis., J. Chem, Res., Synop., 4,101 (1984).

50. K. Nagao, K. Takehira, A .Suzui, M. Nakagawa, Jap. Patent, JP 6140, 259

(1986); Chem. Abstr., 105, 60526x (1986).

51. R. Grigg, H. O. N. Gunaratue, J. Chem. Soc., Chem. Commun., 10, 661

(1984).

52. A. Kasahara, T. Izumi, H. Yanai, S. Murakami and M. Takatori, J. Chem.

Technol. Biotechnol., 36 (12), 562 (1986).

53. A. K. Sinhababu, R. T. Borchardt, J. Org. Chem., 48 (19), 3347 (1983).

54. G. M. Brooke, J. Chem. Soc. Perkin. Trans., 4 (1), 821 (1983).

55. T. Sakamoto, Y. Kondo, H. Yamanaka, Heterocycles, 22 (6), 1347 (984).

56. T. Kawasaki, K. Watanabe, K. Masuda, M. Sakamoto, J. Chem. Soc., Chem.

Commun., 381 (1995).

37
 Chapter - 1
57. T. Kakigami, T. Usui, K. Tsukamoto, T. Kataoka, Chem. Pharm. Bull., 46,
42 (1998).

58. E. Arai, H. Tokuyama, M. S. Linsell, T. Fukuyama, Tetrahedron Lett., 39, 71

(1998).

59. D. M. Ketcha, Q. Zhou, D. Grossie, Synth. Commun., 24, 565 (1994).

60. P. A. Wender, A. W. White, Tetrahedron, 39 (22), 3767 (1983).

61. S. J. Sanishefsky, G.B. Philips, Tetrahedron Lett., 25 (30), 3159 (1984).

62. O. Micyano, H. Shiyuyama, Y. Tsutsumi, Jap. Patent, JP 6150, 968 (1988);

Chem. Abstr., 105, 60528z (1986).

63. M. M. Rapport, A. A. Green, 1.H. page, Federation Proc., 6, 184 (1947).

64. V. Erspamer, Arch. Expti. Pathol. Pharameol. Naunyan Schmiedebergs, 196,

366 (1940).

65. V. Erspamer, B. Asero, Nature, 169, 800 (1952).

66. J. H. Graddum, J. Physiol., 121, 15 (1953).

67. L. Gyermek, Pharmacol, Rev., 13, 399 (1961).

68. D. W. Wolley, E. Shaw, Ann. New York Acad. Sci, 66, 649 (1957).

69. (a) E. Shaw, D. W. Wooley, J. Pharmacol Exptl. Therap., Ill, 43 (1954). (b)
E. Shaw, D. W. Wooley, J. Amer. Chem. Soc., 79, 3561 (1957).

70. A. H. Amin, T. B. B. Crawford, J. H. Graddum, J. Physiol., 126, 596 (1954).

71. D. F. Bogdanski, H. Weissbach, S. Udenfriend, J. Neurochem., 1, 272

(1957).

72. E. Costa, M. H. Aprison, J. Nervous Mental Disease, 126, 289 (1958).

73. N. J. Giarman, D. X. Freedman, Nature, 186, 480 (1960).

74. D. W. Woolley, E. Shaw, Science, 119, 597 (1954).

75. D. W. Woolley, E. Shaw, Proc. Nat. Acad. Sci., US Patent, 40, 228 (1954).

76. D. F. Bodanski, H. Weissbach, S. Udenfriend, J. Pharmacol Exptl. Therap.

17, 133 (1959).

77. S. Udenfriend, “Biochemistry of Serotonin and other Amines”, Vitamins.

Horm., 17, 133 (1959).

38
 Chapter - 1
78. H. E. Himwich, Science, 127, 70 (1958).

79. D. W. Wolley, “The Biochemical Bases of Psychoses” Wiley, New York

(1962).

80. Mann, J. Chem. Ber., 478 (1989).

81. Mann, J. Murder, Magic and Medicine, Oxford University press, Oxford.,
(1992).

82. R. C. Glen, G. R. Martin, A. P. Hill, R. M. Hyde, P. M. Wollard, J. A.

Salmon, J. Buckingham, A. D. Robertson, J. Med. Chem., 38, 3566 (1995).

83. A. B. Lerner, J. D. Case, J. Am. Chem. Soc., 81, 6084 (1959).

84. H. M. Hugel, D. Kennaway, J. Org. Prep. Proc. Int., 27, 1 (1995).

85. G. Spadoni, C. Balsamini, A. Bedini, G. Diamantini, B. D. Giacomo, A.

Tontini, G. Tarzia, J. Med. Chem., 41, 3624 (1998).

