1

PROJECT REPORT
ON
INDOLE AND BENZIMIDAZOLE NUCLEUS

BY
K.SRINIVAS
2008A5PS816P

ACKNOWLEDGEMENT
Apart from the efforts of me, the success of any project depends largely on the encouragement
and guidelines of many others. I take this opportunity to express my gratitude to the people who
have been instrumental in the successful completion of this project.
First, I would like to show my greatest appreciation to Mr. Mahaveer Singh, I cant say thank
you enough for his tremendous support and help. Without his encouragement and guidance this
project would not have materialized. Then I would like to thank the PHARMACY DEPT.
GROUP LEADER Mr. SRIKANTH CHARDE, BITS PILANI Staff members for providing this
wonderful course to study on.
I would also like to thank Chemsketch, Microsoft Excel and Microsoft Word for without these
programs my report would not have been completed.
.

CONTENTS
1)
2)
3)
4)

COVER....1
ACKNOWLEDGEMENTS.2
CONTENTS.3
INDOLE...4
a) INTRODUCTION.4
i)
HISTORY..4
ii)
GENERAL PROPERTIES4
b) CHEMICAL REACTIONS OF INDOLE.5
i)
ELECTROPHILIC SUBSTITUTION...5
ii)
NITROGEN-H ACIDITY AND ORGANOMETALLIC INDOLE ANION
COMPLEXES5
CARBON ACIDITY AND C-2 LITHIATION6

iii)
iv)
OXIDATION OF INDOLE..6
v)
CYCLOADDITIONS OF INDOLE.7
c) SYNTHESIS 8
i)
FISCHER INDOLE SYNTHESIS.9
ii)
INDOLE FROM ANILINE AND ETHYLENE GLYCOL..9
iii)
LEIMGRUBER-BATCHO INDOLE SYNTHESIS9
d) DERIVATIVES...10
i)
3-ACETYLINDOLE10
ii)
4-NITROINDOLE11
iii)

4-BENZYLOXYINDOLE12

iv)

3-BENZOYLINDOLE..13

5) BENIMIDAZOLE.16
a) INTRODUCTION...16
b) SYNTHESIS17.
i)
SYNTHESIS 1.17
ii)
SYNTHESIS 2.18.
iii)
SYNTHESIS 3.19.
c) DERIVATIVESAND THEIR USES...20
i)
FUNGICIDAL PROPERTIES.20
ii)
ANTI-HYPERTENSIVE PROPERTIES.23
iii)
ANTI-BACTERIAL ACTIVITY, ANTI DIABETIC AND ANTI
ASTHMATIC ACTIVITY..26
6) REFERENCES..32

INDOLE
INTODUCTION
Indole is a white crystalline compound obtained from coal tar or various plants, and found in the
intestines and feces as a product of the bacterial decomposition of tryptophan. It is also called
ketole. It has a bicyclic structure, consisting of a six-membered benzene ring fused to a fivemembered nitrogen-containing pyrrole ring. Indole is a popular component of fragrances and the
precursor to many pharmaceuticals. Compounds that contain an indole ring are called indoles.
The indolic amino acid tryptophan is the precursor of the neurotransmitter serotonin.
HISTORY OF INDOLE:

The name indole is a combination of the words indigo and oleum since indole was first isolated
by treatment of the indigo dye with oleum. Indole chemistry began to develop with the study of
the dye indigo. Indigo can be converted to isatinand then to oxindole. Then, in 1866, Adolf von
Baeyer reduced oxindole to indole using zinc dust. In1869, he proposed a formula for indole.
Certain indole derivatives were important dyestuffs until the end of the 19th century.

In the 1930s, interest in indole intensified when it became known that the indole nucleus is
present in many important alkaloids, as well is in tryptophan and auxins, and it remains an active
area of research today
GENERAL PROPERTIES:

Indole is as solid at room temperature. Indole can be produced by bacteria as a degradation

product of the amino acidtryptophan. It occurs naturally in human feces and has an intense fecal
odor. At very low concentrations, however, it has a flowery smell, and is a constituent of many
flower scents (such as orange blossoms) and perfumes. It also occurs in coal tar. The
corresponding substituent is called indolyl.

Indole undergoes electrophilic substitution, mainly at position 3. Substituted indoles are

structural elements of (and for some compounds the synthetic precursors for) the tryptophanderived tryptamine alkaloids like the neurotransmitterserotonin, and melatonin. Other indolic
compounds include the plant hormone Auxin (indolyl-3-acetic acid, IAA), the anti-inflammatory
drug indomethacin, the betablockerpindolol, and the naturally occurring hallucinogen
dimethyltryptamine (N,N-DMT).
Basicity:
Unlike most amines, indole is not basic. The bonding situation is completely analogous to that in pyrrole.
Very strong acids such as hydrochloric acid are required to protonateindole. The protonated form has an
pKa of 3.6. The sensitivity of many indolic compounds (e.g., tryptamines) under acidic conditions is
caused by this protonation

CHEMICAL REACTIONS OF INDOLE:

Electrophilic substitution:

The most reactive position on indole for electrophilic aromatic substitution is C-3, which is 1013
times more reactive than benzene. For example, Vilsmeier-Haackformylation of indole will take
place at room temperature exclusively at C-3. Since the pyrrollic ring is the most reactive portion
of indole, electrophilic substitution of the carbocyclic (benzene) ring can take place only after N1, C-2, and C-3 are substituted.

