Review Article
ISSN: 0974-6943
Mohd Rashid et al. / Journal of Pharmacy Research 2011,4(2),413-419
Available online through
http://jprsolutions.info
Benzimidazole: A Valuable Insight Into The Recent Advances and Biological Activities
1.
Asif Husain1 , M.M. Varshney2 , Mohd Rashid1*, Ravinesh Mishra1, Afroz Akhter1
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Jamia Hamdard (Hamdard University), Hamdard Nagar, New Delhi-110062 (INDIA).
2.
Dept of Pharmacy, Raj Kumar Goel institute of Technology, 5th km stone Delhi-Meerut road, Ghaziabad (U.P.), (INDIA).
Received on: 10-11-2010; Revised on: 15-12-2010; Accepted on:09-01-2011
ABSTRACT
Considerable research works have been done on benzimidazole and their derivatives to evaluate their antibacterial, antiviral, anticancer, anticonvulsant, antihistaminic,
anthelminitic and antidepressant activity and some of works have provided very promising results in antiasthamatic and antidiabetic activity. A wide variety of
benzimidazole derivatives have been described for their chemotherapeutic importance. However there is a great need to study the various pharmacological actions
derived from benzimidazole nucleus through research work. This account gives an overview of the benzimidazole based system and their relevance in medicinal
chemistry.However there is a great need to study the various pharmacological actions derived from benzimidazole nucleus through research work. The chemical
reactions of benzimidazole with various reagents resulting in substituted benzimidazole derivatives which have a diverse biological importance.
Key words: Benzimidazole, aminobenzimidazoles, benzimidazolecarboxylic acids, antibacterial, anticancer, anticonvulsant.
INTRODUCTION
C
C
O
N
H
1
S
N
H
2
Fig . 1
Benzimidazoles which contain a hydrogen atom attached to nitrogen in the 1position readily tautomerize (3-4) as shown in Fig. 2. This tautomerism is analo
gous to that found in the imidazoles and amidines. Infact, the benzimidazoles may
be considered as cyclic analogs of the amidines. Because of this tautomerism in
benzimidazoles certain derivatives which appear at first to be isomers are in reality
tautomers although two non-equivalent structures can be written only one com
pound is known. This may be illustrated with 5 or 6-methylbenzimidazole5.
:
H
N
N
N
N
3
H
4
Fig. 2
Thus, 5-methylbenzimidazole (5) is a tautomer of 6-methylbensimidazole (6) and
both structures (5 and 6) represent the same compound as shown in Fig. 3. When
the group attached to the nitrogen in the l-position is larger than hydrogen such
tautomerism is not indicated and isomeric forms exist. Thus 1,5dimethylbenzimidazole and 1,6-dimethylbenzimidazole are separate and distinct
compounds.
N
:
H
H 3C
H3C
N
N
N
:
CHEMICAL PROPERTISE OF BENZIMIDAZOLES
The benzimidazoles contain a phenyl ring fused to an imidazole ring. Historically
the first benzimidazole was prepared in 1872 by Hoebrecker who obtained 2, 5 or
2, 6- dimethylbenzimidazole by the reduction of 2-nitro-4-methylacetanilide.
Several years later Ladenburg obtained the same compound by refluxing 3,4diaminotoluene with acetic acid. The benzimidazoles are known also as
benziminazoles or benzoglyoxalines. Thus, benzimidazole according to this nomenclature would be called methenyl-o-phenylenediamine and 2methylbenzimidazo. Also, they have been named as derivatives of the grouping
composing the imidazole portion of the ring4. Thus, for example, benzimidazole
has also been called 2 (3H)-benzimidazolone (1) and 2(3H)-benzimidazolethione
(2) are also known as o-phenyleneurea and o-phenylenethiourea respectively
H
N
H
N
:
Compounds bearing benzimidazole nucleus have been of great interest to synthetic
and medicinal chemists for a long time due to their unique chemical and biological
properties mainly related to traditional anthelminitics, albendazole and
oxibendazole. Benzimidazole derivatives have also been found to possess biological
activities such as antiviral, antibacterial and anticancer.1 Continuous increase in
bacterial resistance to existing drugs has been resulted due to wide spread use of
antibacterial agents leading to research on new substances possessing antimicrobial
activity. Several benzimidazoles are commercially available as pharmaceuticals,
veterinary products and fungicides. Standard methods of synthesis of these ring
systems involve cyclization reactions. For which 1, 2-disubstituted benzenes of
the appropriate type are the most common starting materials. This synthesis can
usually be adapted to incorporate additional substituents in the benzenoid ring
system, if required, for this reason electrophilic substitution reactions have not
been widely used, although it is possible to carry out nitration, halogenation and
similar reactions. Benzimidazole is attacked preferentially at the 5-position,
imidazole at the 3 and 5-position and benzotriazole at the 4-position. The position
of benzimidazole is susceptible to nucleophilic attack. Chloride is displaced from
the 2-position of benzimidazole and N-alkyl benzimidazole by alkoxides, amines,
thiols and other nucliophiles their activity towards nucliophiles is lower than
corresponding benzoxazole and benzothiazole.2 1-substituted benzimidazoles can
be directly aminated at the 2-position by heating with sodamide. Benzimidazole
derivatives like enviroxime have been show high degree of antiviral activity
against picorna viruses. Other benzimidazole compounds like LY 122771-72 and
LY 127123 shown very significant antiviral activity against picorna viruses. 3
Various benzimidazoles derivatives have been found to be useful pharmacophores
in building anticonvulsive agents with suitable substituents.
5
H
6
Fig. 3
shown in Fig. 1.
*Corresponding author.
Mohd Rashid,
Department of Pharmaceutical Chemistry,
Faculty of Pharmacy, Jamia Hamdard University,
Hamdard Nagar, New Delhi-110062, India.
REACTIONS OF THE BENZIMIDAZOLE RING
The benzimidazole ring possesses a high degree of stability. Benzimidazole for
example is not affected by concentrated sulfuric acid when heated under pressure
to 270°C nor by vigorous treatment with hot hydrochloric acid or with alkalis.
Oxidation cleaves the benzene ring of benzimidazole only under vigorous conditions. The benzimidazole ring is also quite resistant to reduction however tetrahydro
and hexahydrobenzimidazoles in which the benzene ring is reduced may be prepared by catalytic reduction under certain conditions6.
Journal of Pharmacy Research Vol.4.Issue 2. February 2011
413-419
Mohd Rashid et al. / Journal of Pharmacy Research 2011,4(2),413-419
REACTIONS INVOLVING THE NITROGENS AT THE 1 AND 3-POSITIONS
Benzimidazoles form salts with acids readily. Thus benzimidazole readily forms a
monohydro chloride, monopicrate, mononitrate, monoacetate, etc. Benzimida
zole also forms a salt with 2-nitro-l,3-indanedione and with copper azide7.