86. P. K. Gessner, 1.H.Page, Amer. J. Physiol., 203, 167 (1962).

87. P. A. Shore, A. Pietscher, E. G. Tomich, A. Grolsson, R. Kuntzmann, B.

Brodie, Ann. New York Acad. Sci., 66, 609 (1957).

88. A. Rahman, A. Basha, Indole Alkaloids, Harwood Academic Publishers,

Amsterdam (1998).

89. T. L. Gilchrist, Heterocyclic Chemistry, Longman, Singapore., (1997).

90. D. W. Wolley, E. Shaw, J. Amer. Chem. Soc, 74, 2948 (1952).

91. L. Schneider, F. R. Jung F. R. Demands 2, 679, 561 (1993); Chem, Abstr.,

119, 95332x (1993).

92. A. Cerietti, Progr. Drug Tes., 2, 227 (1960).

93. T. F. Anderson, Science, 101, 565 (1945).

94. P. Fields, H. N. Rydon, Brot. J. Expt. Pathol., 28, 211 (1947).

95. T. S. Muir, C. Hans, Plant Physiol., 28, 281 (1950).

96. W. Schindler, Helv. Chim. Acta., 41, 1441 (1958).

97. M. Kelli, Med. J. Australia, 51, 541 (1964).

98. R. J. Flower, S. Moncada, J. R. Vane, Goodman and Gilman’s the

pharmacological Basis of therapeutics, 7th ed.; MacMillan: New York., 695
(1985).

39
 Chapter - 1
99. P. F. Moore, D. L. Larson, I. G. Otterness, A. Weissman, S. B. Kadin, F. J.
Sweeney, J. D. Eskara, A. Nagahisa, M. Sakakibara, T. J. Carty, Inflammm.
Res., 45, 54 (1996).

100. T. J. Carty, H. J. Showell, L. D. Losee, S. B. Kadin, Arthritis Rheum., 31,

589 (1998).

101. B. McDonald, L. Loose, L. J. Rosenwasser, Arthritis Rheum., 31, 517

(1988).

102. E. Moilanen, J. Alanco, M. Z. Asmawi, H. Vepaatalo, Eicosanoids., 7, 35

(1988).

103. J. H. Guddum, K. A. Hammed, D. E. Hathway and F. F. Stevens, J. exptl,

Physiol, 40, 49 (1955).

104. A. M. Greco, F. Masson, S. M. Corchohan, Amer J. Physiol, 187, 509

(1956).

105. K. Rajasekhar, “Synthetic studies in the Indole Field.” Ph.D. Thesis,

Gulbarga University, Gulbarga (1989).

106. S. P. Hiremath, K. Rajasekhar, U. Ashok, M. G. Purohit, Presented at the

11th International Conference of Heterocyclic Chemistry, Heidleberg,
Germany, Aug 16-22 (1987).

107. Science, Vol. 243, 1611 (1989).

108. S. M. Rothman, J. Neuro Sci. 5, 1843 (1985).

109. T. Wicloch, Science, 230, 681 (1985).

110. N. M. Gray, B.K. Cheng, W. F. Hood, M.S. Drappen, A. A. Cordi, Eur. Pat,
396, 124 (1990); Chem. Abstr., 114, 178399x (1991).

111. J. E. Buttler, N. J. Cuthbert, Eur. Pat, 409, 027 (1991). Chem. Abstr., 114,
228729c (1991).

112. M. Kinugawa, H. Arai, H. Nishikawa, A. Sakaguchi, T. Ogasa, S. Tomioka,

M. Kasai, J. Chem. Soc., Perkin Trans., 1, 2677 (1995).

113. M. S. Mayadeo, S. A. Gandhi, J. Indian Chem. Soc., 71, 281 (1994).

114. J. M. Pawlak, V. V. Khau, D. R. Hutchison, M. J. Martinelli, J. Org. Chem.,

61, 9055 (1996).

115. C. J. Claude, Fur. Pt, 394, 112 (1990)., Chem. Abstr., 115, 22205r (1991).

40
 Chapter - 1
116. T. M. Williams, T. M. Ciccarone, W. S. Saari, J. S. Wai, W. J. Greenlee, S.
K. Balani, M. E. Goldmanand A. D. Theoharides, Eur. Pat, 530, 907 (1993);
Chem. Abstr, 119, 953289 (1993).

117. A. Agarwal, S. K. Agarwal, D. S. Bhakuni, S. N. Singh, R. K. Chatterjee,

Indian J. Chem., 32B (4), 453 (1993).

