Synthesis, characterization of some benzazoles bearing pyridine moiety: Search for novel anticancer agents

Article abstract of DOI:10.1016/j.ejmech.2011.05.075

Thirteen novel benzazole derivatives were synthesized as possible anticancer agents. The first intermediate 1,3-benzothiazol-2-ylacetonitrile (2) was synthesized via cyclodeamination reaction of o-aminothiophenol (1) with malononitrile. Also, the second i

Full text of DOI:10.1016/j.ejmech.2011.05.075

European Journal of Medicinal Chemistry 46 (2011) 4025e4034
Contents lists available at ScienceDirect
European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Original article
Synthesis, characterization of some benzazoles bearing pyridine moiety:
Search for novel anticancer agents
Heba S.A. Elzahabi
Department of Pharmaceutical Chemistry, Faculty of Pharmacy (Girls), Al-Azhar University, Cairo, Egypt
a r t i c l e i n f o
a b s t r a c t
Article history:
Thirteen novel benzazole derivatives were synthesized as possible anticancer agents. The first inter-
mediate 1,3-benzothiazol-2-ylacetonitrile (2) was synthesized via cyclodeamination reaction of o-ami-
nothiophenol (1) with malononitrile. Also, the second intermediate 5,6-dimethyl-1H-benzimidazol-2-
ylacetonitrile (10) was afforded via cyclocondensation reaction between 4,5-dimethyl-1,2-
phenylenediamine (9) and ethylcyanoacetate. Nucleophilic reaction of benzimidazolyl NH of
compound (10) with ethylcyanoacetate afforded benzimidazolyl-3-oxopropanenitrile (11). On the other
hand, methylenation of CH2 function of compound (10) with dimethylformamide/dimethylacetal affor-
ded benzimidazolylprop-2-enenitrile 12. The synthesis of benzothiazoylpyridines 5a,b and 8a,b as well
as benzimidazolylpyridines, 14a,b and 17aed was carried out through Michael addition of compounds 2
or 10 with arylidenemalononitriles 3a,b and 4aed. The combination of pharmacophoric anticancer
moieties, pyridine and benzazoles was the base on which target compounds 5a,b, 8a,b,14a,b and 17aed were
designed. Among the synthesized compounds, four derivatives 10 and 17bed were selected by National
Cancer Institute (NCI), USA to be screened for their anticancer activity at a single high dose (10ꢀ5 M)
against a panel of 60 cancer cell lines. Compound 17b 4-[p-chlorophenyl]pyridine and 17d 4-[p-
methoxyphenyl] pyridine exhibited a broad and moderate antitumor activity against 41 tumor cell lines
belonging to the nine subpanels employed and are selected for further evaluation at five dose level
screening.
Received 8 April 2011
Received in revised form
28 May 2011
Accepted 31 May 2011
Available online 12 June 2011
Keywords:
Benzothiazoles
Benzimidazoles
Michael addition
Anti-tumor activity
Ó 2011 Elsevier Masson SAS. All rights reserved.
1. Introduction
benzimidazoles are well known for their antimicrobial [5e9]
anthelmintic [10] antiviral [11e14] and antifungal [15e19] activi-
Benzimidazole derivatives have provided a large number of
biologically active compounds that have been intensively used in
medicinal chemistry as drugs. They are structural isosteres of
naturally occurring nucleotides, which allow them to interact easily
with the biopolymers of the living system and different kinds of
biological activity have been obtained. Some 2-aminoben-
zimidazoles displayed an appreciable antimicrobial effect. Their
corresponding carbamate derivatives have been synthesized for
their significant in vivo antifilarial activity [1].Concerning the high
affinity that they display towards a variety of enzymes and protein
receptors, they could be considered as pivotal structures in drug
design [2]. Optimization of benzimidazole-based structures has
resulted in marketed drugs e.g. Omeprazole [3] and Pimobendan
[4] that are therapeutically useful in the management of peptic
ulcer and congestive heart failure respectively. Many derivatives of
ties. The antifungal agent benomyl was firstly reported as a fungi-
cide against a wide range of agriculture fungal disease [20]. Many
years later, it was proved to be a potent antiproliferative agent
against Hela cancer cell line and could be used as adjuvant in cancer
chemotherapy [21]. Benzimidazole derivatives containing ester
groups on the benzene ring were reported for their antifungal,
insecticidal and herbicidal activities [22e24]. Furthermore, many
dichlorobenzimidazoles proved high potency against methicillin
resistant Staphylococcus aureus (MRSA) [25]. Since 1985, benz-
imidazole containing compounds have been reported as well
known anticancer agents [26e31], The role of mammalian DNA
topoisomerases as molecular targets for anticancer drugs has been
recognized. Some benzimidazoles have been reported as top-
oisomerase inhibitors e.g. Hoechst 33258 and Hoechst 33342 (Fig. 1)
[32]. On extension of this work, head to head bis-benzimidazole
compounds approved high efficacy as DNA binders [33]. Some
widely used anticancer drugs such as RAF265 (CHIR-265; Novartis
Pharmaceuticals, Basel, Switzerland) and AZD6244 (ARRY-142886;
E-mail address: helzahabi@yahoo.com.