Gramine, a useful synthetic intermediate, is produced via a Mannich reaction of indole with
dimethylamine and formaldehyde. It is the precursor to indole acetic acid and synthetic
tryptophan.

Nitrogen-H acidity and organometallic indole anion complexes:

The N-H center has a pKa of 21 in DMSO, so that very strong bases such as sodium hydride or
butyl lithium and water-free conditions are required for complete deprotonation. The resulting

alkali metal derivatives can react in two ways. The more ionic salts such as the sodium or
potassium compounds tend to react with electrophiles at nitrogen-1, whereas the more covalent
magnesium compounds (indoleGrignard reagents) and (especially) zinc complexes tend to react
at carbon-3 (see figure below). In analogous fashion, polar aprotic solvents such as DMF and
DMSO tend to favour attack at the nitrogen, whereas nonpolar solvents such as toluenefavour C3 attack.

Carbon acidity and C-2 lithiation:

After the N-H proton, the hydrogen at C-2 is the next most acidic proton on indole. Reaction of
N-protected indoles with butyl lithium or lithium diisopropylamide results in lithiation
exclusively at the C-2 position. This strong nucleophile can then be used as such with other
electrophiles.
Bergman and Venemalm developed a technique for lithiating the 2-position of unsubstituted
indole.

Alan Katritzky also developed a technique for lithiating the 2-position of unsubstituted indole.
Oxidation of indole

Due to the electron-rich nature of indole, it is easily oxidized. Simple oxidants such as Nbromosuccinimide will selectively oxidize indole 1 to oxindole (4 and 5).

7
Cycloadditions of indole

Only the C-2 to C-3 pi-bond of indole is capable of cycloaddition reactions. Intermolecular
cycloadditions are not favorable, whereas intramolecular variants are often high-yielding. For
example, Padwaet al. have developed this Diels-Alder reaction to form advanced strychnine
intermediates. In this case, the 2-aminofuran is the diene, whereas the indole is the dienophile.

Indoles also undergo intramolecular [2+3] and [2+2]

cycloadditions.

Indole and its derivatives have captured the imagination of organic chemists for more than
a century. Early works in this area mainly focused on the preparation of dyestuffs
containing indole nucleus. However, since the isolation of indole alkaloids as the active
principles from medicinal plants (i.e. antibiotics, anti-inflammatory, antihypertensive and
antitumor agents), the indole nucleus has taken on considerable pharmacological
importance. Therefore, it is not surprising that up to now many methods have already
been developed for the synthesis of this kind of heterocyclic system1. However, due to
the unavailability of some patterns of indole substitution using classic methods and the
need for efficient ways to synthesize more elaborate structures possessing biological
activity, the development of novel and convenient methods for the preparation of indole
derivatives still remains an active research area.
The titanium-induced coupling of carbonyl compounds to alkenes is a particularly useful tool for
the formation of carbon-carbon bonds and has witnessed its potential in the preparation of natural
products and the formation of strained olefins and carbocycles. Recently, this transformation has
been extended to the synthesis of heterocycles. Thus, on treatment with titanium on graphite2,
suitably substituted acylamido carbonyl compounds were smoothly cyclized to indole derivatives
in good to excellent yields, although amides were hitherto considered to be essentially inert
towards low-valent titanium3. Unfortunately, this process necessitates the using of hazardous
compound such as metallic potassium or potassium-graphite laminate (C8K) to prepare the
active titanium species. What is more, as much as 6 equiv of metallic potassium, 50 equiv of
graphite laminate relative to 1 equiv of substrate must be employed to get the desiredproduct in
reasonable yield. Besides TiCl3/C8K, low-valent titanium reagent prepared from TiCl3/Zn
system has also been reported as an efficient promoter in this coupling process4~6. But this
method still has the disadvantage of needing excessive reagents. In fact, as many as 2~3 equiv of
TiCl3 and 4~8 equiv of zinc dust must be involved for a complete conversion of 1 equiv of
substrate. On the other hand, we have reported that low-valent titanium reagent could also be
prepared from Cp2TiCl2-Sm7a or TiCl4-Sm7b system and the low-valent titanium reagent so
formed has been successfully used in various reductive coupling processes. Herein, we wish to
report that low-valent titanium reagent prepared from metallic samarium and TiCl4 can
efficiently promote acylamido carbonyl compounds (1) to undergo intramolecular reductive

cyclization to give Indole derivatives (2) in moderate to good yields under mild reaction
conditions. The results were listed in

SYNTHESIS
Preparation of indole through Sm/TiCl4 induced intramolecular reductive coupling of acylamido
carbonyl compounds

