1

PROJECT REPORT

ON

INDOLE AND BENZIMIDAZOLE NUCLEUS

BY

K.SRINIVAS

2008A5PS816P

2

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.

.

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CONTENTS

1) COVER....1

2) ACKNOWLEDGEMENTS.2

3) CONTENTS.3

4) 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

iii) CARBON ACIDITY AND C-2 LITHIATION6

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

4

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 five-

membered 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.

5

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

structural elements of (and for some compounds the synthetic precursors for) the tryptophan-

derived 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 N-

1, 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

6

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 C-

3 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 N-

bromosuccinimide will selectively oxidize indole 1 to oxindole (4 and 5).

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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

8

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

R1CH3

O

NH

OR

R1

NH

R

Sm/TiCl4

THF, reflux, 1h

R1 R Yield %

H C6H5 89 H 4-CH3C6H4 91 H 4-FC6H4 94 H CH3 83 H CH3CH2 81 Cl C6H5 90 Cl 4-CH3C6H4 86 Cl 4-ClC6H4 83 Cl 4-FC6H4Ph 88 Cl CH3 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.

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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.

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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-o-

chloroanilide to 2-phenylbenzoxazole (69%),5 of o-chlorohydrocinnamonitrile to 1-

cyanobenzocyclobutene (61%),6 and of methanesulfone(N-methyl-o-chloro)anilide to 1-methyl-

2,1-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-2-

nitrotoluene 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: 3-

BENZYLINDOLE AND 3-BENZOYLINDOLE

[1H-Indole, 3-(phenylmethyl)- and Methanone, 1H-indole-3-ylphenyl-]

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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-alkyl-

and 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-dithian-

2-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 1,3-

dithian-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-ribosyl-

dimethylbenzimidazole, 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.

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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.

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Synthesis 3:

CuI/l-proline catalyzed coupling of aqueous ammonia with 2-iodoacetanilides and 2-

iodophenylcarbamates affords aryl amination products at room temperature, which undergo in

situ additive cyclization under acidic conditions or heating to give substituted 1H-

benzimidazoles 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, 5-

diphenylditetrazolium)-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 helminth-

specific. 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..

N+

O-

O

NH

R1

R2

N+

O-

O

N

S

CH3

NH4SCN, Br2, MeOH

N+

O-

O

NH

CH3

S

CH3

S

CH3

N

N

CH3

F

F

F

1-PrBr, KCN, 1-PrOH

H2,Pd/C 10%, MeOH

CF3COOH, HCl, reflux

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 renin-

angiotensin 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 non-

peptide 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

NH2

+

O

R1

R

N

NH

R

N

NH

R

N+

O-

O

HNO3 H2SO4

5-Nitro-2-phenyl

25

Benzimidazole

O

O OH

NH

O

CH3

O OH

Cl

N

N

R

O OH

N+

O-

O

N

N

R

O OH

NH2

KOH H2SO4

(HCHO)n

POCl3

DMF/K2CO3

N

NH

R

N+

O-

O

EtOH

SnCl2.2H2O

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 5-Nitro-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

NH2

NH2

+

O OH

Br

PPA

1800 C /4 hr

90 %

N

NH

Br

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)

N

NH

Br

Alkylating agents

NaH/DMF

N

N

Br

R

R

a) Methyl

b) Ethyl

c) Propyl

d) Butyl

another method for derivative (a):

NH2

NH CH3

+

O OH

Br

PPA

1800 C / 4 hr

N

N

Br

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

N

N

Br

R

+

CH2

OO

CH3

CH3

CH3

N

N

R

OO

CH3

CH3CH3

TEA / Pd(OAc)2

tri-o-tolylPhosphine

DMF, 110oC, 3 h

R

e) Ethyl

f) Methyl

g) Propyl

h) Butyl

Scheme 3

N

N

Br

R

+

CH2

N

N

R

TEA / Pd(OAc)2

TEA / Pd(OAc)2

R

i) Methyl

ii) Ethyl

iii) 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-(2- hydroxyoxalyl)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 0.1 1 10 100 200 500 APP.MIC

COMPOUNDS

Z

++ ++ ++ + -- -- 200

a

++ ++ + P -- -- 200

b

++ ++ ++ + -- -- 200

c

++ ++ ++ + P -- 200

d

++ ++ ++ + P -- 200

e

++ ++ + P P -- 200

f

++ ++ ++ + P -- 200

g

++ ++ ++ + P -- 200

h

++ ++ + P P -- 200

i

+ + + P -- -- 200

ii

+ + P P -- -- 200

iii

+ + + P -- -- 200

Cephlaxin

++ ++ -- -- -- -- 10

30

TABLE 2 Antibacterial activity of compounds against Salmonella typhimurium

Column1 CONCENTRATIONS 0.1 1 10 100 200 500 APP.MIC COMPOUNDS

Z

++ ++ ++ + -- -- 200

a

++ ++ + P -- -- 200

b

++ ++ ++ + -- -- 200

c

++ ++ ++ + P -- 200

d

++ ++ ++ + P -- 200

e

++ ++ ++ P -- -- 200

f

++ ++ ++ + -- -- 200

g

++ ++ ++ ++ P -- 200

h

++ ++ ++ + -- -- 200

i

++ ++ + P -- -- 200

ii

+ + P P -- -- 200

iii

++ ++ + P -- -- 200

Cephlaxin

++ ++ + P -- -- 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 PTP1B PDE-IV DPP-IV

COMPOUNDS 30um% inhibition

1um% inhibition

0.3um% inhibition

um= micrometer

Z 3.87 33.25 13

a 5.01 22.05 2

b 7.21 10.86 3

c 12.45 15.86 2

d 8.95 12.11 5

e 0.42 4.48 0

f 3.79 35.54 0

g 3.43 13.53 0

h 11.66 0 0

i 14.35 38.78 0

ii 12.78 0 0

iii 0 29.3 0

31

REFERENCES:

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

H. A. Barker, R. D. Smyth, H. Weissbach, J. I. Toohey, J. N. Ladd, and B. E. Volcani (February 1, 1960). "Isolation and Properties of Crystalline Cobamide Coenzymes Containing Benzimidazole or 5,6-Dimethylbenzimidazole". Journal of Biological Chemistry 235 (2): 480488. PMID 13796809. http://www.jbc.org/cgi/reprint/235/2/480.

R. Jackstell, A. Frisch, M. Beller, D. Rottger, M. Malaun and B. Bildstein (2002). "Efficient telomerization of 1,3-butadiene with alcohols in the presence of in situ generated palladium(0)carbene complexes". Journal of Molecular Catalysis A: Chemical 185 (12): 105112. doi:10.1016/S1381-1169(02)00068-7.

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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