0223-5234/$ e see front matter Ó 2011 Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.ejmech.2011.05.075

4026
H.S.A. Elzahabi / European Journal of Medicinal Chemistry 46 (2011) 4025e4034
Fig. 1. Examples of topoisomerase inhibitors containing benzimidazole nucleus.
AstraZeneca, London, England) are known to contain benzimid-
azole moiety. RAF265 resulted in a reduction in tumor cell growth
and in tumor cell apoptosis [34]. Compound AZD6244 suppresses
the growth of melanoma cells through the induction of cytostasis
[35]. 2-Arylbenzimidazole moiety has been defined as a pharma-
cophore for a new class of DNA intercalating agents [36]. The
importance of naphthalene benzimidazole compounds as antioxi-
dant on hepatic cytochrome has been explored since 1997 [37e39].
On the other hand, the antiviral activity of 5-chloro and 5,6-
dichloro-2-substituted benzimidazole derivatives against several
viruses e.g. influenza, human cytomegalovirus, hepatitis B virus.
(HBV), hepatitis C virus (HCV) and human immunodeficiency
retrovirus (HIV-1) was reported [40e42]. These compounds were
also reported as anticancer agents against breast and prostate
cancer cell lines [43] or as potential topoisomerase II inhibitors [44].
In 2010 a new series of 2-substituted benzimidazole derivatives
having 5-chloro or 5-underivatized carboxylic acid group were
reported to exhibit antitumor activity against hepatocellular
carcinoma (HEPG2), human breast adenocarcinoma (MCF7) and
human colon carcinoma (HCT 116) cell lines [45].
6a,b and 7a,b was ruled out and the corresponding isomers ben-
zothiazolylpyridines 5a,b and 8a,b were considered more likely. This
finding is based on The 1H NMR spectra of the obtained compounds
that showed no signals due to the aliphatic 3H-pyridobenzothiazole
proton (typically d 3.20 ppm) [59] which excluded the possible
pyridobenzothiazole structures 6a,b and 7a,b. On the other hand, 1H
NMR spectrum revealed an aromatic 2-pyridyl CH proton (typically
d
8.14e8.69 ppm) [59]. In continuation of this work, the second part
that includes the synthesis of benzimidazolylpyridines 14a,b and
17aed began with the synthesis of the key intermediate 5,6-
dimethyl-1H-benzimidazol-2-ylacetonitrile (10). In 2007, 5-
Substituted benzimidazol-2-ylacetonitrile was reported to be
synthesized via heating the corresponding 1,2-phenylenediamine
with ethylcyanoacetate in oil bath for 20 min [60]. Herein, 5,6-
dimethyl-1H-benzimidazol-2-ylacetonitrile (10) was prepared in
acceptable yield by a one pot two components solvent free reaction
of 4,5-dimethyl-1,2-phenylenediamine (9) and ethylcyanoacetate
for 2 h, using glycerol bath at 170 ꢁC. IR spectrum of the product
clearly showed the C^N stretching at 2197 cmꢀ1, in addition to the
stretching of NH function at 3240 cmꢀ1. The 1H NMR spectrum
Further, benzothiazoles play an important role as biologically
active natural products, marketed drugs or drug candidates
[46e49]. Various benzothiazoles are known as industrial chem-
icals, dyes and drugs [50,51]. Many compounds with benzothiazole
skeleton are reported to possess different therapeutic effects as
anticancer, antibacterial, antifungal and anthelmintic activities
[52,53]. Also, no one can ignore the role of pyridine as an appre-
ciable pharmacophore for antimicrobial and anticancer activity
[54,55]. These promising findings oriented our study to the
synthesis of new compounds containing a substituted pyridine
moiety directly attached to benzazole nucleus. Further, the recent
study in 2010 that proved the anticancer activity of a variety of 5-
chloro and 5,6-dichlorobenizimidazoles [45], prompted the
author in this work to design new benzimidazole compounds
substituted at 5 and 6 positions with two methyl groups aiming to
get a new anticancer agents.
exhibited D2O-exchangeable signal of NH proton at
addition to the singlet of the 5,6-dimethyl groups at
Also, a sharp singlet was recorded at 4.29 ppm assigned the proton
d
12.27 ppm, in
d
2.29 ppm.
d
of the methylene group linked to benzimidazole nucleus. Heating
compound 10 with 1 mol equivalent of ethylcyanoacetate was
carried out on-neat leading to the synthesis of benzimidazolyl-3-
oxopropanenitrile 11. So, a nucleophilic reaction was suggested
between benzimidazolyl NH and CO moiety of ethylcyanoacetate
with removal of 1 mol of ethanol. Spectral and elemental analyses
support the proposed structure of 11. Proton NMR spectrum
exhibited two singlets at 3.82 and 3.87 ppm (two protons of each)
assigned the two acetonitriles CH2 groups (Scheme 2). Refluxing 5,6-
dimethyl-1H-benzimidazol-2-ylacetonitrile (10) with equivalent
amount of dimethylformamide/dimethylacetal (DMF/DMA) in dry
xylene under base catalysis, afforded the corresponding enamino-
nitrile derivative 12, in good yield (Scheme 2). Elemental and
spectral analyses was consistent with the proposed structure of 12.