O
H3C

1
Sm/TiCl4

THF, reflux, 1h

NH
R

R
N
H

R1

Yield %

H
H
H
H
H
Cl
Cl
Cl
Cl
Cl

C6H5
4-CH3C6H4
4-FC6H4
CH3
CH3CH2
C6H5
4-CH3C6H4
4-ClC6H4
4-FC6H4Ph
CH3

89
91
94
83
81
90
86
83
88
78

In summary, we have found that low-valent titanium reagent derived from metallic samarium
and TiCl4 can efficiently promote acylamido carbonyl compounds to undergo intramolecular
reductive cyclization to give indole derivatives in fair yields. Several merits of our method are
worth to be mentioned here. Firstly, in contrast with the process reported in the literatures2, 4~6,
in which excess reagents relative to the substrates should be employed, 2 equiv of metallic
samarium and titanium tetrachloride is enough to push the reductive cyclization to be completed
with our process. Secondly, both substrates bearing electron donating groups and substrates
bearing electron withdrawing groups undergo smoothly reductive cyclization process and give
the desired products with equally fair yields. It means that this method may afford a general
method for the preparation of 2,3-disubstituted indole derivatives with good yields under mild
reaction conditions.

1.Fischer Indole Synthesis:

The conversion of aryl hydrazones to indoles requires elevated temperatures and the addition of
Brnsted or Lewis acids. Some interesting enhancements have been published recently; for
example a milder conversion when N-trifluoroacetylenehydrazines are used as substrates.
2. INDOLE FROM ANILINE AND ETHYLENE GLYCOL:

In large-scale syntheses, indole (and substituted derivatives) form via vapor-phase reaction of
aniline with ethylene glycol in the presence of catalysts.

The reactions are conducted between 200 and 500 C. Yields can be as high as 60%. Other
precursors to indole include formyltoluidine, 2-ethylaniline, and 2-(2-nitrophenyl)ethanol, all of
which undergo cyclizations. Many other methods have been developed that are applicable
3. LEIMGRUBER-BATCHO INDOLE SYNTHESIS:

The Leimgruber-Batchoindole synthesis is an efficient method of synthesizing indole and

substituted indoles. Originally disclosed in a patent in 1976, this method is high-yielding and can

10

generate substituted indoles. This method is especially popular in the pharmaceutical industry,
where many pharmaceutical drugs are made up of specifically substituted indoles.
OTHER INDOLE FORMING REACTIONS:
Bartoliindole synthesis
Bischler-Mhlauindole synthesis
Fukuyama indole synthesis
Gassmanindole synthesis
Hemetsbergerindole synthesis
Larockindole synthesis
Madelung synthesis
Nenitzescuindole synthesis
Reissertindole synthesis
Baeyer-Emmerlingindole synthesis

In the Diels-Reese reaction dimethyl acetylenedicarboxylate reacts with

diphenylhydrazine to an adduct, which in xylene gives dimethyl indole-2, 3-dicarboxylate
and aniline. With other solvents, other products are formed: with glacial acetic acid a
pyrazolone, and with pyridine a quinoline.

DERIVATIVES: 3-ACETYLINDOLE:

[Oxindole,

3-acetyl-]

1. The o-acetoacetochloroanilide used was the technical product of Union Carbide Chemicals
Co.; m.p. 107109.

11

2. If the reaction of potassium with liquid ammonia slows down before all the potassium is
consumed, an additional pinch of ferric nitrate hydrate is added.
3. Discussion
3-Acetyloxindole has been made by condensing ethyl acetate with oxindole in the presence of
sodium ethoxide3 and by heating N-acetyloxindole with sodium amide in xylene.4 The present
method was developed by Hrutfiord and Bunnett.5 It illustrates a general principle for the
synthesis of heterocyclic and homocyclic compounds. This principle involves the creation of an
intermediate species that is of the benzyne type and has a nucleophilic center located so that it
can add, intramolecularly, to the "triple bond" of the benzyne structure. Other applications of the
principle using essentially the present procedure are the conversion of thiobenz-o-bromoanilide
or thiobenz-m-bromoanilide to 2-phenylbenzothiazole (90% and 68% respectively), of benz-ochloroanilide to 2-phenylbenzoxazole (69%),5 of o-chlorohydrocinnamonitrile to 1cyanobenzocyclobutene (61%),6 and of methanesulfone(N-methyl-o-chloro)anilide to 1-methyl2,1-benzisothiazoline 2,2-dioxide (66%).
4-NITROINDOLE
1. 2-Methyl-3-nitroaniline and triethylorthoformate were purchased from Fluka AG.
2. Trimethylorthoformate is not suitable for this preparation because of side-product formation.
3. Diethyl oxalate was purchased from Merck and Company, Inc., and was used without further
purification. Potassium ethoxide was purchased from Alfa Products, Johnson Mathey Co. or
preferably was prepared from potassium metal and absolute ethanol.
4. The diethyl oxalate/potassium ethoxide complex can also be prepared by adding the oxalic
ester to an ethanolic solution of potassium ethoxide and evaporating the solvent. However, this
complex is less active and is difficult to store.