Alkylation
Benzimidazoles, upon alkylation with alkyl halides yield l-alkylbenzimidazoles
(7) and under morevigorous conditions 1,3-dialkylbenzirnidazolium halides8 as
shown in Fig. 4.
CLEAVAGE OF THE IMIDAZOLE RING
The imidazole ring of benzimidazoles may be readily cleaved by one of several
methods:
Aroyl halides in the presence of water
Benzimidazoles when treated with benzoyl chloride yield first Nbenzoylbenzimidazoles. In the presence of additional acid chloride and in the
presence of water further reaction may occur and N N’-dibenzoyl-ophenylenediaminea (11) are obtained as shown in Fig. 8. This transformation has
been postulated as occurring as follows16.
R
C OC 6H 5
H
N
N
N
RX
N
X
RX
N
H
R
N
R
N
C 6H 5C OC l
R
N
H
N
R
H
N
N
(CH 3 CO)2 O
+ CH 3C O OH
N
H
+
C O2
N
8
N H CO C 6 H 5
RCO OH
H 2O
11
N
CO C 6 H 5
C OC 6H 5
Fig. 8
N
H 3C
N
C aO C l 2
CH 3
CH 3
N
H
N
12
F ig. 9
H3 C
H 3C
N
C H3
N
CH3
sol ution
N
Cl
13
F ig. 10
N
70-74 oC
CH2CH 2 C6 H4N(CH 3)2-P
H3C
N
Cl
R
Cl
10
Cl
The bromination of 2-methylbenzimidazole has been studied by Baczynski and
von Niementowski.The addition of two moles of bromine to a cold acetic acid
solution of 2-methylbenzimidazole gives a tetrabromo derivative (15) as shown in
Fig. 12. 2-Methyl-6-bromo benzimidazole and 2-methyl-4-bromobenzimidazole
under the same conditions give 2-methyl-2,3,4,6-tetrabromobenzimidazolinhey.
2-Methyl-3,4,6-tribromo benzimidazole at steam bath temperature adds bromine
across the 2,3- double bond18.
N
O
N
H
14
F ig . 1 1
Br
H
N
H2
R = - (C H 2 )n C O O H (w h e r e n = 0 , 3 ,4 ).
CH3
N
H
Hartmann and Panizzon however first showed that certain benzimidazoles could
be reduced to 4, 5, 6, 7-tetrahydrobenzimidazoles in good yield with platinum
(Adam’s catalyst) in acetic acid solution at atmospheric pressure (10) as shown in
Fig. 7. The reduction is successful only with those benzimidazoles which contain
a substituent in the 2-position. Thus 2-methyl, 2-ethyl and dimethylbenzimidazoles
give the corresponding tetrahydrobenzimidazoles and 2-phenyl benzimidazole
yields 2- cyclohexyl tetrahydrobenzimidazole. Benzimidazole and those benzimidazoles containing a substituent in the l-position (but not in the 2- position) could
not be reduced with platinum according to this method15.
Pt
N
C aO C l 3
C H3
9
Fig. 6
H 3C
N
N
H
N
H
H
Cl
CH=CHC 6H 4N(CH 3) 2-P
Ni, H2
Cl
h eat ben zen e
N
N
O
OH
NC OR
Halogenation
When 2,5 or 2,6-dimethylbenzimidazole in an aqueous acid solution is treated
with a saturated solution of bleaching powder at 35°C l-chloro-2,5 or 2,6dimethylbenzimidazole (12) is obtained17 as shown in Fig. 9. The N-chloro compound loses chlorine quite readily even at relatively low temperatures. When
heated under reflux in benzene solution a rearrangement of the chlorine atom to
the benzene ring takes place (13) as shown in Fig. 10. The N-chloro derivative
(14) of this compound may then be prepared by treatment again with bleaching
powder as shown in Fig. 11.
H 3C
REDUCTION OF BENZIMIDAZOLES, HYDROGENATED BENZIMIDAZOLES, DEHYDROGENATION OF REDUCED BENZIMIDAZOLES
Until very recently it was thought that the benzimidazole ring was stable to
reduction. Treatment of benzimidazole, 2-methylbenzimidazole, or 2,5 or 2,6dimethylbenzimidazole with red phosphorus and hydriodic acid even to 300°C
gives no reduced product. Red phosphorus and hydriodic acid have been used in
fact to cleave arylamino groups from benzimidazoles without affecting the benzimidazole ring in the process (9) as shown in Fig. 6. Sodium in refluxing absolute
alcohol also causes no reduction of the benzimidazole ring11,12. Catalytic reduction
of benzimidazole even under high pressure with nickel as the catalyst is reported
to give negative results13,14.
H
N
C OC 6H 5
N
R
N HC O C 6H 5
N H COC 6 H 5
C OC 6H 5
H2O
C O CH 3
Fig. 5
R
N
C OC 6H 5
Acylation
N-Acylbenzimidazole (8) may be prepared by the action of acid chlorides or
anhydrides on Benzimidazoles as shown in Fig. 5. The reaction is usually carried
out in the absence of water. In the presence of water and especially in alkaline
solution cleavage of the imidazole ring may occur. 1-Benzoyl benzimidazole and
l-acetylbenzimidazole may be prepared by the action of benzoyl chloride and
acetyl chloride, respectively on benzimidazole. l-Benzoyl and l-acetyl derivatives
have been prepared by the action of these acid chlorides on the silver salts of
benzimidazolea9,10.
Cl
R
N
7
F ig. 4
N
H
N
C6H 5 COCl
CH
Br
N
2B r2
CH3
3
.H B r
Br
N
H
F ig . 1 2
15
N
H
F ig . 7
Journal of Pharmacy Research Vol.4.Issue 2. February 2011
413-419
Mohd Rashid et al. / Journal of Pharmacy Research 2011,4(2),413-419
Nitration
The nitration of benzimidazoles proceeds readily. In most cases nitration appears
to take place preferentially at the 5- or 6-position. However the nitro group may
also enter the 4- or 7-position especially if the 5- or 6-position is blocked.
H
N
H3C
N
H 3C
C H3
N
C 6 H5 CH O
C H= C H C 6H 5
N
H
16
N
H
N
C - OH
N
H
REACTIONS INVOLVING SUBSTITUENT GROUPS
A number of reactions of benzimidazoles involve common place transformations
such as the conversion of an acid to its ester etc.