IR spectrum revealed the presence of C^N group stretching band at
2193 cmꢀ1. Also, 1H NMR showed a singlet at 3.24 ppm for the
protons of dimethylamino group, together with a singlet at 7.88 ppm
for the proton of ethenyl group. MS spectrum proved that the base
peak was the molecular ion peak appeared at 240m/z. In 1993 fused
pyridobenzimidazole-2,4-dicarbonitriles were reported as the final
products of the reaction that was carried out between benzimida-
zol-2-ylacetonitrile and different arylidenemalononitriles [61]. On
the other hand, Kovalenko et al in 1998 [62] reported a condensation
reaction of benzimidazol-2-ylacetonitrile with salisaldehyde deriv-
atives under base catalysis condition to yield benzimidazolyl-2-
iminocoumarines. Later on, in 2006 Samia Rida et al. [63] unex-
pectedly synthesized the fused pyrido [1,2-a]benzimidazole-4-
carbonitriles rather than the corresponding benzimidazol-2-
ylpyridines, when a mixture of appropriate acetophenones, p-
chlorobenzaldehyde and ammonium acetate was refluxed with
2. Results and discussion
2.1. Chemistry
This work focused on the synthesis of novel benzazole
compounds through preparation of two key elements. The first key
element, 1,3-benzothiazol-2-ylacetonitrile (2) was afforded via
a convenient one-step cyclization reaction between o-amino-
thiophenol (1) and malononitrile at room temperature in absolute
ethanol and glacial AcOH adopting the reported procedures [56,57].
Compound 2 was subjected to Michael addition with various aryli-
denemalononitriles 3a,b and 4a,b in ethanol under base catalysis
adopting the reported reaction condition [58] (Scheme 1). However
the reported literature [58] mentioned that the final product of the
reaction was fused pyrido [1,2-b]benzothiazole-2,4-dicarbonitriles
(6a,b) and (7a,b). Herein, the structure of the fused compounds

H.S.A. Elzahabi / European Journal of Medicinal Chemistry 46 (2011) 4025e4034
H2N
4027
N
N
NC
CN
S
x
O
S
CN
-5a-
-5b-
x
3a,b
x
5a,b
S
N
CN
X
N
S
b
H
H2N
CN
CN
6a,b
CN
S
-2-
N
R
H
H2N
NC
NC
CN
7a,b
H2N
a
R
CN
N
S
N
NC
4a,b
NH2
CN
SH
-1-
R
R
8a,b
8a
8b
OH
OCH3
Scheme 1. Reagents and conditions: (a) absolute ethanol, AcOH (b) absolute ethanol, piperidine.
benzimidazol-2-ylacetonitrile in ethanol. In this study, the reaction
of 5,6-dimethyl-1H-benzimidazol-2-ylacetonitrile (10) with aryli-
denemalononitriles 3a,b and 4aed was performed under similar
reaction condition, used for the synthesis of compounds 5a,b and
8a,b to afford in each case only one isolable product as examined by
TLC. The ethanolic reflux continued until the starting substrate 10
was completely consumed resulting in the formation of the target
products benzimidazol-2-ylpyridines 14a,b and 17aed that sepa-
rated while hot from the reaction medium (Schemes 3 and 4). Fused
benzimidazoles 15a,b and 18aed could be also considered as final
products. Their synthesis was assumed to proceed via nucleophilic
attack of benzimidazolyl NH function on C^N group of the non-
isolable intermediates 13a,b and 16aed. However, The structure of
benzimidazolylpyridines 14a,b and 17aed was preferred based on
theirspectralanalyses. IRspectrum revealedC^N stretchingat range
of 2236e2200 cmꢀ1. In addition NH stretching was confirmed in IR
spectra at a range of 3407e3467 cmꢀ1 with concomitant appearance
with the corresponding fused pyridobenzimidazole 18a having the
molecular formula C21H15N5. These mass spectral features are also
recorded for compounds 14a,b and 17bed.
