pharmacological evaluation of benzimidazole derivatives...

Pharmacological evaluation of benzimidazolederivatives with potential antiviral and antitumoractivity

Sherifa M. Abu-Bakr • Fatma A. Bassyouni •

Mohamed Abdel Rehim

Received: 29 February 2012 / Accepted: 19 April 2012 / Published online: 11 May 2012

� Springer Science+Business Media B.V. 2012

Abstract In recent years the synthesis of benzimidazole and its derivatives has

attracted the attention of many organic chemists because of the compounds’

interesting biological activity and the crucial importance of the benzimidazole unit

in the function of these biologically important molecules. Benzimidazole-based

polyheterocyclic compounds have several interesting biological properties. Simple

synthetic strategies leading to benzimidazole-based fused polyheterocyclic systems

and the antiviral and anticancer biological activity of the compounds are surveyed in

this review article.

Keywords Benzimidazole derivatives � Combinatorial synthesis �Microwave-assisted synthesis � Heterocycles � Topoisomerase inhibitors �Protein kinase inhibitor � Antitumor � Antiviral

Introduction

Many important drugs with different therapeutic application contain the benzimid-

azole ring [1, 2], for example proton pump inhibitors (omeprazole), antihypertensives

(candesartan, telmisartan), antihistamines (astemizole), antihelmintics (albendazole,

mebendazole), and several other kinds of therapeutic agent which are still under

S. M. Abu-Bakr

Department of Chemistry of Natural and Microbial Products, National Research Centre,

12622 Cairo, Egypt

F. A. Bassyouni (&)

Department of Chemistry of Natural and Microbial Products and Pharmaceutical Research,

Center of Excellence for Advanced Sciences, National Research Centre, 12622 Cairo, Egypt

e-mail: [email protected]

M. A. Rehim

Department of Analytical Chemistry, Stockholm University, 10691 Stockholm, Sweden

123

Res Chem Intermed (2012) 38:2523–2545

DOI 10.1007/s11164-012-0569-y

investigation, including antitumor and antiviral derivatives [3, 4]. In addition, the

benzimidazole moiety is a structural isostere of naturally occurring nucleotides;

hence, it has been extensively utilized as a drug scaffold in medicinal chemistry. The

connection between a wide range of biological activity and compounds containing the

benzimidazole nucleus is well documented in the literature. Benzimidazole deriva-

tives have much interesting pharmacological activity including antiviral, antitumor,

antihypertensive, proton pump inhibitory, antimicrobial, and anti-inflammatory

activity. Many publications have covered the synthesis, structure, reactivity, and

biological activity of benzimidazole derivatives [5, 6].

General scope for synthesis of benzimidazole derivatives

From o-phenylenediamine derivatives with carboxylic acids

o-Phenylenediamines react with most carboxylic acids to give 2-substituted

benzimidazoles in good yield. This reaction is carried out by heating the reactants

together on a steam bath, or under reflux, or in a sealed tube [7–10]. An important

modification of the reaction of o-phenylenediamines with different carboxylic acids

forms benzimidazoles.

NH2

NH2 N

N

R`

H

R`COOH 2H2O+

+

12 3

R R

The mechanism of condensation of o-phenylenediamine with organic acids, and

the catalytic role of mineral acid, was explained as:

O

OH

R`

H2N

H3N

..

NH2

NH3

OHHOR

+R

N

N

H

R`

H

- H2O

+

2R

R

+H

+

+

- H +

+OH

OH

R`

OH

OH

R`

+

2524 S. M. Abu-Bakr et al.

123

It has been reported that the tri-substituted benzimidazole 10 can be synthesized

by reaction of a substituted aniline with acid chloride derivatives [11].

CF3

NH2

NCCL

O

NO2

F

O

NO2

F

CF3

NH

NC

DMA/rt,

4h

4- F-benzylamine

DIPEA/ DMF,rt. 4h

+

O

NO2

NH

CF3

NH

NC

F

O

NH2

NH

CF3

NH

NC

F

NH4Cl

IPA, 70 C, 6h0

2,4-dichlorobenzoylchloride, TEA, MDC

rt. 3h

O

NH

CF3

NH

NC

F

NH

O

Cl Cl

AcOH

90 C0

O

CF3

NH

NC

N

N

F

Cl

Cl

4 5 6

7 8

9

10

, 8h

From o-phenylenediamine derivatives with acid anhydrides

Depending on the conditions used, reaction of acid anhydrides and o-phenylenedi-

amines leads to the formation of benzimidazole derivatives 11. Time is very

important factor, and after heating under reflux for long time, benzimidazole

derivative 11 is formed. For example, when o-phenylenediamine was heated under

reflux for several hours with acetic anhydride; 2-methylbenzimidazole was obtained

in a good yield [12].