Reactions involving the 2-methyl or methylene group
The methyl group of 2-methylbenzimidazoles is comparable in its activity to the
methyl group of a-picoline, quinaldine, or methyl ketones and shows most of the
same reactions of these compounds. The benzimidazole ring like the pyridine and
quinoline ring because of its electron-attracting nature imparts a positive character to the carbon atom of the 2-methyl group. 2-methyl benzimida zoles (16) as
shown in Fig. 13 for example react with aromatic aldehydes in aldol-type condensations in a manner analogous to a-picoline and quinaldine 19.
N
C= O
POCl3
C- Cl
N
H
N
H
20
Fig. 16
A sO 3 H 2
A sO 3 H 2
N
CH 2 ClCOO H
C -O H
N
N a 2 CO 3
C -O C H 2 C OO H
N
N
CH 3
21
Fig. 17
2(3H)-benzimidazolethiones or 2-mercaptobenzimidazoles are generally stable
substances and are soluble in dilute alkali. Alkylation occurs readily with replacement of the mercapto hydrogen to yield S-alkylated derivatives and a number of
these derivatives have been prepared. 2(3H)-Benzimidazolethione for example
may be alkylated (22) as shown in Fig. 18 with chloroacetic acid by refluxing in
2 N sodium hydroxide solution26,27.
N
F ig. 13
N
CH 2 C lC O O H
S -H
Reactions of d-benzimidazolecarboxylic acids
Benzimidazoles containing a carboxyl group in the 2-position readily undergo
decarboxylation on Heating20. 2-Benzimidazolecarboxylic acid on heating above
its melting point for example yields benzimidazole (17) as shown in Fig. 14. 5 or
6-Methyl-2-benzimidazolecarboxylic acid is decarboxylated in a similar manner
by melting or by boiling the acid in acetic acid 21 . l-Phenyl-5-nitro-2benzimidazolecarboxylic acid and the corresponding ethyl ester may be decarboxylated by heating with concentrated hydrochloric acid in a sealed tube at150°C.
2-Benzimidazolecarboxylic acid may not be converted to its acid chloride with
phosphorus chlorides or thionyl chlorides. With excess thionyl chloride a yellow
cyclic diamide containing no chlorine is obtained in 86 percent yield22.
N
CH 3
N aO H
C -S C H 2 C O O H
N
H
N
H
22
F ig. 1 8
Aminobenzimidazoles
2-Aminobenzimidazole is soluble in water and soluble in alkali.2Aminobenzimidazole is converted to 2-(3H)-benzimidazolone upon heating with
barium hydroxide and a little water to 180-190°C or by treatment with nitrous and
acid28. Hypochlorous or hypobromous acid causes a series of color changes to take
place29. Treatment with two moles of cyanogen bromide in the presence of water
potassium bicarbonate or treatment with biuret at 180°C yields a tricyclic compound (23) as shown in Fig. 19.
N
C O2
CO O H
N
H
17
B rC N
o r b iu r e t
N
H
Reactions of 2-(haloalkyl) benzimidazole
2-Chloromethylbenzimidazole (18) and other 2-(a-haloalkyl) beneimidazoles are
highly reactive. Structurally they are related to allyl and benzyl halides since they
possess the same =CCH and l grouping23. The reactivity of these benzimidazoles is
probably due to the existence of such resonating structures as (19) as shown in Fig.
15. 2-Chloromethylbenzimidazole is quantitatively hydrolyzed with boiling water
in 30-60 min. Other 2 or chloroalkylbenzimidazoles that were studied are hydrolyzed in a somewhat shorter time and the 2- (chloroisopropyl) derivative is
completely hydrolyzed by water at room temperature.
N
CH2Cl
N
H
a nd
C H2
N
C=O
NH
23
F ig . 1 9
Oxidation
Benzimidazoles are stable to oxidation30. By very vigorous conditions of oxidation (potassium Perm anganate in hot alkaline solution) it is possible to partially
oxidize benzimidazole to obtain a small amount of imidazoledicarboxylic acid
(24) as shown in Fig.20 Because of the stability of the benzimidazole ring to
oxidation it is possible to oxidize substituent groups without affecting the ring31.
By the oxidation of substituent groups a variety of benzimidazole carboxylic acids
have been prepared.2-Benzimidazolecarboxylic acid (25) as shown in Fig. 21 may
be conveniently prepared in good yield by the oxidation of 2hydroxymethylbenzimidazole which may be prepared by the action of glycolic
acid on o-phenylenediamine32.
H O OC
N
K M nO 4
N
C
N
O =C
N
N
N
C -NH 2
F ig . 1 4
18
N
N
N
H
C
H OOC
N
H
C H2
NH 2
N
H
24
F ig . 20
19
N
F ig . 1 5
Reactions of 2-(SH)-benzimidazole
2(3H)-Benzimidazolones or 2-hydroxybenzimidazoles are extremely stable substances. 2-(3H)- Benzimidazolone is not split by treatment with benzoyl chloride
in alkaline solution24. 2 (3H)- Benzimidazolones show many of the reactions of 2hydroxypyridines and 2-hydroxyquinolines for example treatment of 2-(3H)benzimidazolone with phosphorus oxychloride or phosphorus pentachloride yields
the 2-chloro derivative (20) as shown in Fig. 16. 2-Hydroxybenzimidazolea have
been alkylated on the oxygen in good yields (21) as shown in Fig. 17 by treatment
with chloroacetic acid in sodium carbonate solution25.
C H 2 OH
N
KMnO 4
COO H
N
H
Fig. 21
25
N
H
BIOLOGICAL EVALUATION OF BENZIMIDAZOLES
Benzimidazole and their derivatives possess a variety of biological actions described as below.
Journal of Pharmacy Research Vol.4.Issue 2. February 2011
413-419
Mohd Rashid et al. / Journal of Pharmacy Research 2011,4(2),413-419
Antibacterial
N-[4-(2-amino)-6-aryl-3-cyano-pyridin-4-yl)-phenyl]-2-[5-nitro-1Hbenzimidazol-2-yl) benzamide, N-[4-(2-mercapto-6-aryl-pyrimidin-4-yl)-phenyl]2-(5-nitro-1H-benzimidazol-2-yl)-benzamide and N-[4-(5-aryl-isoxazol-3yl)phenyl]-2-(5-nitro-1H-benzimidazol-2yl)-benzamide synthesis from the starting compound N-(4-acetylphenyl)-4-(5-nitro-1H-benzimidazol-2-yl)-benzamide
with 4-nitro-1,2-diaminobenzene,phthalic anhydride and 4- amino acetophenone. Where [R =2,4-dichloro phenyl, 2-nitrophenyl, 2-chlorophenyl, 4hydroxyphenyl, phenyl etc.] all show antimicrobial activity against gram positive and gram negative bacteria 33. Synthesis of 2-alkyl-1-substituted anilinomethylbenzimidazoles from 2-alkyl benzimidazole in the presence of formalin
and aromatic amine show wide range of antibectarial activity.in which zone size
greater than 10mm are those compounds where R1 (aromatic amine) and R (at
second position of benzimidazole) = 4-Br and H, 4-I and H, 2-methoxy and H, 2ethoxy and H show antibectarial activity against E.coli and S.typhi Presence of
amino group at the position 5 exhibit inhibitory activity against growth of saccharomyces cerevisiae .at the position of 2 subsituted pyridyl or aryl (26) as
mentioned in Fig. 22 prepared procedure of Porai-Koshits et al. by reaction of ophenylenediamine and aromatic acid 34. The compounds were found to be active
against the growth of S. aureus and E. coli. Fifty compounds of 2-alkyl-1(1’dihydropyridylmethyl) benzimidazoles (27) as mentioned in Fig. 23 were
screened for their antimicrobial activity against A. brassicicola, fusarium, staphylococcus (gram+ve), E.Coli (gram-ve). Filter paper disc method used at 500 ppm
conc. The controlled were used carbendazim and tetracycline35.