As illustrated in Scheme 5, the formation of benzazolylpyridines
5a,b, 8a,b, 14a,b and 17aed was assumed to occur via Michael
addition between the carbanion radical of compounds 2 or 10
(which generated under base catalysis) to the double bond of ary-
lidenemalononitriles 3a,b and 4aed to give the non-isolable
Micheal adduct I. Next, intramolecular cyclization of I occurred
through the nucleophilic attack of the imine group onto C^N
moiety to give intermediate II. Finally ring rearrangement of II via
1,3-migration of 2 hydrogen atoms should lead to benzazolylpyr-
idines 5a,b, 8a,b, 14a,b and 17aed.
2.1.1. Mass spectroscopy
The mass spectrum decomposition modes of compound 17a has
been suggested and investigated. The molecule of m/z 339 frag-
mented as illustrated in Scheme 6 via different pathways as
representative example. Fragmentation of the molecule afforded
different peaks ranged from moderate to high intensity. Compound
17a, m/z 339 could be fragmented into two molecular ion peaks,
one possesses m/z 145 representing dimehtylbenzimidazole moiety
and the second one possesses m/z 194 representing phenylpyridine
moiety. Both molecular ion peaks afforded further fragmentations
that led to ions of m/z 115, m/z 117 and m/z 91 respectively. Other
fragmentations could be afforded through loosing hydrogen
radical, phenyl cation, ammonia or ethane molecules as outlined in
of bands corresponding to NH2 function at
a range of
3250e3368 cmꢀ1. Also, 1H NMR of the obtained compounds showed
characteristic signals due to aromatic 2-pyridyl CH proton (typically
at a range of d 8.08e8.46 ppm). The elemental analyses and mass
spectra also support the assigned structures of benzimidazol-2-
ylpyridines 14a,b and 17aed rather than fused pyridobenzimi-
dazole-2,4-dicarbonitriles 15a,b and 18aed. For example mass
spectrum (m/z 339) of the reaction product 17a was compatible with
the molecular formula C21H17N5 of 6-amino-5-(5,6-dimethyl-1H-
benzimidazol-2-yl)-4-phenylpyridine-3-carbonitrile (17a) but not

4028
H.S.A. Elzahabi / European Journal of Medicinal Chemistry 46 (2011) 4025e4034
H3C
NH2
H3C
NH2
-9-
O
a
O
H3C
CN
H3C
N
N
H
CN
H3C
-10-
O
c
b
O
H3C
DMFDMA
CN
CH3
CH3
H3C
N
H3C
N
N
N
CN
H3C
N
H
CN
H3C
O
-11-
-12-
CN
Scheme 2. Reagents and conditions: (a) glycerol bath, 170 ꢁC, 2 h, 36% (for solvent free); (b) dry xylene; (c) glycerol bath, 170 ꢁC, 1h.
Scheme 6. From the foregoing results it can be concluded that
benzazol-2-ylpyridines 5a,b, 8a,b, 14a,b and 17aed are the final
products of Micheal addition of the active methylene of benzazole
acetonitriles 2 and 10 to arylidenemalononitriles 3a,b and 4aed as
outlined in schemes 1,3 and 4.
Compounds 10 and 17c produced a little antitumor activity at
single dose assay (10ꢀ5 M). Almost all cell lines showed weak
sensitivity towards both of them with the only exception of Renal
cancer cell line (UO-31) which exhibited appreciable sensitivity
towards compound 17c (GI 33.40%). On the other hand, most of the
tested cancer cell lines exhibited reliable sensitivity towards
compounds 17b and 17d. They were selected to five dose assay and
the response parameters for both were calculated e.g. log10GI50
(log10 of molar sample concentration resulting in 50% growth inhi-
bition), log10TGI (log10 of molar sample concentration resulting in
total growth inhibition, cytostatic activity) and LC50 (median lethal
concentration, cytotoxic activity) Table 1. Both compounds 17b and
17d displayed limited activity against Leukemia cell lines with GI50
2.2. Anticancer activity
Compounds 10, 17bed were selected by National Cancer Insti-
tute (NCI) to be evaluated for their in-vitro antitumor activity. They
are evaluated at a single dose assay (10ꢀ5 M) on a panel of 60
human cell lines. The cancer cell lines are derived from nine cancer
types: Leukemia, Non-Small Cell Lung Cancer, Colon Cancer, CNS
Cancer, Melanoma, Ovarian Cancer, Renal Cancer, Prostate Cancer
and Breast Cancer. Compounds that satisfy pre-determined
threshold inhibition criteria would progress to the five dose
screen. Selected compounds are tested again in all 60 cell lines in
5ꢂ 10 fold dilutions with the top dose being10ꢀ4 M ending with
10ꢀ8 M. The data were reported as a mean graph of the percent
growth of treated cells and presented as percentage growth inhi-
bition (GI%) caused by the test compounds. Anticancer assay was
performed in accordance with the protocol of the Drug Eval-
uatiotion Branch, National Cancer Institute, Bethesda [64e66].