NH2

NH2N

N

CH3

H

2(CH3CO)2O 3CH3COOH+ +

1 11

From o-phenylenediamine derivatives with esters

Reaction of o-phenylenediamine with esters forms benzimidazoles [13]. For

example, condensation of 1,2-phenylenediamine-5-methylcarboxylate 12 with ethyl

cyanoacetate 13 gave methyl-2-(cyanomethyl)-1H-benzimidazol-5-carboxylate 14[14]. However, this method has not been used frequently for the synthesis of

benzimidazoles because of the low yield of the product.

Pharmacological activity evaluation of potential benzimidazole derivatives 2525

123

Reaction of 1,2-diamino-4,5-difluorobenzole 15 with cyano acetic ether produced

5,6-difluoro-2-cyanomethyl-1H-benzimidazole 16 [15].

NH2

NH2

F

F NH

N

CN

F

F

15 16

O O

OC2H5CN+

From o-phenylenediamine derivatives with amides

A few amides, for example urea and thiourea, have been used for the synthesis of

benzimidazoles 18; good yields are usually obtained [16].

NH2

NH2

O2N

N

N

H

OH

O2N

+

NH2H2N

O

2NH3+

17 18

From o-phenylenediamine derivatives with cyanogen bromide

Cyanogen bromide reacts with o-phenylenediamines to form 2-aminobenzimidaz-

oles 19 in good yield [17–19].

NH2

NH2N

N

NH2.HBr

H

BrCN+

191

R R

From o-phenylenediamine derivatives with nitrile derivatives

Nitriles, when reacted with o-phenylenediamine hydrochloride, give 2-substituted

benzimidazoles 20 [20]. This reaction proceeds under acidic conditions and

probably involves hydrogen-ion catalysis.

NH2

NH2

O

MeOCNCH2COOC2H5

NH

N

CN

O

MeO

+

12 13 14


123

NH2

NH2

NH2

NH2 R

NH

Cl

NH2.HCl

NH

NH

R

.HCl + RCN

NH

N

R+

+ NH4Cl

20

1

From o-phenylenediamine derivatives with aldehydes

Under specific conditions, aldehydes react with o-phenylenediamines to produce

2-substituted benzimidazole derivatives, for example compound 23 [21–23].

The reaction is performed under oxidizing conditions, and may be achieved by

use of air or other oxidizing agents, for example cupric acetate or p-benzoquinone

[24].

NH2

NH2

N

NH

NO

H NH

N N

N

NH

+p-benzoquinone

21 22 23

From o-phenylenediamine derivatives with ketones

Reaction of o-phenylenediamines with ketones has been investigated [15, 25].

NH2

NH2

R`COR``N

N

H

H

R`R``

N

N

R`

H

+

R``H

N

N

R``

H

+

+

R`H

24 25

26

27

1

By reaction of mono and diacyl-o-phenylenediamine derivatives

Monoacyl-o-phenylenediamines are probably involved as intermediates in the

synthesis of benzimidazole derivative 29 from o-phenylenediamines and organic

acids and related compounds.

A relatively large number of monoacyl and diacyl-o-phenylenediamines have

been converted to benzimidazole derivatives 29 by use of dilute (approx 4N)

hydrochloric acid, the general method of Philips [25].


123

Miscellaneous synthesis

Microwave synthesis

Some novel 1,3-diarylpyrazino[1,2-a]benzimidazole derivatives have been synthe-

sized by use of microwave irradiation [26, 27] as a facile synthetic method.

30

31

NH

N

O

Cl

R

K2CO3/CH3COCH3NH

N

O

R

N

N

O

R

O

R R

NR

N

NCH3COONH2/CH3COOH

H, CH3, OCH3

TEA, pyridine, rt

stirr. rt

MW/2min.(850W

+w- Br- acetophenon deriv.

32

33 34

R=

Tetracyclic benzimidazole derivatives 37 have been synthesized by condensation

of 2,3-pyrazinedicarboxlic acid 35 with o-phenylenediamine derivatives in 1:1

molar ratio. The mixture was irradiated in a microwave oven for 4–6 min at a power

level of 850 W [28].