Reaction of 3-(2-methylbenzimidazol-1-yl) propionic acid hydrazide with CS2/
KOH gave oxadiazole 2 which underwent Mannich reaction to give 3.compound
2 was treated hydrazine hydrate to give triazole 4 which was treated with both
aldehydes and acetic anhydride to give 5 and 6 respectively carbohydrazide 1 was
reacted with ethyl acetoacetate, acetylacetone and aldehydes to give 7, 8 and 9
respectively. Cyclocondensation of 9 with thioglycolic and thiolactic acids give
10 and 11 respectively. Some of these compounds (29) showed potential antibacterial activities against B. cereus, E. coli, S. cerevisae, A. Niger38 as mentioned in
Fig. 25.
N
CH3
N
N
CH2R
N
CH2CH3
3a-c
O
S
5-[2-(2-Methylbenzimidazol-1-yl) ethyl ][1,3,4]oxadiazole-2(3-H)-thione
a R= -N(C2H5)2
b R= -N O
N
CH3
H 2N
N
N
N
N
CH2CH3
R
N
H
SH
N
26
R = A l k y l d e r iv a t i v e s , a r y l d e r i v a t i v e s , p y r i d y l d e r i v a ti v e s
F ig . 2 2
5a-b
RCHN
5-[2-(2-Methylbenzimidazol-1-yl) ethyl ]-4-arylidenimino-[1,2,4]triazole-3-thiol
a R=
OCH3
N
N
CH3
R
Cl
C OR'
R' '
b R=
N
29
Fig.25
H 3C
C O R'
R = C H 3, R '= C H 3, R ''= 4'-C H 3
27
F ig. 23
Some new derivatives like chalcones, cyanopyridines, thienopyrimidines and
isoxazoles bearing benzimidazoles nucleus has been investigated in order to study
as antibacterial agents36. N- (4-Acetylphenyl)-4-(5-nitro-1H-benzimidazole-2yl)-benzamide.N-[4-(3-Aryl-acrylol)-phenyl]-2-(5- nitro-1H-benzimidazole-2yl)-benzamide.WhereR=2a(2-Cl-C 6 H4 ),2b(2,4-Cl2 -C 6H3),2c(2-OHC 6H4 ), 2d(3OCH3-4-OH-C 6H3 ),2e(4-OCH3 -C 6 H4 ),2f(2-NO 2-C 6H4)N-{4-[2-Amino-6-aryl-3cyanopyridine -4-yl]-phenyl}-2-(5-nitro-1H-benzamide.where R=3a(2-ClC6H4),3b(2,4-Cl2-C6H3) Replacement of nitrogen by sulfur at position 1 exhibit
antiparasitic, antibacterial, antiviral, antitubercular and antifungal activities. Synthesis of 5,6-Disubustituted 2-(substituted phenyl carboxamido) benzothiazoles
(28) reported as potential anthelminitic antimicrobial agents as mentioned in
Fig. 24. Some of the compounds were screened for their in vivo anthelminitic
activity against Hymenolepsis Nana in mice. All the compounds were screened for
their in vitro antitubercular activity against H37Rv strain of Mycobecterium
tuberculosis.also screened for their in vitro antibacterial and antifungal activity
against S.aureus, S.typhi. Candida albicans37.
The ligand [C16H10O2N4S2] L has been synthesized by the condensation reaction of
2-mercaptobenzimidazole and diethyloxalate. The ligand L was allows to react
with bis(ethylenediamine) CU/NI complexes to yield[C 20 H 22 N 8 S 2 Cu] and
[C20H22N8S2Ni]Cl2 complexes. The Ni (II) complex was synthesized only to elucidate the structure of the complex. Elemental analyses, IR, NMR, EPR, UV-vis
spectroscopy and molar conductance measurements characterized the complexes
1 and 2. Both the complexes are ionic in nature and possess square-planar geometry. The antibacterial and antifungal studies of the [C7H6N2S], [C4H16N4Cu] Cl2
were carried out against S.aureus, E.coli and A.niger. All the results revealed the
complex 1 is highly active against the bacterial strains and also inhibits fungal
growth39.
A series of 5-(N, N-disubstituted aminomethyl)-2-[(4-carbethoxymethylthiazole2-yl) imino]-4-thiazolidinones 4a-m (30) have been synthesized as mentioned in
Fig. 26. Their structures are confirmed by elemental analysis and spectral data.
The antibacterial activities of the compounds against Staphylococcus aureus,
S.epedermidis, S.typhi, E.coli etc and antifungal activity against candida albicans
are tested using disk diffusion method40.
O
O
N
CH3
O
HN
N
S
N
R
4 a-m
NHCO
S
a
b
c
d
e
H
S
R'
R = 5 - C l , 6 -F , R '= H
R = 5 C l,6 - F , R '= 2 -F
R = 5 , 6 -D iC l, R '= 2 -F
R = 5 -C l , 6 -F , R '= 3 - F
R = 5 , 6 D iC L , R '= 3 - F
28
F ig . 2 4
R
R
R
R
R
R
a
b
c
d
e
f
=
=
=
=
=
=
C H 2R
d i m e t h y l a m in e
d ie th y l a m i n e
p y r r o l id i n e
d io x o p y r o ll i d i n e
p i p er i d in e
2 - m et h y l p ip e r i d i n e
30
F ig . 2 6
Journal of Pharmacy Research Vol.4.Issue 2. February 2011
413-419
Mohd Rashid et al. / Journal of Pharmacy Research 2011,4(2),413-419
The presence of 5,6-dimethylbenzimidazole nucleus in the structure of vitamin
B12 played significant role in the synthesis of several derivatives of benzimidazole,
for illustration 5-methyl, 4,5-dimethyl and 2,5-dimethyl benzimidazoles as antagonists of this vitamin. From these observation, synthesized the substituted 1Arylaminomethyl-5,6-dimethylbenzimidazoles and related products respectively
and were found to be active against S.aureus, E.coli, S.typhi and Bacillus
megaterium by agar diffusion method41.