values ranged from 5.55 mM to a value higher than 100 mM. Non-
Small Cell Lung Cancer subpanel exhibited variable sensitivity
profiles, HOP-92 was the most sensitive line for both 17b and 17d
with GI50 values of 0.275 and 2.65
Cancer, Compound 17b exhibited GI50 value of 3.47
116 while KM12 was the most sensitive line towards 17d (GI50
4.79 M) in this subpanel. SF-539 and SNB-75 belonging to CNS
Cancer were the most sensitive lines for 17b and 17d respectively
(GI50 2.07 and 2.36 M). Compound 17d displayed more
pronounced activity than 17b against Melanoma Cancer as MDA-
mM respectively. Regarding Colon
mM against HCT-
m
m

H.S.A. Elzahabi / European Journal of Medicinal Chemistry 46 (2011) 4025e4034
4029
H3C
N
N
CN
H3C
NC
H
-10-
CN
a
3a,b
x
CN
NC
x
H3C
N
N
H
CN
H3C
13a,b
x
H3C
N
N
CN
CN
H
N
X
H3C
H3C
N
N
H3C
H2N
CN
H2N
14a,b
15a,b
x
a
b
O
S
Scheme 3. Reagents and conditions: (a) absolute ethanol, piperidine.
MB-435 and SK-MEL-2 cell lines were relatively the most sensitive
lines for 17d (GI50 1.95 and 1.08 M respectively). RXF 393 cell line
that belongs to Renal Cancer showed reliable sensitivity against 17b
with GI50 value of 3.18 M, while the rest of the tested cell lines
and p-methoxy groups as in compounds 17b and 17d respectively,
significantly improve the antitumor activity. Both compounds 17b
and 17d displayed a broad spectrum activity against 23 different
human cancer cell lines belonging to the nine subpanels employed.
m
m
displayed a weak sensitivity for both compounds.
2.3. Structural activity relationship
3. Experimental
Four benzimidazole derivatives 10 and 17bed were selected to
be evaluated for their antitumor activity against 60 human cancer
cell lines. Compounds 17b (p-chlorophenyl at pyridine-C4) and 17d
(p-methoxyphenyl at pyridine- C4) were significantly more effective
than the parent benzimidazolylacetonitrile 10 and the compound
17c (p-hydroxyphenyl at pyridine- C4). The synergistic action was
not achieved via introduction of p-hydroxyphenylpyridine moiety to
the parent compound 10 as both compounds 10 and 17c did not
show a pronounced activity against most of cancer cell lines. On the
other hand, replacement of p-hydroxy group in 17c with p-chloro
3.1. General
Melting points were measured with a Gallenkamp apparatus
(Weiss-Gallenkamp, London, UK) and are uncorrected. IR spectra
were recorded on Shimadzu FT-IR 8101 PC infrared spectropho-
tometer (Shimadzu, Tokyo, Japan). NMR spectra were determined
in DMSO-d6 at 300 MHz (1H NMR) and at 75 MHz (13C NMR) on
a Varian Mercury VX-300 NMR spectrometer (Varian Inc., Palo Alto,
CA, USA). Chemical shifts are quoted in d and were related to that of
the solvents. Mass spectra were measured on a GCMS-QP1000 EX

4030
H.S.A. Elzahabi / European Journal of Medicinal Chemistry 46 (2011) 4025e4034
H3C
N
N
H
CN
H3C
-10-
R
a
CN
NC
4a-d
CN
NC
H C
3
R
N
N
H
CN
H C
3
-d
16a
H N
2
H3C
H C
3
N
N
N
N
CN
N
H
H3C
H C
3
R
CN
H2N
18a-d
17a-d
CN
R
R
a
b
c
d
H
Cl
OH
OCH
3
Scheme 4. Reagents and conditions: (a) absolute ethanol, piperidine.
spectrometer (Shimadzu) at 70 eV. Elemental analyses were carried
out at the Microanalytical center of Cairo University.
4,5eDimethyl-1,2-phenylenediamine and dimethylformamide/
dimethylacetal (DMFDMA) were obtained from Aldrich and used
without further purification. Ethylcyanoacetate was obtained from
Merck.
3.3. Synthesisof(5,6-dimethyl-1H-benzimidazol-2-yl)acetonitrile(10)
A mixture of 4,5-dimethyl-1,2-phenylenediamine (9) (0.01 mol)
and ethylcyanoacetate (0.01 mol) was heated on-neat in a glycerol
bath at 170 ꢁC for 2 h, after cooling the residue was broken up and
washed several times with ether. The product was then washed
several times with hot ethanol and crystallized from the proper
solvent. 10: brown powder (36%); mp 208e210 ꢁC (DMF); IR (KBr)
cmꢀ1 3277 (NH), 2227 (C^N), 1629 (C]N); 1H NMR (DMSO-d6)
3.2. Synthesis of 1,3-benzothiazol-2-ylacetonitrile (2)
A mixture of o-aminothiophenol (1) (0.01 mol) and malononi-
trile (0.01 mol) was stirred in absolute ethanol (10 ml) and glacial
AcOH (1 ml) at RT for 10 h, the precipitate was filtered and crys-
tallized from the proper solvent. 2: yellow powder (85%); mp
100e102 ꢁC (EtOH) [56,57].