N

N COOH

COOH H2N

H2N

+N

NN

N

O R

R

35 36 37

MW

R=O,P –CH3

NH2

NH

O

NO2NO2

N

N

H

H+

28 29


123

Combinatorial synthesis

Combinatorial chemistry has recently been for preparation of benzimidazole

derivatives with increasing diversity [29–31]. For example: 2-alkylthio-5-carba-

moylbenzimidazole 44 has been synthesized by use of solid-phase combinatorial

chemistry:

O

N

HF

NO2

NH2

O

N

HNH

NO2

R`O

N

HNH

NH2

R`

O

N

H N

N

S

H

R`O

N

H N

N

S

R`

R

O

NH2

N

N

S

R`

R

ab

c d

fe

3839 40

41 42

43 44

Reagents and conditions: (a) 4-F,3-NO2-PhCO2H/HATu/DIEA/DMF. (b) R0NH2/

DMF. (c) SnCl2�H2O/DMF. (d) TCD/THF. (e) RCH2Br/DIEA/DMF. (f) TFA/H2O

(95:5).

Liquid-phase combinatorial chemistry has enabled efficient synthesis of substi-

tuted benzimidazolone derivative 49 [31]:

O

O

F

NO2

O

ONO2

NH

R

O

ONH2

NH

RO

O

N

N

H

R

O

O

OCH3

N

N

H

R

O

a b

cd

4546 47

48 49

Reagents and conditions: (a) RNH2/CH2Cl2/rt/1 h. (b) Zn/NH4Cl/CH3OH/rt/3 h.

(c) triphosgene/Et3N/CH2Cl2/rt/8 h. (d) 1 % KCN/CH3OH/rt.


123

Applications of benzimidazole derivatives as antiviral and anticancer drugs

This review covers literature reports of the antiviral and antitumor activity of some

benzimidazole derivatives.

Antiviral activity

Benzimidazoles are remarkably effective at inhibiting virus activity. The antiviral

properties of benzimidazole derivatives have been reported in a variety of studies

using different virus strains, for example human immunodeficiency virus (HIV)

[32–34], hepatitis C virus (HCV) [35–42], human cytomegalovirus (HCMV)

[43–45], and herpes simplex virus-1 (HSV-1) [46]. Tonelli et al. [4] reported

synthesis of seventy-six 2-phenylbenzimidazole derivatives and their evaluation in

cell-based assays for cytotoxicity and antiviral activity against ten RNA and DNA

viruses. Among the antiviral benzimidazoles, 2-aryl/hetero aryl benzimidazole

derivatives have important activity against Coxsackie virus B3 or against specific

hepatitis C virus enzymes.

NH

YX

NH

N

O R

N

NR1

O

X= N, Y= CN: R= H, 2-Me, 3-Br,

X= CH, Y=N: R=H, 2-F

(COXSaKie Virus B3

heteroary

Heteroaryl= furan-3-yl; pyridin-2-yl

HCVNS5Bpolymarase( )

R1= OH, NH R2

)

50 51

Tewari et al. [47] reported the screening of benzimidazole derivatives 52a–c and

53a, b against tobacco mosaic viruses and sun hemp rosette viruses.

N

N

R

R1

N

N

R3

R2

R2= -C6H5Cl

R3= C2H4COOH(a)

R3= - C6H4OH(O)(b)

R1= C7H7, R= - C2H4COOH(a)

52

- CH=CHC6H5(c)

C6H4OH(o)(b)

53


123

Several new benzimidazole-coumarin conjugates inhibit HCV replication; for

example, compounds 54a, b have significant EC50 values of 3.4 and 4.1 lM,

respectively [35].

A series of 1-cycloalkyl-2-[(4-diarylmethoxy)phenyl]-benzimidazole-5-car-

boxylic acid derivatives have been reported to have inhibitory activity against

hepatitis C virus NS5B RNA-dependent RNA polymerase (HCV, NS5B, RdRp).

For example, compounds 55a, b had significant RNA polymerase inhibitory

activity; selective activity against DNA polymerases, with low cytotoxicity, were

also observed [36].

N

N

X

O

HOOC

Ar2

Ar1

55, a: X= H

b: X= F

Ar1, Ar2= C6H5, 4-MeC6H4, 4-ClC6H4, 4-FC6H4, 3-FC6H4.

A newly investigated series of benzimidazole derivatives bearing a

di-arylmethylene group have been tested for their inhibitory activity against

HCV, NS5B, and RdRp. Compound 56 (JTK-109) was discovered to have a

favorable pharmacokinetic profile—high selectivity for NS5B polymerase and a

good safety profile—in addition to potential as a clinical candidate for treatment

of hepatitis C [37–39].