Antimicrobial and anthelminitics
Synthesis of 1-[N- (phenyl/bromo/chloro/methyl subustituted phenyl) acetate/
propionate] benzimidazoles (31) reveals their antimicrobial and anthelminitic
activity as mentioned in Fig. 27. The synthesized compounds presented by the
following formula. The compounds 3 (a-z) were evaluated for antihookworm and
ceticidal activity on Ancylostoma ceylancim and Hymenolepsis nana by the
method of Steward42.
N
N
R
CHR
COO
co m pou n d s (3a,c,e,g ,i,k, m ,o,q ,s,u,w ,y),
co m pou n d s (b ,d,f ,h,j,l,n,p,r ,t ,v,x,z),
31
Antiviral
Syntheses of 5-methoxy 1,3-disustituted-benzimidazolin-2-thiones (35) as shown
in Fig. 30 were found to active against sunhemp rosette virus. 5methoxybenzimidazolin-2-thion achieved by reaction of 4-methoxy-o-phenylenediamine and CS2 in presence of ethanolic KOH. Later the derivatives were synthe
sized as mannich bases by using formaldehyde solution and various amines46.
Benzimidazoles are remarkably effective compounds both with respect to their
virus inhibitory activity for illustration enviroxime active against Picorna virus.
Various α–[(aryl amido/imido/alkyl/aralkyl)-α-naphthyl]-2-methoxy-benzimida
zoles (36) as shown in Fig. 31 were found to exhibit antiviral activity, in vitro
ranging from 20 to 50%. Presence of trichloromethyl group increased the antiviral activity. The compounds 1b (R=benzamido, R’=trichloromethyl) and2b
(R=phthalimido, R’=trichloromethyl) were found to be 50% and 40% antiviral
activity. However none of the compounds showed any significant antiviral activity in chick embryo system in vivo. These compounds also show enzymological
activity such compounds are better MAO inhibitors as MAO activity (43% to
60%). R=benzamido and R’=trichloromethyl inhibits MAO activity up to 60.12%.
The anticonvulsant data clearly indicates that except compound 2b
(R=phthalimido, R’=trichloromethyl) all the compounds exhibit protection ranging
from 20 to 80%. compounds having R= benzamido and R’=trichloromethyl exhibited 30% protection with high mortality47.
w rere R = H
w he re R = C H 3
CO CH 3
N
N
S
S
F ig . 27
A series of 2-(trifluoromethyl)-1H-benzimidazole derivatives (32) with various 5and 6- position bioisosteric substituents (-Cl, -F, -CF3, -CN), namely 1-7 were
prepared using a short synthetic route. Each analogue was tested in vitro against
the protozoa Giardia intestinalis and Trichomonas vaginalis in comparision with
albendazole and metronidazole. Several analogues had IC 50 values< 1 ìM against
both species, which make them significantly more potent than either standard.
Compound 4 [2,5(6)-bis(trifluoromethyl)-1H-benzimidazole], was 14 times more
active than albendazole against T.vaginalis43. Mebendazole, a benzimidazole (33)
carbamate compound, is currently in use for human medical practice against soiltransmitted helminthiasis (STH) and enterobiasis as mentioned in Fig. 28. However, it has been demonstrated that its spectrum of activity is broad and goes
beyond those infections. Several studies provide evidence that this drug, taken at
higher doses than used for STH and enterobiasis, could be sufficiently effective on
some protozoa, nematodes and cestodes 44.
H3 C O
N
H 3 CO
N
CO CH3
a
b
c
d
e
f
g
h
A = mo rph oli no
A = pip eri din o
A = an ilin o
A = 4-C l -a ni lin o
A = 4-B r-a n ili n o
A = 4-C H 3 - a n ilin o
A = 4-O C H 3 -an i l ino
A = 4-N O 2 - a n ilin o
CO
N
CO
CF 3
R
N
N
F ig. 3 0
R
R'
CH
N
N
R1
O
R = -H, -CH 3
R1 = -C2 H5, -CH2 Cl, -CH2 CH2 Cl,
-C6 H5, 2ClC6H 4
R = be n z am id o , R = C C L 3
R = ph t h a la m i d o , R ' = C 6 H 5
R' = 2 - O H ; C 6 H 4
36
33
Fig. 28
Novel bisbenzimidazoles, characterized by 3, 4-ethylenedioxy-extension of
thiophene core, revealed pronounced affinity and strong thermal stabilization
effect toward ds-DNA (34) as mentioned in Fig. 29. They interact within ds-DNA
grooves as dimmers or even oligomers and agglomerate along ds-RNA. Compounds have shown moderate to strong antiproliferative effect toward panel of
eight carcinoma cell lines. some compound displayed the best inhibitory potential
and in equitoxic concentration (IC 50 = 1 × 10-6 M) induced accumulation of cells
in G2/M phase after 48 h of incubation. Fluorescence microscopy showed that 5
entered into live HeLa cells within 30 min, but did not accumulate in nuclei even
after 2.5 h. Compound 5 inhibited the growth of Trypanosome45.
O
O
N
N
S
N
H
R
HN
R
NH
N
N H
5R -
4R N H2
6R N
H
H N
3 4
A
O CH 2
CH 2
X=Cl, F, CF 3, CN
32
N
35
N
N
N
H
A
S
H 3C O
N
X
N
N
F ig . 3 1
Antimicrobial and antioxidant
A number of benzimidazole compounds namely, N-(4-(1H-benzimidazol-2yl)phenyl)-4-(1H-benzimidazol-2- yl)-benzamide derivatives and N-(3- or 4-(1Hbenzimidazol-2-yl)phenyl)-2-phenyl-1H-benzimidazole-5-carboxamide derivatives were synthesized and antibacterial and antioxidant activities were evaluated.
Antibacterial activities of some compounds against MRSA-isolate are equal to
ampicillin. Some Compounds displayed better antifungal activities against Candida albicans. Antioxidant properties were evaluated by several methods, such as
inhibition of lipid peroxidation, superoxide anion production, and DPPH stable
free radical, and also their effects on hepatic cytochrome P450 (CYP) dependent
ethoxyresorufin O-deethylase (EROD) enzyme were determined in rats in vitro.