d 2.29 (s, 6H, 2CH3), 4.29 (s, 2H, CH2eCN), 7.30 (s, 2H, 4,7 benz-
imidazole H), 12.27 (1H, D2O-exchangeable NH); MS m/z (%) 186
(Mþ1, 18.8), 185 (Mþ, 100), 170 (99.2), 145 (4.0). Anal. Calcd for
C11H11N3: C, 71.33; H, 5.98; N, 22.69. Found: C, 70.83; H, 6.09; N,
22.49.

H.S.A. Elzahabi / European Journal of Medicinal Chemistry 46 (2011) 4025e4034
4031
2CH
3
-
H2N
H2N
(-C
6
H )
5
H
N
(C
2
H
6
-)
H
N
H3C
H3C
N
N
N
N
CN
CN
C H N
3
m6/z 3117
C H N
2
m7/z 3115
C H N
2
m9/z 9145
-CN
4.8%
2.9%
2.1%
m/z 1934
2.3%
H2N
C
12
H N
8
N
C
5
H N
2
m/z391
10.8%
H2N
2CH
3
-
H2N
H2N
H
N
H3C
H
N
N
N
N
N
H2C
H3C
-H
N
(C
2
H6
-)
H
N
H3C
N
CN
CN
CN
C
21H N
5
m/z 13638
C
19H N
5
m/z 11145
C
21H N
5
m/z 13739
36.6%
2.6%
11.8%
H-
(-C
6
H )
5
-NH
3
H2N
H
N
H3C
H3C
HN
N
H3C
H3C
N
N
H3C
H3C
N
N
N
N
N
CN
CN
CN
m/z 12262
4.7%
C
15H N
5
m/z 13522
8.1%
C
21H N
4
m/z 13537
C
21H N
5
100%
Scheme 5. Mass fragmentation pattern of compound 17a.
R
R
NC
1
NH
N
x
1
R
R
-
CH
R
R
+
N
N
CN
N
x
H
B+
N
I
CN
1
H
R
R
NC
H
H
N
x
R
R
N
x
R
N
H
B:
HN
II
1
R
CN
R
R
N
x
N
H2N
Scheme 6. Proposed mechanism of the reaction leading to compounds 5a,b, 8a,b, 14a,b, 17a-d; R[H, CH3; X[S, NH; R1[Aryl.

4032
H.S.A. Elzahabi / European Journal of Medicinal Chemistry 46 (2011) 4025e4034
Table 1
NCI DTP in-vitro testing results of compounds17b and 17d at five dose assay.
Panel
Cell Line
17b values (uM)
17d values (uM)
GI50
TGI
LC50
GI50
TGI
LC50
Leukemia
CCRF-CEM
K-562
MOLT-4
RPMI-8226
SR
24.6
31.5
100
5.55
28.7
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
25.6
6.03
>100
32.5
5.64
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
Non-Small
Cell Lung Cancer
A549/ATCC
EKVX
HOP-92
4.17
14.4
0.275
6.36
4.07
8.10
27.7
3.04
15.0
24.9
76.7
5.23
21.7
27.9
30.7
>100
>100
46.3
>100
>100
44.2
55.9
96.5
99.7
>100
>100
100
6.54
15.8
2.65
3.65
474
5.37
15.5
18.1
16.4
72.5
>100
16.3
14.4
54.7
33.3
>100
>100
>100
>100
>100
>100
HOP-62
45.2
NCI-H522
NCI-H23
NCI-H322M
NCI-H460
NCI-H226
>100
>100
>100
>100
>100
Colon Cancer
COLO 205
HCC-2998
HCT-15
HCT-116
HT29
6.24
20.9
30.6
3.47
6.06
14.8
32.4
83.4
>100
>100
19.7
>100
>100
>100
>100
>100
>100
7.78
11.0
5.81
4.63
4.79
3.47
6.76
63.7
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
66.3
>100
>100
>100
KM12
SW-620
CNS Cancer
SF-265
SF-295
SF-539
SNB-19
SNB-75
U251
19.8
10.0
2.07
19.5
12.9
5.48
84.2
27.5
5.78
75.6
32.4
21.4
>100
9.80
6.41
11.5
7.06
2.36
3.65
65.7
>100
68.2
>100
>100
32.4
53.9
75.6
27.0
>100
81.3
66.2
23.4
41.9
57.1
8.19
12.7
Ovarian Cancer
OVCAR-4
OVCAR-3
OVCAR-8
OVCAR-5
IGROV1
4.40
13.9
4.53
14.7
18.7
15.7
11.9
25.4
76.0
29.6
>100
>100
>100
>100
22.5
14.8
5.20
52.4
16.0
6.84
4.84
