pharmacological evaluation of benzimidazole derivatives...
TRANSCRIPT
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
2526 S. M. Abu-Bakr et al.
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].
Pharmacological activity evaluation of potential benzimidazole derivatives 2527
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
2528 S. M. Abu-Bakr et al.
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.
Pharmacological activity evaluation of potential benzimidazole derivatives 2529
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
2530 S. M. Abu-Bakr et al.
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
Pharmacological activity evaluation of potential benzimidazole derivatives 2531
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
2532 S. M. Abu-Bakr et al.
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
Pharmacological activity evaluation of potential benzimidazole derivatives 2533
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
2534 S. M. Abu-Bakr et al.
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)
Pharmacological activity evaluation of potential benzimidazole derivatives 2535
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].
2536 S. M. Abu-Bakr et al.
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
Pharmacological activity evaluation of potential benzimidazole derivatives 2537
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].
2538 S. M. Abu-Bakr et al.
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
Pharmacological activity evaluation of potential benzimidazole derivatives 2539
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
2540 S. M. Abu-Bakr et al.
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].
Pharmacological activity evaluation of potential benzimidazole derivatives 2541
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].
2542 S. M. Abu-Bakr et al.
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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