Compounds had strong scavenger effect on superoxide anion ( 90% and 99%,
respectively) at 10-3 M concentration48. Some compounds showed significant
inhibition on EROD activity with 98%, which is better than that of caffeine being
a specific inhibitor of EROD activity (85%).
Antidepressant and anticonvulsant
2-alkyl 1-(4’-benzhydrazide) aminomethylbenzimidazoles (37) were founds to
active as MAO inhibitors as shown in Fig. 32. Although hydrazide derivatives
have been shown to be potent inhibitors of the enzyme MAO. Benzimidazole also
possesses CNS depressant activity49. All benzimidazole hydrazides were found to
F ig . 2 9
Journal of Pharmacy Research Vol.4.Issue 2. February 2011
413-419
Mohd Rashid et al. / Journal of Pharmacy Research 2011,4(2),413-419
N
R
N
C H 2N H
CO NH NH 2
37
F ig . 3 2
inhibit MAO activity during oxidative deamination of both knuramine and 5hydroxytryptamine.the degree of enzyme inhibition in general was not only of a
low orde when tyramine was used as the substrate, but compounds d (R=H) and e
(R=CH3) were devoid of inhibitory effects under similar experimental conditions.
These results reflect the greater sensitivity of benzimidazole hydrazides to inhibit
MAO during oxidative deamination of kynuramine as compared to tyramine. All
of benzimidazole hydrazides where (R=H, CH3, C2H5, n-C3H7, iso-C3H7) exhibit
low anticonvulsant activity which was found to be maximum with compound
(R=C2H5) where 50% protection against pentylenetetrazol induced seizures50.
Anticancer
1-(3-1,2,4-nitrotriazole-1-yl)-propanhydroxyiminoamide
and
1-(6nitrobenzoimidazole-1-yl)-propanhydroxy iminoamide were synthesized and radiolabel with 99mTc. The 99mtc labeled complexes continuously accumulated in
hypoxic murine sarcoma S180 cells in vitro but not in aerobic cells. Biodistribution
result in mice bearing S180 tumor indicated that the tracers could localize in tumor
and eliminate from slowly. These results suggested that the 99mTc labeled
nitrobenzimidazole and nitrotriazole might be the novel tumor hypoxia markers51.
Synthesis of new 4-aryl/alkyl-1- [substituted benzimidazol-2’-yl]-5-thio-124
triazolidin-3-ones were (Fig. 11) found to as potential antitumour agents. The
cytotoxicity of 4-propyl-1- [benzimidazole-2’-yl]-5-thio-1, 2,4 triazolidin-3ones were evaluated in culture using KB, Vero and K-562 cell line. A total of
fourteen title compounds were prepared by using three steps reaction. In step 1,
substituted 2-hydrazinobenzimidazoles were prepared by reacting hydrazine hydrate with substituted 2-mercapto benzimidazoles which was treated with
carbonoxysulfide gas in the presence of triethyl amine and benzyl chloride to
produce benzyl-b-[substituted benzimidazole-2’-yl]-thiocarbazinate. The title
compounds were prepared by reacting substituted aryl/ alkyl isothiocyanates52-54.
The cytotoxicity and physical properties of the pyrrolo [1,2-a] benzimidazole
(PBI) and pyrrolo[1,2-a] indole (PI) aziridinyl quinines were compared in order to
assess the influence of the benzimidazole ring on antitumor activity and DNA
reductive alkylation. The benzimidazole ring may provide binding interaction
required for the interaction with DNA55.
logical investigations compounds and were the most significant inhibitors of
LPS-stimulated NO generation from raw murine macrophage 264.7, and, as another result, compounds and had a weak radical scavenging activity against
DPPH radicals. Moreover, and had a concomitant strong cytotoxicity against
both colon carcinoma cells (HCT-116) and hepatocellular carcinoma cells (HepG2) while showed specific cytotoxicity only against colon carcinoma cells58.
In this study, twelve bis-benzimidazole derivatives were synthesized by selecting
di(1H-benzo[d]imidazol-2-yl) methane as the main compound. The numbers of
carbons at 2 positions of bis-benzimidazole derivatives were changed from 1 to 4,
and derivatives were synthesized with methyl substitutions at 5- and/or 6- positions. The compounds were screened via in vitro plasmid superciol relaxation
assays using mammalian DNA topoisomerase I and cytostatic assays were carried
out against HeLa (cervix adenocarcinoma), MCF7 (breast adenocarcinoma) and
A431 (skin epidermoid carcinoma) cells for selected derivatives. Our results suggest that the malonic acid derivatives of bis-benzimidazoles, namely, bis(5-methyl-1H-benzo[d]imidazol-2-yl) methane and bis(5,6-dimethyl-1Hbenzo[d]imidazol-2-yl) methane, were remarkably active compounds in interfering with DNA topoisomerase I and the former compound was also found to be
cytotoxic against MCF7 and A431 cells. The inhibitory effects obtained with
these derivatives are significant as these compounds can be potential sources of
anticancer agents 59,60.
Antihistaminic
A number of benzimidazoles having several substituents on the azole and benzene
nuclei and C-2 (methyl amino ethylenediamine, morpholine, piperazine, piperidines) were prepared regioselective synthesis was designed for the N’-alkyl
substituted benzimidazoles. X-ray structure analysis of (14) was revealed. Compounds were evaluated for their in vitro H1-antihistaminic activity in the isolated
guinea-pig ileum method61. The benzimidazole core of the selective non-brainpenetrating H1-antihistamine mizolastine was used to identify a series of brainpenetrating H1-antihistamines for the potential treatment of insomnia. Using
cassette PK studies, brain-penetrating H1-antihistamines were (39) identified and
in vivo efficacy was demonstrated in a rat EEG/EMG model as shown in Fig. 34.
Further optimization focused on strategies to attenuate an identified hERG liability62 .
N
R1
N
N
H
N
F
A series of 1-cycloalkyl-2-phenyl –1H-benzimidazole-5-carboxylic acid derivatives (38) was synthesized as shown in Fig. 33 and evaluated for inhibitory
activity against HCV NS5B RNA-dependent RNA polymerase (RdRp). A SAR
study was performed and led to identify the 2-[(4-diarylmethoxy) phenyl]-benzimidazole as potent inhibitors. They inhibit subgenomic HCV RNA replication in
the replicon cells at low micromolar concentrations. They are selective against
DNA polymerases and exhibit low cytotoxicity56.