5. Dimethyl sulfoxide (DMSO) prevents precipitation of intermediate salts, which can also be
achieved by using a larger volume of dimethylformamide (DMF) (ca. 200 mL). Attempts to

12

prepare the diethyl oxalate/potassium ethoxide complex in DMSO have not been successful (i.e.,
it is not active).
6. At elevated temperatures (e.g., above 40C) by-products are formed.
7. The reaction can be monitored by TLC (CH2Cl2). The spots were developed with an ethanolic
solution of p-dimethylaminobenzaldehyde/HCl. The product gave a bright-red spot at Rf 0.5, and
the imidate ester gave a yellow spot at Rf 0.6. Addition of small portions of diethyl
oxalate/potassium ethoxide complex was continued if the starting material was not consumed
after the initial reaction period.
8. Crude 4-nitroindole can also be purified by recrystallization from methanol, ethanol, or
acetonitrile giving brownish-yellow crystals, mp204206C.
3. Discussion
This procedure illustrates the synthesis of 4-nitroindoles; the present method can easily be
extended to the 2-alkyl derivatives (using other ortho esters), 5-, 6- and/or 7-substituted
derivatives and 1-alkyl derivatives (from the corresponding N-alkylanilides).2,3 Other published
preparations of 4-nitroindole (e.g., 4) are of no practical value.
The mechanism of the formation of 4-nitroindole parallels the Reissertindole synthesis5
INDOLES FROM 2-METHYLNITROBENZENES BY CONDENSATION WITH
FORMAMIDE ACETALS FOLLOWED BY REDUCTION: 4-BENZYLOXYINDOLE
[1H-Indole, 4-(phenylmethoxy)-]

13

Through the years, widespread interest in the synthesis of natural products and their analogs
bearing the oxygenated indole nucleus has led to the development of several routes to protected
hydroxylatedindoles. However, 4-benzyloxyindole was first prepared relatively recently in
modest overall yield by the Reissert method, which involves condensation of 6-benzyloxy-2nitrotoluene with ethyl oxalate, reductive cyclization to the indole-2-carboxylate, hydrolysis to
the acid, and decarboxylation.5
Although a variety of synthetic methods have been used to prepare indoles, many of these lack
generality and are somewhat restrictive since they employ conditions, such as acid or strongly
basic cyclizations or thermal decarboxylations, which are too harsh for labile substituents. This
efficient, two-step procedure8,9 illustrates a general, simple, and convenient process for preparing
a variety of indoles substituted in the carbocyclic ring. Since many of these examples served to
determine the scope of this method, the yields in most cases have not been optimized. In many
cases, the starting materials are readily available or can be easily prepared.
3-ALKYLATED AND 3-ACYLATED INDOLES FROM A COMMON PRECURSOR: 3BENZYLINDOLE AND 3-BENZOYLINDOLE
[1H-Indole, 3-(phenylmethyl)- and Methanone, 1H-indole-3-ylphenyl-]

14

There are other convenient methods for the preparation of 3-benzylindole and 3-benzoylindole.
The present procedure, however, has two useful elements of flexibility: it produces both 3-alkyland 3-acylindoles from a single precursor, and it tolerates the presence of a wide variety of
substituents.
The pivotal step in this sequence is an electrophilic substitution on indole. Although the use of
1,3-dithian-2-yl carbanions is well documented, it has been shown only recently that 1,3-dithian2-yl carbenium ions can be used in a FriedelCrafts type reaction. This was accomplished
initially using 2-methoxy-1,3-dithiane or 2-methoxy-1,3-dithiolane and titanium tetrachloride as
the Lewis acid catalyst. 2-Substituted lysergic acid derivatives and 3-substituted indoles have
been prepared under these conditions, but the method is limited in scope by the difficulties of
preparing substituted 2-methoxy-1,3-dithianes. 1,3-Dithian-2-yl carbenium ions have also been
prepared by protonation of ketene dithioacetals with trifluroacetic acid, but this reaction cannot
be used to introduce 1,3-dithiane moieties into indole.
The procedure described herein is fairly general for indoles, and since 2-methylthio-1,3-dithianes
are readily available, it should prove versatile. Two further examples are as follows:

In attempting to extend the method to other activated aromatics, it was found that pyrroles give
mixtures of 2-and 3-substituted products, and that naphthol ethers and benzo[b]thiophene fail to
react.
The hydrolytic step (Part D) uses conditions described by Narasaka, Sakashita, and Mukaiyama.
It was necessary to modify the original stoichiometry, since the recommended molar ratio of
substrate: copper(II) chloride: copper(II) oxide (1:2:4) gave only a 57% yield of 3-benzoylindole.
The more generally known mercuric oxide-mercuric chloride hydrolysis2 may also be used, and
in the present case it gives a yield of about 90%. The reductive desulfurization of Part E, also
based on the work of Mukaiyama,13 is clearly superior to Raney nickel desulfurization, which
gives only 3545% of 3-benzylindole.
Some new reagents of the same general type, leading to intermediate carbocations of dithians,
have been reported in the literature recently. Hiratani, Nakai, and Okawara synthesized 1,3dithian-2-yltrimethylammonium iodide. Corey and Walinsky15 applied 1,3-dithian-2-yl

15

fluoroborate, prepared by hydride ion exchange from 1,3-dithian and trityl fluoroborate, to a
new kind of electrophilic reaction for the preparation of cyclopentane derivatives.

Further, substantial progress leading to a generally applicable method is shown by the

preparation of 2-chloro-1,3-dithiane and its application in electrophilic substitution reactions
with reactive aromatic molecules like phenol and N,N-dimethylaniline.17

So far, however, no reagent of the dithianylcarbocation type has been found which allows
electrophilic substitution reactions with unactivated aromatic molecules such as benzene.