>100
30.4
26.8
>100
>100
>100
>100
62.2
>100
>100
>100
>100
>100
>100
>100
>100
>100
NCI/ADR-RES
SK-OV-3
27.9
65.1
18.4
59.6
Melanoma
LOX IMVI
5.83
14.5
2.62
20.4
10.0
5.8
26.0
78.8
>100
>100
33.4
40.2
82.6
53.2
80.7
>100
5.74
6.0
>100
48.3
5.39
98.0
>100
>100
>100
>100
>100
>100
100
>100
>100
>100
>100
>100
MALME-3M
MDA-MB435
SK-MEL-2
SK-MEL-5
SK-MEL-28
UACC-257
UACC-62
>100
>100
>100
>100
>100
>100
1.95
10.8
8.78
17.2
52.0
72.2
11.4
11.0
Renal Cancer
A498
11.8
11.1
12.1
3.18
31.0
4.67
59.2
>100
>100
>100
42.6
>100
69.5
10.7
3.98
14.6
6.68
25.4
5.94
63.6
>100
>100
20.4
>100
26.4
>100
>100
>100
54.1
>100
99.6
ACHN
CAKI-1
RXF 393
SN12C
TK-10
>100
>100
13.7
>100
21.3
Prostate Cancer
Breast Cancer
PC-3
DU-145
65.9
5.68
39.3
27.1
>1.00
93.1
8.86
6.92
>1.00
23.8
>1.00
61.8
MCF7
9.34
10.5
12.0
37.6
4.63
12.4
>100
44.2
>100
>100
>100
>100
6.34
8.28
5.87
30.6
15.4
6.22
>100
>100
MDA-MB-231
HS 578T
BT-549
T-47D
MDA-MB-468
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
51.5
23.1
68.0
3.4. Synthesis of3-[2-(cyanomethyl)-5,6-dimethyl-1H-benzimidazol-
1-yl]-3-oxopropanenitrile (11)
several times with hot ethanol and crystallized from the proper
solvent. 11: brown powder (73%); mp 249e251 ꢁC (DMF); IR (KBr)
cmꢀ1 2204 (C^N), 1661, 1623 (C]O), (C]N); 1H NMR (DMSO-d6)
A mixture of 10 (0.01 mol) and ethylcyanoacetate (0.01 mol) was
heated on-neat for 1 h, after cooling the residue was broken up and
washed several times with ether. The product was then washed
d 2.33 (d, 6H, 2CH3), 3.82 (s, 2H, CH2-CN), 3.87 (s, 2H, NeCH2eCN),
7.20 (s, 1H, 4-benzimidazole H), 7.82 (1H, 7-benzimidazole H); MS
m/z (%) 253 (Mþ1, 23.9), 252 (Mþ, 100), 212 (Mþ ꢀ CH2CN, 97.0), 186

H.S.A. Elzahabi / European Journal of Medicinal Chemistry 46 (2011) 4025e4034
4033
(10.4), 184 (212 - CO, 40.3), 186 (10.4), 171 (6.00), 169 (184 e CH3,
26.9), 159 (22.4), 77 (22.4). Anal. Calcd for C14H12N4O: C, 66.65; H,
4.79; N, 22.21. Found: C, 66.33; H, 4.52; N, 22.47.
8.92 (s, 2H, D2O-exchangeable NH2); MS m/z (%) 344 (Mþ, 24.95),
302 (Mþ ꢀ C]N, NH2, 24.07), 168 (21.85), 134 (35.40), 91 (26.21),
75 (25.38). Anal. Calcd for C19H12N4OS: C, 66.26; H, 3.51; N, 16.27.
Found: C, 66.01; H, 3.22; N, 16.30.
3.5. Synthesis of ((2E)-3-(dimethylamino)-2-(5,6-dimethyl-1H-
benzimidazol-2-yl)prop-2-enenitrile (12)
3.6.4. 6-Amino-5-(1,3-benzothiazol-2-yl)-4-(4-methoxyphenyl)-
pyridine-3-carbonitrile (8b)
A mixture of compound 10 (0.01 mol), dimethylformamide/
dimethylacetal (DMFDMA) (0.01 mol) and piperidine (0.2 ml) in dry
xylene (30 ml) was refluxed for 7 h, then left to cool. The solid
product was filtered off and crystallized from the proper solvent.