O
N
X
O
N
X = N H 2, O H
39
R 1 = P h , B n , -(C H 2 )2 P h , M e, C H e Y , H , m o rp h o l in y l
F ig . 3 4
Antiasthmatic and anti diabetic
Synthesis of some novel 2-(6-fluorochroman-2-yl)-1-alkyl/acyl/aroyl-1H-benzimidazoles (40) as shown in Fig. 35 by the condensation of O-phenylenediamine
with 6-fluoro-3, 4-dihydro-2H-chroman-2-carboxylic acid and subsequent reactions with different types of electrophiles, have been reported. Some compounds
exhibited promising anti-bacterial activity against salmonella typhimurium; however, they showed poor activity against S.aureus. The biological activity against
PDE IV for potential anti-asthmatic effect and against DP-IV and PTB IB for
potential antidiabetic effects was disappointing63.
N
O
38
F ig . 3 3
N
F
R
Ethyl 6-bromo-3-methyl-1,3-thiazolo[3,2-a]benzimidazole-2-carboxylate was
prepared by the ambient temperature bromination of ethyl 3-methyl-1,3thiazolo[3,2-a] benzimidazole-2-carboxylate . The acid hydrazide was obtained
by the reaction of ester with hydrazine hydrate. Treatment of compound with
benzaldehyde or 2-thiophenaldehyde yielded the corresponding hydrazones and,
respectively, while the reaction of acid hydrazide with ethoxymethylene
malononitrile or with ethyl ethoxymethylene cyanoacetate in refluxing ethanol
afforded pyrazole derivatives and, respectively57. Taken together, from the bio-
R = m e t h yl , e th y l , p r o p y l, n -B u t y l
- c oo - e th y l, - c o o - te r t -B u t yl
40
F ig . 35
Journal of Pharmacy Research Vol.4.Issue 2. February 2011
413-419
Mohd Rashid et al. / Journal of Pharmacy Research 2011,4(2),413-419
Synthesis of a series of novel and functionalized benzimidazole derivatives by the
condensation of OPDA with 4-bromobenzoic acid and subsequent reactions of the
product obtained with phenylacetylene and 6-ethynyl-4,4-dimethylthiochroman
utilising Sonogashira coupling has been reported. The Sonogashira coupling products were then alkylated at the benzimidazole –NH with different electrophilic
reagents leading to functionalized derivatives. All the compounds synthesized
were screened for their potential anti-bacterial, anti-asthmatic and anti-diabetic
properties, which exhibited moderate activities in screening studies in vitro. A
novel series of non-covalent, benzimidazole-based inhibitors of DPP-4 has been
developed from a small fragment hit using structure-based drug design. A highly
versatile synthetic route was created for the development of SAR, which led to the
discovery of potent and selective inhibitors with excellent pharmaceutical properties 64.
Anti-inflammatory
In this study, a novel series of 6-oxopyridazinyl benzazoles and 3, 6dioxopyridazinyl benzazoles were prepared from the starting compounds, 2hydrazinobenzimidazole, 2-hydrazinobenzothiazole and 2-hydrazinobenzoxazole
by reaction with butyric acid derivatives and cyclic anhydrides respectively. The
structures of the new compounds were confirmed by elemental analysis as well as
1
H NMR, IR and MS data. Some of the newly prepared compounds were subjected
to evaluation for their anti-inflammatory activity using carrageenan induced paw
edema at dose 100 mg kg-1 using indomethacin as a reference standard and were
found to be bioactive65.
2-Amino-1H-benzimidazoles and 1,2-dihydro-2-iminocycloheptimidazoles were
synthesized and evaluated for antiinflammatory and analgesic activities. The
compounds in the series were synthesized via phenylthioureas or 2-chloro-1Hbenzimidazole. Most of compounds were synthesized by two methods. One was
the reaction of carbodiimides with 2-amino-2,4,6-cycloheptatrien-1-one. The
other was the reaction of guanidines with 2-chloro-2,4,6-cycloheptatrien-1-one.
Some of the compounds exhibited potent antiinflammatory and analgesic activities when compared to timegadine or tiaramide hydrochloride (HCl) . It was of
interest that 1-(2-benzothiazolyl)-2-cyclohexylimino-1,2 dihydrocyclo
heptimidazole showed superior analgesic activity to timegadine or tiaramide HCl
(ED_<50>=1.7 mg/kg p.o. in the acetic acid-induced writhing test, ED_<30>=14.0
mg/kg p.o. in Randall-Selitto method) in spite of no effect on prostaglandin E_2
synthesis 66.
Angiotensin receptor antagonist
A series of substituted 2-butylbenzimidazoles (41) bearing a biphenyl methyl
moiety at position-1 was prepared via three synthetic routes and evaluated for
angiotensin second receptor activity (in vitro and in vivo) as shown in Fig. 36.
Binding affinity was determined using bovine adrenal cortical membrane. Substitution at the 4-, 5-, 6 positions reduce the affinity relative to that of unsubstituted
compound. However most of the compounds with substitutent at position 7showed binding affinity comparable to that losartan67.
N
Bu
N
CONCLUSION
Benzimidazole nucleus has been reported to possess several medicinal properties
such as antibacterial, antiviral, anticancer, anticonvulsant, antihistaminic,
anthelminitic, antidepressant, antiasthamatic and antidiabetic activity etc. however; more experimental and clinical researchers should be conducted to support
its therapeutic use. In conclusion, synthesis at different position of benzimidazole
makes a wide variety of compounds. Given its broad spectrum of pharmacological
activity benzimidazole presents itself as a novel nucleus.
REFERENCES
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
23.
24.
25.
26.
27.
28.
29.
30.
31.
32.
33.
34.
35.
36.
37.
38.
39.
40.
41.
42.
43.
44.
45.
46.
47.
48.
49.
50.
51.
52.
53.
54.
55.
56.
57.
R1
58.
R 1 = H , 5 -O M e , 6 - O M e , 6 -C l, 5 -C l
41
F ig . 3 6
59.
60.
61.
CHK inhibitor
CHK-1 is one of the key enzymes regulating checkpoints in cellular growth
cycles. Novel 4-(4-aminoalkylamino)-3-benzimidazole-quinolines (42) were prepared and assayed for their ability to inhibit CHK-1 as shown in Fig. 37. These
compounds are potent cell permeable CHK-1 inhibitors and showed synergistic
effect with a DNA-damaging agent, comptothecin68.
62.
63.
64.
65.
66.
67.
68.
R
Data NJ, Parikh AR, Deo K, Bhatt SB. Indian J Pharm Sci. 2003; 65(1): 39-43.
Gilchrist TL. in Hetrocyclic Chemistry. published by Pearson Education Pvt. Ltd, vol III, 2005,
p.315.
Pandey VK, Gupta M. Indian Drugs. 1995; 33(2): 57-60.
Hobreckerf, Ber. 1872; 6: 920.
Fischer O. Ber. 1889; 23: 645.
Vanagsg and Dombrowsak. I, Ber. 1942; 76B: 82.