16

BENZIMIDAZOLE

Containing an heterocyclic ring made of benzene and imidazole nucleuses, benzimidazole has
played a major role in the modern day. Its most prominent form exists as N-ribosyldimethylbenzimidazole, which serves as an axial ligand for cobalt in vitamin B12.

Benzimidazole, in an extension of the well-elaborated imidazole system, has been used as carbon
skeletons for N-heterocyclic carbenes. The NHCs are usually used as ligands for transition
metal complexes. They are often prepared by deprotonating an N,N'-disubstituted
benzimidazolium salt at the 2-position with a base.
Benzimidazoles are among the important heterocyclic compounds found in several natural and
non-natural products such as Vitamin B12, marine alkaloid kealiiquinone, benzimidazole
nucleosides etc. Some of their derivatives are marketed as anti-fungal agents such as
Carbendazim, anti-helmintic agents such as Mebendazole and thiabendazole and anti-psychotic
drug such as Pimozide and other derivatives have been found to possess some interesting
bioactivities such as anti-diabetic, anti hypertensive, etc.

17

Synthesis 1:

A one-pot procedure for the conversion of aromatic and heteroaromatic 2-nitroamines into
bicyclic 2H-benzimidazoles employs formic acid, iron powder, and NH4Cl as additive to reduce
the nitro group and effect the imidazole cyclization with high-yielding conversions generally
within one to two hours. The compatibility with a wide range of functional groups demonstrates
the general utility of this procedure.

18

Synthesis 2:

The proposed reaction pathway follows the below

A convenient method for the synthesis of 2-substituted benzimidazoles and benzothizoles offers
short reaction times, large-scale synthesis, easy and quick isolation of the products, excellent
chemoselectivity, and excellent yields as main advantages.

19

Synthesis 3:

CuI/l-proline catalyzed coupling of aqueous ammonia with 2-iodoacetanilides and 2iodophenylcarbamates affords aryl amination products at room temperature, which undergo in
situ additive cyclization under acidic conditions or heating to give substituted 1Hbenzimidazoles and 1,3-dihydrobenzimidazol-2-ones, respectively.

20

DERIVATIVES AND THEIR USES:

There are many uses for derivatives containing this nucleus:

1. Fungicidal properties:
They are known to have broad spectrum fungicidal properties, i.e. they are known to act on
a variety of worms.
Examples:
1 ALBENDAZOLE
2 BENOMYL
3 CARBENDAZIM
4 CHLORFENAZOLE
5 CYPENDAZOLE
6 DEBACARB
7 FUBERIDAZOLE
8 MECARBINZID
9 RABENZAZOLE
10 THIABENDAZOLE
Thiabendazole:
Action of the Fungicide Thiabendazole, 2-(4-Thiazolyl) Benzimidazole :
Thiabendazole, 2-(4-thiazolyl) benzimidazole (TBZ) inhibited the growth of Penicillium
atrovenetum at 8 to 10 g/ml. Oxygen consumption with exogenous glucose was inhibited at 20
g/ml, but endogenous respiration required more than 100 g/ml. TBZ inhibited completely the
following systems of isolated heart or fungus mitochondria: reduced nicotinamide adenine
dinucleotide oxidase, succinic oxidase, reduced nicotinamide adenine dinucleotide-cytochrome c
reductase, and succinic-cytochrome c reductase at concentrations of 10, 167, 10, and 0.5 g/ml,
respectively. Cytochrome c oxidase was not inhibited. Antimycin A and sodium azide caused the
usual inhibition patterns for both fungus and heart terminal electron transport systems. In the
presence of antimycin, the fungicide inhibited completely succinate-dichloro-phenolindophenol
reductase and succinate-2, 2-di-p-nitrophenyl-(3, 3-dimethoxy-4, 4-biphenylene-5, 5diphenylditetrazolium)-reductase at 2 and 4 g of TBZ per ml, respectively. Coenzyme Q reductase
required 15 g/ml. TBZ reduced the uptake by P. atrovenetum of glucose and amino acids and
decreased the synthesis of various cell components. At 120 g/ml, the incorporation of labeled
carbon from amino acids-U-14C was decreased: lipid, 73%; nucleic acids, 80%; protein, 80%; and a

21

residual fraction, 89%. TBZ did not inhibit peptide synthesis in a cell-free protein-synthesizing
system from Rhizoctonia solani. Probably the primary site of inhibition is the terminal electron
transport system and other effects are secondary.

Albendazole:
Albendazole, marketed as Albenza, Eskazole, Zentel and Andazol, is a member of the
benzimidazole compounds used as a drug indicated for the treatment of a variety of worm
infestations. Although this use is widespread in the United States, the U.S. Food and Drug
Administration (FDA) has not approved albendazole for this indication. It is marketed by
Amedra Pharmaceuticals. Albendazole was first discovered at the SmithKline Animal Health
Laboratories in 1972. It is a broad spectrum anthelmintic, effective against: roundworms,
tapeworms, and flukes of domestic animals and humans

As a vermicidal, albendazole causes degenerative alterations in the tegument and intestinal cells
of the worm by binding to the colchicine-sensitive site of tubulin, thus inhibiting its
polymerization or assembly into microtubules. The loss of the cytoplasmic microtubules leads to
impaired uptake of glucose by the larval and adult stages of the susceptible parasites, and
depletes their glycogen stores. Degenerative changes in the endoplasmic reticulum, the
mitochondria of the germinal layer, and the subsequent release of lysosomes result in decreased
production of adenosine triphosphate (ATP), which is the energy required for the survival of the
helminth. Due to diminished energy production, the parasite is immobilized and eventually dies.