N

NS

O

O

BrR

OAcO

OAc

OAc

OAc

54a,b

a: R=H

b: R=F


123

A series of benzimidazole-5-carboxylic acid derivatives have been discovered

which specifically inhibit HCV, NS5B, and RdRp. Compound 57 is regarded as one

of the most potent compounds of this series [40].

N

NHOOC O

57

Optimization of a previously discovered series of substituted-5-carboxybenzi-

midazole, by replacement of the ionizable carboxylic acid with a neutral substituent,

modified their physicochemical properties and hence increased their cellular

permeability. Compound 58 had improved cell culture activity and was not

cytotoxic to the host cells [41–43].

N

N

O

NH

NH

OH

S

N

O

58

2-Bromo-5,6-dichloro-1-(b-D-ribofuranosyl)benzimidazole (BDCRB), 59a and

its 2-chloro analog (TCRB), 59b, have been reported to be potent and selective

inhibitors of HCMV replication. However, these compounds were found to have

low in-vivo activity because of rapid metabolic cleavage of the glycosidic linkage at

the 1-position [44].

N

N

F

O

NO

HOOC

Cl

56

JTK-109


123

Efforts made to overcome this limitation led to the discovery of compound 60, Maribavir,

(GW1263W94),oneof themostpromisinganti-HCMVdrugs inclinical development. Ithas

advantages over otheranti-HCMVdrugs in its in-vitro potency, bioavailability, safety profile

in acute, chronic, and genetic toxicology testing, and the lack of cross-resistance inherent in

its novel mechanism of action which involves inhibition of viral DNA synthesis [45].

N

NCl

Cl

NH

CH3

CH3

O

OH OH

OH

60 Maribavir (GW1263W94)

Several benzimidazoles nucleosides and acyclonucleosides have been studied to

assess their antiviral activity against HCMV and HSV-1. Only the 2-thiobenzyl

analogues 61 and 62 had high activity, confirming the favorable effect of the

thioether linkage at the 2-position on antiviral activity [45].

N

NCl

Cl

ClO

OH OH

OH

N

NBr

Cl

ClO

OH OH

OH

59a 59b

BDCRB TCRB

N

NS

OOH

OHOH

Cl

Cl

N

NS

OOH

Cl

Cl

61 62

63, a: Ar = C6H5

b: Ar = o-F-C6H5N

N N

O NH

Ar

H

63


123

A series of 2-pyridyl-1H-benzimidazole-4-(N-substituted-carboxamide) deriva-

tives have excellent inhibitory activity against Coxsackie virus B3. Compounds 63a,b were found to be more active than ribavirin [46].

Pyrido[1,2-a]benzimidazoles 64–66 have been screened on a culture of Vero

cells for cytotoxicity and for antiviral activity against ortho-pox viruses which are

pathogenic to humans [47].

N

NF

F

O OR

OH

CN N

NF

F

CH3

N

CN

N

NF

F

OH

CN

O

R=C2H5(a), CH3 (b) R1= (CH2)5CH3(a)

C6H4N(CH3)2(c)=

=

64 65

R1

OMe

66

A series of 2-aryl-1H-benzimidazole-4-(NR2-carboxamide) derivatives 67 have

been designed and synthesized. They had inhibitory activity against CVB3. Ribavirin

(RBV), a nucleoside analogue virustatic drug was used as positive control. These

compounds were significant because their IC50 values ([350 lg/mL) showed they

were more active than RBV [48].

N

NR1

H

O NH

R2

N

N

OH

F

N

R1=

O ONO2

, ,

, ,

,

R2= ,

H

H

H

OH

HOH

NO2

H

H

H

OH

HH

Cl

,

,

67


123

Study of the antiviral activity of 2-substituted-5–amidino-benzimidazoles

revealed that compounds with a pyridine moiety at C-2, e.g. 68, had the most

distinct and selective activity against Coxsackie viruses and echoviruses. Com-

pounds 68 and 69 also had strong activity against adenoviruses [24].

NH

N NNH

NH

NH

N N

CH3NH

NH2

6869

1-Cyclopropyl-1,3-dihydro-3-[[1-(4-hydroxybutyl)-1H-benzimidazol-2-yl)methyl]-

2H-imidazo[4,5-c]pyridin-2-one, (BMS-433771), 70, has been identified as potent

respiratory syncytial virus (RSV) inhibitor with good oral bioavailability [49–52].