118. J. Perregaard, J. W. Stenberg, Eur. Pat, 376, 607 (1990); Chem. Abstr., 114,
17583m (1991).

119. C. J. Swian, R. Baker, C. Kneen, J. Moseley, J. Saunders, E. M. Seward, G.

Stevenson, M. Beer, J. Stanton, K. Watling. J. Med. Chem., 34 (1), 140
(1991).

120. J. E. Macor, M. J. Wythes, P. C. T. 9206, 973 (1992); Chem. Abstr., 117,

17125n (1992).

121. Y. Girard, P. Hamel, US 5, 128, 364 (1992); Chem. Abstr., 117, 171219s
(1992).

122. C. H. Lin, J. C. Sih and S. P. Tanis, P.C.T. 9207, 829 (1992). Chem. Abstr.,
117, 90139 (1992).

123. Y. Chen, A. M. Nataliya, C. L. Richard, Tetrahedron., 65, 8908 (2009).

124. L. Simone, A. Francesca, T. Andrea, M. Paola, M. Mauro, D. Andrea,

Tetrahedron Lett., 52, 2812 (2011).

125. G. Ramin, A. Somayeh, I. S. Ghazaleh, B. Ayoob. Tetrahedron Lett., 51, 499

(2010).

126. S. Nidhi, C. Papia, Chemical Physics Lett., 71, 548 (2012).

127. G. Yingchun, F. Xuening, L. Yuru, W. Yiqi, Y. Xu, J. Luminescence., 134,

184 (2013).

128. Y. Ezhumalai, K. R. Ajay, Z. Matthias, J. R. P. Karnam, Eur. J. Med.

Chem., 47, 228 (2012).

129. Z. Song-Lei, J. Shun-Jun, S. Xiao-Ming, S. Chang, L. Yu, Tetrahedron Lett.,

49, 1777 (2008).

130. M. Dorota, S. Iwona, W. Irena, N. M. M. Maria, M. Maj-Zurawska,

Bioelectrochemistry., 69, 1 (2006).

131. G. S. Suresh Kumar, S. Kumaresan, A. Antony Muthu Prabhu, N.

Bhuvanesh, P. G. Seethalakshmi, Spectrochimica Acta Part A: Molecular
and Biomolecular Spectroscopy., 101, 254 (2013).

132. K. Atul, S. Siddharth, A. M. Ram. Tetrahedron Lett., 50, 5937 (2009).

41
 Chapter - 1
133. V. Kameshwara Rao, S. C. Bhupender, N. S. Amir, T. Rakesh, P.
Keykavous, K. Anil, Bioorg. Med. Chem. Lett., 21, 3511 (2011).

134. Y. S. Wang, H. P. He, Y. M. Shen, X. Hong, X. J. Hao, Phytochemistry., 66,

416 (2003).

135. T. S. Wu, M. L. Wang, P. L. Wu, Phytochemistry., 43, 785 (1996).

136. X. H. Gu, X. Z. Wan, B. Jiang, Bioorg. Med. Chem. Lett., 9, 569 (1999).

137. L. Xue, Z. Shi-Long, L. Xian, L. Ju-Lian, O. Qiang, L. Rui, H. Ling, Eur.

J. Med. Chem., 54, 42 (2012).

138. S. C. Shikha, G. Leena, M. Monika, V. Preeti, G. Suman, M. S. C. Prem,

Bioorg. Med. Chem. Lett., 20, 6191 (2010).

139. N. A. Tarunkumar, P. R. Jignesh, Eur. J. Med. Chem., 46, 5573 (2011).

140. B. V. Subba Reddy, N. Rajeswari, M. Sarangapani, G. Roopa Reddy, C. H.

Madan, K. Pranay Kumar, M. Srinivasa Rao, Bioorg. Med. Chem. Lett., 21,
6510 (2011).

141. R. B. Maria, D. L. Laura, C. Alba, F. Stefania, G. Rosaria, J. A. Alvarez-

Builla, Ramon, Bioorg. Med. Chem., 21, 4575 (2013).

142. K. Cigdem, K. Hachemi, C. Tulay, S. Sibel, D. W. Andrew, Bioorg. Med.

Chem. Lett., 23, 2671 (2013).

143. Y. Thirupathi Reddy, R. S.Konjeti, S. Nidhish, P. Narsimha Reddy, M. L.

Freeman, A. C. Peter, Bioorg. Med. Chem. Lett., 20, 600 (2010).