22

Albendazole also has been shown to inhibit the enzyme fumarate reductase, which is helminthspecific. This action may be considered secondary to the effect on the microtubules due to the
decreased absorption of glucose. This action occurs in the presence of reduced amounts of
nicotinamide-adenine dinucleotide in reduced form (NADH), which is a coenzyme involved in
many cellular oxidation-reduction reactions.
Albendazole has larvicidal effects in necatoriasis and ovicidal effects in ascariasis, ancylostomiasis, and
trichuriasis..
S
O

NH4SCN, Br2, MeOH

CH3

NH
R

1
1-PrBr, KCN, 1-PrOH

CH3

CH3
O

H2 ,
Pd/C 10%, MeOH

F
F

CF3COOH, HCl, reflux

NH
CH3

N
CH3

ALBENDAZOLE ANALOGUE

23

2. Anti-hypertensive properties of some benzimidazole derivatives:

The renin-angiotensin system (RAS) plays a key role in regulating cardiovascular homeostasis
and electrolyte/ fluid balance in normotensive and hypertensive subjects. Activation of the reninangiotensin cascade begins with renin secretion from the juxtaglomerular apparatus of the kidney
and culminates in the formation of the octapeptide angiotensin II (AII), which then interacts
with specific receptors present in different tissues. Two basic types of receptors, both having a
broad distribution, have been characterized so far: the AT1 receptor, responsible for the majority
of effects attributed to this peptide, and the AT2 receptor, with a functional role yet
uncertain. The main effects of AII are the regulation of blood pressure through vasoconstriction,
thereby effecting an increase in vascular resistance, the regulation of volemia through the
stimulated release of vasopressin and aldosterone, which induces saline retention, and the
regulation of the adrenocorticotropic hormone (ACTH). Thus, reducing the levels of AII by
inhibition of one of the RAS enzymes or directly blocking the AII receptors is in theory a good
approach for treating hypertension, confirmed by the success of angiotensin-converting enzyme
(ACE) inhibitors as antihypertensive . It also stimulates the release of vasopressin luteinizing
hormone oxytocin and corticotropin. ANG II further induces vagus suppression and
-adrenergic potentiation and increases inotropy and chronotropy. Stimulation of the
cardiacfibroblast matrix formation has also been described. ANG II stimulates synthesis of
prostaglandin endothelin and elicits procoagulatory effects by activating the plasminogen
activator (PA) plasmin system. The beneficial effect of a chronic RAS blockade was first shown
for inhibitors of the angiotensin converting enzyme (ACE) such as captopril quinapril enalapril
and ramipril in patients with ischemic heart disease congestive heart failure the
development of potent drugs that interfered with the RAS: the angiotensin receptor type 1 (AT1)
antagonists. To find a more specific blockade of ANG II at its AT1 receptor highly selective
nonpeptidic AT1-receptor antagonists were designed and developed as competitive antagonists
with virtually no agonistic effect at the receptor level. Losartan was described as the first nonpeptide AT1 receptor antagonist and the coined group name was sartans. Today irbesartan
candesartan and valsartan are all established in the market and others e.g. tasosartan and
telmisartan are following closely. Most of these compounds share the biphenyl tetrazole unit or
replacements thereof with the original advanced lead losartan. Some variations of the parent
biphenyl tetrazole alone were reported in the meantime excluding the obvious variation of the
biphenyl spacer. The carboxylic acid another common moiety of the sartans appears to establish
another important interaction with the receptor but it often hampers oral absorption. Therefore
several prodrug concepts had to be realized to mask the carboxylic acid as either a labile ester or
an oxidatively labile precursor that delivers the acid after absorption. Recent findings indicate the
involvement of this peptide also in situations concerning tissue remodelling, such as cardiac
hypertrophy and cancer. All these responses are mediated by two distinct subtypes of Ang II
receptors [type 1 (AT1) and type 2 (AT2)]. In particular, AT1 receptors mediate all of the known
effects associated to Ang II that constitutes the principal target of an effectiveness therapy
against the cardiovascular pathology. The Ang II effects may be reduced by inhibiting almost
partially the enzyme responsible of biosynthesis of Ang II or through the interaction with AT1
receptor. To date, many orally available sartans have been developed and are used in the
treatment of both hypertension and damage associated with diseases like atherosclerosis and
diabetes. In particular, the good properties of new non peptide Ang II antagonists, such as
losartan, have stimulated the design of many different congeners. All these drugs contain some