N

NN

O

N

N

OH

70

(BMS-433771)

The benzimidazole derivative 71 (JNJ 2408068) was been discovered to have

inhibitory activity against RSV at nanomolar concentrations, so its activity is

approximately 100,000 times better than that of ribavirin [53].

N

NNH

N

NH2

NMe

OH

Me

71

(JNJ 2408068)


123

Recently, 2,6-dihalophenyl-substituted-1H,3H-thiazolo[3,4-a]benzimidazoles (TBZs)

have been tested against enteroviruses. Structure–activity relationship analysis

revealed that the presence of a substituent at position 6 of the tricyclic system

positively affected antiviral activity whereas substitution at position 7 was less

beneficial. Hence, compound 72 had selectivity comparable with that of enviroxime

but was not cytotoxic at high concentration [54].

N

NS

F

Cl

CH3

4

5

67

72

Antitumor activity

Several promising antitumor agents contain the benzimidazole ring system. They

exert their antitumor activity by acting mainly as topoisomerase inhibitors [55] and

as antiangiogenic agents [56–61].

Topoisomerase inhibitors

Topoisomerases are enzymes that regulate DNA topology by successive cleavage-

regulation reactions; hence, they represent an effective pharmacological target for

the development of cancer chemotherapeutics [62].

It has been demonstrated that several bi and ter-benzimidazole derivatives act as

topoisomerase I inhibitors. For example, Hoechst 33342 (73a) and Hoechst 33258

(73b) bind to the minor groove of DNA, trapping the reversible complex derived

from DNA and topoisomerase I and causing a limited number of highly specific

single strand DNA breaks. However, Hoechst 33342 (73a) was not effective against

tumor cell lines which over-express multi drug resistance (MDR1). Among the

several bis-benzimidazoles which have been synthesized to overcome this limitation

of Hoechst 33342, compound 74 has significant similar cytotoxicity against variants

of human tumor cells that either over-express MDR1 or are camptothecin-resistant

[60].


123

A series of N-aminomethyl-1H-benzimidazole-5-carboxylic acid derivatives 75a–dand their derivatives with the ligand 1-(5(or 6)-carboxy-1H-benzimidazol-2-

ylmethyl)pyridinium chloride have been synthesized. New benzimidazole complexes

76, 77 with Cu2? were also prepared and their inhibition of the growth of 21 human cancer

cell lines was studied [63]; in a relaxation assay, compound 77 inhibited topoisomerase

activity at a concentration a factor of 10 lower than that of other toposides.

N

N

N

N

O

HH

R

NNCH3

73

(Hoechst 33342) 73a: R=C2H5

(Hoechst 33258) b: R=H

N

N

N

N

O

HH

CH3

n(H2C)NCH3

CH3

n = 0-3

74

N

N NHAr

OH

O

Ar= pyrid-4-yl

= pyrid-2-yl

= thiazo-2-yl

= benzimidazol-2-yl

N

N

OH

O

H

N

Cl-

+

N

N

OH

O

N

Cl-

+

CuCl

Cl

75a-d

76 77


123

Antiangiogenic agents

Angiogenesis, the formation of new blood vessels from existing vasculature, is

regarded as a critical aspect of the growth and metastasis of solid tumors. Growth

factors including vascular endothelial growth factor, fibroblast growth factor, and

platelet-derived growth factor are regarded as the most important positive regulators

of angiogenesis. Hence, inhibitors of these growth factors and their tyrosine kinase

receptors, including platelet-derived growth factor receptor (PDGFR) and insulin-

like growth factor receptor-1 (IGF-1R), have been of interest as potential anticancer

drugs [62].

New classes of 1-phenylbenzimidazoles have been reported to be selective

inhibitors of PDGFR. Structure–activity relationship studies revealed that

substituents in the 5 or 6 position, only, enhanced activity. For example, the

5-OMe derivative 78a was found to be the most potent and the most PDGFR-

selective. Analogues bearing solubilizing cationic groups at this position,

e.g. 78b, had threefold greater potency than 78a while retaining good selectivity

[55].

N

NR

78a,ba, R= OMeb,R=O(CH2)3NMe2

When a series of 3-(1H-benzo[d]imidazol-2-yl) pyridin-2(1H)-ones were

synthesized and tested for inhibitory activity against IGF-1R, compounds 79–82had potent cytochrome P450 (CYP) inhibition profiles. Results indicated the

pendant imidazole was primarily responsible for potent (CYP) inhibition.