Cirulisa and Straumanmis. J prakt Chem. 1943; 162: 307-28.
Bambergeer and Berlb B. Ann. 1893; 273: 360.
Gerngros OS, German patent 282, 491. Chem Zentr. 1915; 88.
Hellerg. Ber. 1904; 37: 3116.
Bambergeer and Lorenzejn. Ann. 1893, 273, 287, 289.
Fischer O. J Prakt Chem. 1924; 107(2): 1649.
BlocIi J J, J Soc Chem Ind. 1919; 38: 118.
Hartmanmn and Panizzoln. Helv Chim Acta. 1938; 21: 1692.
Wasere and Gratsosa. Helv Chim Acta. 1928; 11: 952.
Weidenhagern and Wegnerh. Ber. 1938; 71B: 2129.
Gerngros OS. Ber. 1913; 46: 1913.
Wolff L. Ann. 1913; 399: 297.
Baczy KI, Niementowsks I, Bull Acad Sci Cracow. 1902; 421, Chem Zentr. 1902; 73: 940.
Bistrzyckai and Lrzeworsk G. Ber. 1912; 46: 3489.
Bambergeer and Berle B. Ann. 1893; 273: 333.
Reisserta and Goll G. Ber. 1905; 38: 102.
Copelandr AB, Daya R. J Am Chem Soc. 1943; 66: 1072.
Manuellci, Recchiv. Chem Zentr. 1900; 71(11): 1207.
Streitwolkf, Fehrlae and Herrmanwn. U. S. patent 1, 919, 579. Chem. Abstracts 27, 4817 1933.
Fichterf. J Prakt Chem. 1906; 74 (2): 326.
Everettj G, J Chem Soc.1930; 240: 2.
Pierronp, Ann chim phys. 1908; 16(8):194. Chem Zentr. 1908; 79(11): 1586.
Pellizzagri and Gaitera, Gaza chim ital. 1918; 48(11): 151. Chem Abstracts. 1919; 13: 1584.
Bambergeer. and berlb. B. Ann. 1893; 273: 323.
Copelandr AB, Daya R. J Am Chem Soc. 1943; 66: 1072.
Andrew T, Athanasia V. Arzeim-Forsch/Drug Res. 1997; 47(1): 307.
Bahadur S, Goel AK, J Ind Chem Soc. 1976; L-III: 1163.
Mane DV, Shinde DV, Thore SN, Shingare MS. Indian J Chem. 1995; 34B: 917.
Data NJ, Parikh AR, Deo K, Bhatt SB. Ind J Pharma Sci. 2003; 65(1): 39.
Brde AR, Khadse BH, Sobade AS. Indian Drugs. 1998; 35(9): 554.
El-Masry AH, Fahmy HH, Molecules. 2000; 5: 1429.
Salgaonkar PD, Velingkar VS. Indian Drugs. 2001; 38(1): 32.
Arjmand F, Mohini B, Eur J Med Chem. 2005; 40: 1103.
Altintas H, Ates O, Ayse K. Ind J Chem. 2005; 44B: 585.
Verma RS. J Ind Chem Soc. 1977; LIV: 727.
Kirti H, Srivastav S. Indian Drugs. 1994; 31(8): 378.
Sandera G, Lsensee RW, J Am Chem Soc. 1954; 76: 5173.
Varma RS, Singh VJ. J Ind Chem Soc. 1979; LXII: 1985.
Pandey VK, Gupta M, Indian Drugs 1995; 33(2): 57.
Mane DV, Shinde DV, Thore S N, Shingare MS. Ind J Chem.1995; 34B: 917.
Paramar SS, Mishra RS, Chaudhary A. J Pharma Sci. 1972; 61(8): 1322.
Singh JM. J Med Chem. 1970; 13: 1018.
Singh JM. J Med Chem.1969; 12: 962.
Zhang Y, Taiwei C, Zhi Y. Bioorg Med Chem Letters 2006: 16: 1831.
Magdum CS, Shirodkar PY, Pannikar KR. Indian Drugs. 2000; 37(11): 528.
Ramesh CB, Edward BS. J Med Chem. 1994; 37: 1625.
Tomio I, Takayoshi S, Shintaro H, Kenji M. Bioorg Med Chem. Letters. 2006; 16:1859.
Keiji K, Yoshiyoki I. J Med Chem. 1993; 36(12): 1772.
Sen AB, Arora SL. Heterocycles. 1999; 51(11): 2561.
Kumar BVS, Sanjay DV, Ramnathan VK. Eur J Med Chem. 2006; 41: 399.
Hatem A, Abdel A, Amira M, Gamal E, Nehal A, Hamdy IM, Fakhr I. Archive der pharma,
2009; 230.
Canan K, Ayhan K, Gulgun, Tuncbilek, Meral, Altanlar, Nurten, Coban, Tulay, Can-Eke,
Benay, Iscan, Mumtaz, Letters in Drug Design and Discovery. 2009; 6: 374.
Alpan SA, Zencir S, Zupk I, Coban G, Réthy B, Gunes HS, Topcu Z, J Enzy Inh Med Chem.
2009; 24:1475.
Coon T, Wilna J, Moree, Binfeng L, Jinghua Y, Kord SZ. Bioorg Med Chem Letters, 2009;
19(15): 4380.
Cañetea R, Escobedob AA, Almirallc A, Gonzálezd ME, Britoe K, Cimermanf S. Transaction
of The Royal Society of Tropical Medicin and Hygiene. 2009; 103: 437.
Keiji K, Yoshiyoki I. J Med Chem. 1993; 36(12): 1772.
Ivana S, Katarina M, Anahi M, Ariel MS, Ivo P, Miroslav B, Ljubica GO. Bioorg Med Chem.
2009; 17:2544.
Refaat, Hanan M, Khalil, Omneya M., Abuel M, Suzan M. J Chem Resear. 2009; 7: 448.
Kiyoshi T, Shinji S, Takotoma O, Chem Pharma Bull. 1993; 41: 301.
Vinodkumara R, Vaidyaa SD, Kumara BVS, Bhisea UN, Bhiruda SB, Mashelkar UC. Euro
J Chem. 2008; 43(5): 986.
Wallace MB, Feng J, Zhang Z, Skene RJ, Shi L, Caster CL, Kassel DB, Rongda XG, Stephen
L. Bioorg Med Chem Letters. 2008; 18 (7): 2362.
Zhi JN, Paul B, Nathan B, Anthony D. Bioorg Med. Chem. Letters. 2006; 16: 3121.
H
N
Source of support: Nil, Conflict of interest: None Declared
N
N
H
O
42
R = N H 2 , O H , N E t2
F ig . 3 7
Journal of Pharmacy Research Vol.4.Issue 2. February 2011
413-419