24

common structural features represented by a biphenyl fragment bearing an acidic moiety (i.e.:
tetrazole, carboxylic- or sulphonamidocarboxyl- group), linked to a heteroaromatic or acyclic
system by means of a methylene group. Almost all of the chemical manipulations within the
fundamental skeleton of sartans concerned the substitution of the imidazole ring of losartan with
several variously substituted heteroaromatic groups or acyclic structures. All these antagonists
possess a central aromatic nucleus bearing the pharmacophores indispensable for activity and
notably a polar function adjustant to biphenyl subsistent while a polar function in this area of
molecule seems to be necessary to maintain activity. Sartans are appropriately substituted
heterocyclic head coupled through a methylene linker to pendent biphenyl system bearing an
acidic function; viz. candesartan is an effective competitive Ang II antagonist with
benzimidazole nucleus as the heterocyclic head The substituent at 6-position on the nucleus
increases the activity whereas small substituent at 5-position decreases the activity compounds
containing tetrazole nucleus are also reported as AT1 receptor antagonists and their protypical
derivative exhibits non-competitive antagonism amino group attach with carboxylic group given
good biological activity In recent years, attention has increasingly been given to the synthesis of
benzimidazole derivatives as a source of new antihypertensive agents. The synthesis of novel
benzimidazole derivatives remains a main focus of medicinal research. Recent observations
suggest that substituted benzimidazoles and heterocyclic, which are the structural isosters of
nucleotides owing fused heterocyclic nuclei in their structures that allow them to interact easily
with the biopolymers, possess potential activity with lower toxicities in the chemotherapeutical
approach in man . In recent years, attention has increasingly been given to the synthesis of
benzimidazole derivatives as a source of new antihypertensive agents.
Benzimidazole structures are classified under several classes of drugs, based on the possible
substitution at different positions of the benzimidazole nucleus. Methods of benzimidazole
synthesis include the condensation of o-aryldiamines and aldehyde in refluxing nitrobenzene the
condensation of o-aryldiamines with carboxylic acids or their derivatives in the presence of
strong acids such as polyphosphoric acid or mineral acids ..

EXAMPLES:
1. (2-{6-Chloro-5-nitro-1-[2-(1H-tetrazol-5-yl) biphenyl-4-ylmethyl] 1H-benzoimidazol-2-yl}-phenyl
2. 4'-(6-Methoxy-2-substituted-benzimidazole-1-ylmethyl)-biphenyl-2-carboxylic acid.

Synthesis of 5-substituted (amino) -2-phenyl-1-(2carboxy biphenyl-4-yl) benzimidazoles

NH2

R
R

N
H

NH2

HNO3

H2SO4

N
O

N
R
N
H

5-Nitro-2-phenyl

25
Benzimidazole

O
NH

O
O

CH3

OH
H2SO4

KOH

(HCHO)n

O
O

OH

N
H

R
N
O

Cl

POCl3

DMF/K2CO3

OH
EtOH
SnCl2.2H2O

H2N

N
R
N

OH

R
PHENYL
ETHYL

IN this we start of with 9H-flourenone which on reaction with KOH gives Biphenyl Carboxylic
acid which gives 4 Acetamido methyl biphenyl-2-caboxylic acid with H2SO4 /(HCHO)n and
then goes on to 4Chloromethylbiphenyl-2-carboxylic acid) with POCl3 which again gives (5-

26

Nitro 2- phenyl-[(2carboxybiphenyl-4-yl) methyl]Benzimidazole with DMF/K2CO3 and 5Nitro-2-phenyl Benzimidazole which finally gives (5-amino-2-phenyl-[(2Carboxy biphenyl-4yl
methyl]Benzimidazole with EtOH/ SnCl2.2H2O

3 Anti-bacterial activity, anti diabetic And anti asthmatic activity of

benzimidazole derivatives:
It was found that benzimidazole derivatives had anti-bacterial and anti diabetic properties as
well.

This can be explained by the following :

The condensation of o-phenylenediamine (OPDA) (1) with 4-bromobenzoic acid (2) was carried
out in presence of polyphosphoric acid at 180 C for 4 h to obtain the known 2-(4-bromophenyl)1H-benzimidazole

OH

NH2

PPA

+
NH2

1800 C /4 hr
90 %

Br

N
Br
N
H

Scheme 1:
Then the act of alkylating the benzimidazole NH with suitable electrophilic reagents to generate
N-alkylatedbenzimidazoles. In this regard, the above product was alkylated with different

27

alkylating agents in N, N-dimethylformamide and in presence of sodium hydride as base to

obtain the corresponding alkylated derivatives.(a,b,c,d)

Alkylating agents

Br

Br

NaH/DMF

N
H

N
R

R
a) Methyl
b) Ethyl
c) Propyl
d) Butyl
another method for derivative (a):

OH
N

NH2

PPA

+
NH

CH3

1800 C / 4 hr

Br

Br
N
CH3

Scheme 2

Compounds a - d were then reacted with tert-butylacrylate in presence of tri-otolylphosphine,

triethylamine and palladium acetate as catalyst under Heck coupling conditions12
to get e h.