144. S. P. Hiremath, S. Siddappa, J .Karnatak Univ., 13, 9 (1964).

145. S. P. Hiremath, M. G. Purohit, Indian J. Chem., 10, 984 (1964-65).

146. S. P. Hiremath, M. G. Purohit, Indian J. Chem., 53, 71 (1976).

147. S. P. Hiremath, M. G. Porohit, K. G. S. Bhat, J. Karnatak Univ (science), 19,

202 (1974).

148. S. P. Hiremath, S. Siddappa, J. Med. Chem., 8, 142 (1965).

149. S. P. Hiremath, S. S. Kaddargi, J. Karnatak Univ., 21, 167 (1976).

150. S. P. Hiremath, S. S. Kaddargi, J. Indian Chem. Soc., 52, 866 (1975).

151. S. P. Hiremath, S. Siddappa, J. Indian Chem. Soc., 42, 836 (1965).

152. S. Y. Ambekar. S. Siddappa, M. Sirsi, Arch. Pharm., 301, 842 (1968).

42
 Chapter - 1
153. S. P. Hiremath, S. Siddappa, J. karnatak, Univ, 11, 28 (1968).

154. S. Shambulingappa, M. S. Channaveeraiah, J. Karnatak Univ, 9, 97 (1965).

155. S. P. Hiremath, M. G. Purohit, Indian. J. Chem., 12, 493 (1974).

156. S. P. Hiremath, S. S. Kaddargi, M. G. Purohit, J. Indian. Chem., Soc., 55,

156 (1978).

157. W. E. Noland, R. J. Sundberg, J. Org. Chem., 28,884 (1962).

158. Y. Kanaoka, M. Machida,O. Yonemitsu, Y. Ban, Chem. Pharm Bull., 13,

1065 (1965).

159. S. P. Hiremath, S. S. Kaddargi, J. Indian. Chem. Soc., 52, 568 (1976).

160. S. S. kaddargi, Ph.D. Thesis, Karnatak UNI., Dharwar (1972).

161. S. P. Hiremath, M. G. Purohit, Indian J. Chem, 10, 984 (1972).

162. S. P. Hiremath, S. Skaddargi, J. Indian Chem. Soc., 13, 801 (1975).

163. J. S. Biradar, Ph.D.Thesis, Gulbarga University, Gulbarga (1982).

164. S. P. Hiremath, N. N. Goudar, M. G. Purohit Indian. J. Chem., 19B, 848

(1980).

165. S. P. Hiremath, P. S.Badami, M. G. Purohit, Indian. J. Chem., 22B, 437

(1983).

166. J. S. Biradar, Praveen S. Mugali, B. Sharanabasappa, B. S. Sasidhar, Indian

J. Heter. Chem., 18, Oct-Dec (2008).

167. J. S. Biradar, S. M. Praveen, B. S. Sasidhar, R. Parveen, Organic Chemistry

an Indian Journal., 4, 6 (2008).

168. J. S. Biradar, B. Sharanabasappa, S. M. Praveen, B. S. Sasidhar, Org.

Chem.: An Indian Journal., 4 (4), (2008).

169. J. S. Biradar, B. S. Sasidhar, R. Parveen, Eur. J. Med. Chem., 45, 4074

(2010).

170. J. S. Biradar, B. S. Sasidhar, Eur. J. Med. Chem., 46, 6112 (2011).

171. S. P. Hiremath, B. H. M. Mruthyunjayaswamy, M. G. Purohit, Indian. J.

Chem., 16B, 789 (1978).

172. S. P. Hiremath, N. N. Goudar, M. G. Purohit Indian J. Chem., 19B, 1031

(1980).

43
 Chapter - 1
173. K. H. Sinnur, Ph.D. Thesis, Karnatak Uni., Dharwar (1980).

174. K. H. Sinnur, S. Siddappa, S. P. Hiremath, M. G. Purohit, Indian. J. Chem.,

25B, 758 (1988).

175. S. P. Hiremath, K. Rajasekhar, M. G. Purohit, Indian J. Chem., 27B, 758

(1988).

176. P. Renukadevi, J. S. Biradar, Indian J. Chem., 38B, 76 (1999).

177. J. S. Biradar, B. S. Sasidhar, Med. Chem. Res., 22, 3518 (2013).

178. S. P. Hiremath, K. M. K. Swamy, B. H. M. Mruthyunjaya Swamy. Indian J.

Chem., 2, 119 (1992).

179. S. Manjunath Yalagatti, Ph.D. thesis, Gulbarga University, Gulbarga (2002).

180. J. S. Biradar, B. Sharanabasappa. Green Chem. Lett. Rev., 2(4), 237 (2009).

44