Replacement of this moiety with other groups, for example imidazoline in

compound 82, resulted in greater separation of IGF-1R activity from (CYP)

inhibition [64].


123

Compound 83 (BMS-536924), which contains a morpholino group at the

5-position, was synthesized and found to be a novel small molecule inhibitor of

IGF-1R with cellular and in-vivo antitumor activity [65, 66].

N

NH

NH

N

O O

NH

OH

Cl

83

(BMS-536924)

Protein kinase inhibitors

Protein kinase inhibitors have been found to inhibit tumor metastasis and slow

cancer growth, hence, they have been extensively utilized as therapeutic agents for

treatment of cancer [67].

N

NHN

N

NHO

NH

N

N

NHN

N

NHO

NH

OH

79 80

N

NHN

N

NH

O

NH

Cl

OH

N

NH

N

N NH

O

NH

OHCl

8281


123

Upon optimization of protein kinase CK2 inhibitors derived from 4,5,6,7-

tetrabromobenzimidazole, compounds 84a, 84b, 84c, and 85 congeners were found

to be the most efficient inhibitors [56, 57].

NH

NN

R1

Br

Br

Br

Br

R2 NH

N

Br

Br

Br

Br

SCH3

84 85

84, a: R1=H, R2=H

b: R1=H, R2=C3H7

c: R1=CH3, R2=CH3

(4-Aryloxy)-2-phenylbenzimidazoles have been discovered to be another inter-

esting series of protein kinase inhibitors. Compounds 86a–d are potent inhibitors of

checkpoint kinase (chk2) [58–60].

NH

NO

O

R1

R286

90 a: R1= NH2, R2= H

b : R1= OH, R2= H

c: R1= NH2, R2= Cl

d: R1= OH, R2= Cl

A novel class of urokinase inhibitors containing the 2-aminobenzimidazole

moiety, e.g. 87a, b, have been identified. The inhibitory potency of this family of

inhibitors was similar to that of compounds containing a guanidine or amidine

group. However, they were improved for pharmacokinetic properties which could

increase their bioavailability [24].

NH

NNH2

RO

87a: R=H

b: R=CH3


123

Miscellaneous antitumor agents

A series of 3,4-dihydrobenzo[4,5]imidazo[1,2-a]pyrimidine derivatives have been

synthesized and evaluated for their anti-neoplastic activity. They had different

activity against a variety of cell lines [68].

N

NN

CHO

N

N CH3

X

N

NN

Cl

X

CHO

88 a: X= H 89 a: X= H

b: X= NO2 b: X= NO2

c: X= OCH3 c: X= OCH3

Recently, the 5,6-dichlorobenzimidazole scaffold has been discovered to be a

potent and selective androgen receptor antagonist. For example, compounds 90–93were synthesized and were significantly more potent than bicalutamide in both

immature and mature rat models [69–71].

NH

N

CF3

OHCl

Cl NH

N

CF3

OHCl

Cl

OH

90 91

NH

N

CF3

Cl

Cl

OH

N

N

CF3

Cl

Cl

OH

Br92 93

Benzimidazole derivatives containing the styryl sulfone moiety at the 2-position

have been tested for their anti-proliferative activity. Compound 94 was synthesized

and was highly efficacious against HT-29 human carcinoma, inhibiting tumor

growth by 51 % at low micromolar concentrations [72].


123

NH

N

SOHO

O

94

A series of 2-methyl-5(6)-nitro-1H-benzimidazole derivatives have been synthe-

sized and evaluated for their cytotoxic activity against breast cancer (MCF7).

Compounds 95 and 96 had good cytotoxic activity [73].

NH

NCH3

O2N

N

NCH3

O2N

S

NNH3C-CO-H2C-S

9596

A series of 2-(1-benzyl-2-methyl-1H-benzimidazol-5-ylimino)-3-(substituted)-

thiazolidin-4-ones have been synthesized and evaluated for their inhibitory activity

against Burkitt’s lymphoma promotion. Compounds 97a, b had high inhibitory

activity [74].

N

NCH3

NS

NR

O

97 a- R=C6H5CO.

b- R=p-OCH3-C6H4.

Compounds 98–100 were synthesized and had high cytotoxic activity against

non-small-cell lung cancer and breast cancer [75].


123

NH

NCH3

NN

N

NH

CH3

CH3

NH

NCH3

NN

N

O

CH3

CH3

98 99

N

NCH3

NH

NH

S

100

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