28
CH2
N
N

TEA / Pd(OAc)2

Br

+
O

tri-o-tolylPhosphine
DMF, 110oC, 3 h

R
H3C

CH3

CH3
CH3

H3C
CH3

R
e) Ethyl
f) Methyl
g) Propyl
h) Butyl

Scheme 3
H2C
TEA / Pd(OAc)2

N
Br

TEA / Pd(OAc)2

N
N
R
N
R

R
i)
ii)
iii)

Methyl
Ethyl
Propyl

29

We then reacted compounds a-c with styrene to get the corresponding alkenylbenzimidazoles i
iii respectively
Biological activity
All the compounds prepared herein were screened for their potential biological activities such as,
anti-bacterial activity against Staphylococcus aureus (gram positive) and Salmonella
typhimurium (gram negative) bacterial strains15 at concentration 500, 200, 100, 10 and 0.1g/ml.
Cephalexin was used as a reference standard. The results of the anti-bacterial activity screening
of the tested compound are summarized in Table 1 & Table 2. Most of the compounds tested
were found to have good anti-bacterial activity against Salmonella typhimurium, however, they
were found to have poor activity against Staphylococcus aureus. Also they were tested against
PDE IV for potential anti-asthmatic effect, and against DPP-IV and PTP1B for potential
antidiabetic effects. No activity was found. The anti-asthmatic activity was carried out using
Phosphodiesterase IV enzyme (PDE-IV) (Table 3) and the primary screening of the
compounds was done at 1uM concentration using human PDIV enzyme, where Rolipram &
Ariflo were used as standard compounds.
The anti-diabetic activity was carried out with dipeptidyl peptidase (DPP-IV) enzyme
(Table 3) and the primary screening of the compounds was carried at 300 nM concentration
Using recombination human DPP-IV enzyme by the use of 1-(2-amino -3,3-dimethylbutanoyl
pyrrolidine -2-carbonitrile as the standard compound at 100 nM. Similarly, the PTP1B18 (Inhouse
compound, also for anti-diabetic) activity (Table 3) was done using the test compounds at
30 M with the standard compound N-[5-[N-Acetyl-4-[N-(2-carboxyphenyl)-N-(2hydroxyoxalyl)amino]-3-ethyl-DL-phenylalanyl-amino]-pentanoyl]-L-methionine at a
concentration of 0.3 M.
TABLE 1 Antibacterial activity of compounds against Staphylococcus aureus
Column1
CONCENTRATIONS
COMPOUNDS
Z
a
b
c
d
e
f
g
h
i
ii
iii
Cephlaxin

0.1

10

100

200

500

APP.MIC

++
++
++
++
++
++
++
++
++
+
+
+
++

++
++
++
++
++
++
++
++
++
+
+
+
++

++
+
++
++
++
+
++
++
+
+
P
+
--

+
P
+
+
+
P
+
+
P
P
P
P
--

---P
P
P
P
P
P
-----

--------------

200
200
200
200
200
200
200
200
200
200
200
200
10

30

TABLE 2

Antibacterial activity of compounds against Salmonella typhimurium

Column1
CONCENTRATIONS
COMPOUNDS
Z
a
b
c
d
e
f
g
h
i
ii
iii
Cephlaxin

0.1

10

100

200

500

APP.MIC

++
++
++
++
++
++
++
++
++
++
+
++
++

++
++
++
++
++
++
++
++
++
++
+
++
++

++
+
++
++
++
++
++
++
++
+
P
+
+

+
P
+
+
+
P
+
++
+
P
P
P
P

---P
P
--P
------

--------------

200
200
200
200
200
200
200
200
200
200
200
200
10

++ High signs of growth of bacteria

-- No growth of bacteria

+ Medium signs of growth

P poor growth of organisms

Table 3: Anti diabetic and anti asthmatic property

Column1
Column2
COMPOUNDS
Z
a
b
c
d
e
f
g
h
i
ii
iii

PTP1B
30um%
inhibition
3.87
5.01
7.21
12.45
8.95
0.42
3.79
3.43
11.66
14.35
12.78
0

PDE-IV
1um%
inhibition
33.25
22.05
10.86
15.86
12.11
4.48
35.54
13.53
0
38.78
0
29.3

DPP-IV
0.3um%
um=
inhibition micrometer
13
2
3
2
5
0
0
0
0
0
0
0

31

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http://www.organic-chemistry.org/synthesis/heterocycles/imidazoles.shtm
http://www.arkat-usa.org/get-file/26118/
http://zoologia.biologia.uasnet.mx/protozoos/protozoa3.pdf
www.wikipedia.org
www.google.com
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(February 1, 1960). "Isolation and Properties of Crystalline Cobamide Coenzymes
Containing Benzimidazole or 5,6-Dimethylbenzimidazole". Journal of Biological
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http://www.jbc.org/cgi/reprint/235/2/480.
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generated palladium(0)carbene complexes". Journal of Molecular Catalysis A:
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H. V. Huynh, J. H. H. Ho, T. C. Neo and L. L. Koh (2005). "Solvent-controlled
selective synthesis of a trans-configured benzimidazoline-2-ylidene palladium(II)
complex and investigations of its Heck-type catalytic activity". Journal of
Organometallic Chemistry 690 (16): 38543860.
doi:10.1016/j.jorganchem.2005.04.053.
E. C. Wagner and W. H. Millett (1943), "Benzimidazole", Org. Synth.,
http://www.orgsyn.org/orgsyn/orgsyn/prepContent.asp?prep=cv2p0065; Coll.
Vol. 2: 65.

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