12: brown powder (54%); mp 275e278 ꢁC (DMF); IR (KBr) cmꢀ1
Yellow powder (98%) mp > 141e142 ꢁC. IR (KBr) cmꢀ13429 (NH2),
2218 (C^N), 1620, 1589 (C]N, C]C); 1H NMR (DMSO-d6)
d 3.88 (s,
3H, OCH3), 7,17 (d, 2H, 2, 6 ArH, J ¼ 9 Hz), 7.47e7.58 (m, 4H, 3, 5
ArH þ 5, 6 benzothiazole H), 8.07e8.18 (m, 4H, 4,7 benzothiazole
H þ D2O-exchangeable NH2), 8.34 (s,1H, 2-pyridyl CH), MS m/z (%)
359 (Mþ1 0.02), 251 (Mþ ꢀ C7H7O,18.62), 224 (2.05), 222 (32.44),197
(2.06),198 (1.32),134 (24.13),108 (78.98), Anal. Calcd for C20H14N4OS:
C, 67.02; H, 3.94; N, 15.63. Found: C, 67.23; H, 4.21; N, 15.50.
3264 (NH), 2193 (C^N), 1628 (C]N); 1H NMR (DMSO-d6)
d 2.25 (s,
6H, 5, 6 benzimidazole 2CH3), 3.24 (s, 6H, N(CH3)2), 7.12 (s, 1H, ]
CH), 7.88 (s, 2H, 4,7 benzimidazole H), 11.64 (s, 1H, D2O-
exchangeable NH); MS m/z (%) 241 (Mþ1 12.4), 240 (Mþ, 100), 239
(18.8), 145 (4.1). Anal. Calcd for C14H16N4: C, 69.98; H, 6.71; N, 23.32.
Found: C, 69.54; H, 6.73; N, 23.00.
3.6.5. 6-Amino-5-(5,6-dimethyl-1H-benzimidazol-2-yl)-4-(furan-2-
yl)pyridine-3-carbonitrile(14a)
Brown powder (50%), mp 289e291 ꢁC. IR (KBr) cmꢀ1 3307 (NH),
3.6. General procedures for synthesis of 6-amino-4-aryl-5-(1,3-benzo-
thiazol-2-yl)pyridine-3-carbonitrile (5a,b) and (8a,b) 6-amino-4-aryl-
5-(5,6-dimethyl-1H-benzimidazol-2-yl)pyridine-3-carbonitrile
(14a,b) and (17aed)
3250 (NH2), 2218 (C^N), 1651, 1610 (C]N, C]C); 1H NMR (DMSO-
d6)
d
2.30 (s, 6H, 2CH3), 6.67e6.76 (m, 2H, 4- furfuryl CH þ 1 D2O-
exchangeable NH), 6.87 (d,1H, 3-furfuryl CH), 7.41(s, 1H, 5-furfuryl
CH), 7.94 (d, 2H, 4,7 benzimidazole H, J ¼ 12 Hz), 8.08 (s,1H, 2-
pyridyl CH), 8.33 (s, 2H, D2O-exchangeable NH2); MS m/z (%) 330
(Mþ1 38.9), 329 (Mþ, 63.9), 328 (48.6), 313 (12.5), 303 (12.5), 285
(40.3), 284 (41.7), 222 (58.3), 209 (100), 185 (37.5), 145 (9.7), 91
(36.1). Anal. Calcd for C19H15N5O: C, 69.29; H, 4.59; N, 21.26. Found:
C, 68.89; H, 4.55; N, 21.20.
A mixture of compounds 2 or 10 (0.01 mol), appropriate aryli-
denemalononitriles 3a,b, 4aed (0.01mol), and piperidine (0.2 ml)
in absolute ethanol (30 ml) was refluxed for 4 h, then left to cool,
the separated product was filtered of and crystallized from proper
solvents.
3.6.6. 6-Amino-5-(5,6-dimethyl-1H-benzimidazol-2-yl)-4-(thiophen-
2-yl)pyridine-3-carbonitrile (14b)
3.6.1. 6-Amino-5-(1,3-benzothiazol-2-yl)-4-(furan-2-yl)pyridine-3-
carbonitrile (5a)
Brown powder (27%); mp >350 ꢁC IR (KBr) cmꢀ1 3430 (NH),
3310 (NH2), 2214 (C^N), 1639, 1615, 1580 (C]N, C]C); MS m/z (%)
345 (Mþ,10.3), 344 (26.9), 343 (100),145 (5.8), 90 (12.2). Anal. Calcd
for C19H15N5S: C, 66.07; H, 4.37; N, 20.27. Found: C, 66.54; H,4.00;
N, 20.29.
Black powder (92%) mp 280e282 ꢁC. IR (KBr) cmꢀ1 3311 (NH2),
2213 (C^N), 1648, 1611 (C]N, C]C); 1H NMR (DMSO-d6)
d
6.71e6.76 (m, 1H, 4-furfuryl CH), 7.14e7.18 (m, 1H, 4-furfuryl CH),
7.29e7.34 (m, 1H, 5-furfuryl CH), 7.42e7.56 (m, 2H, 5, 6 benzo-
thiazole H), 7.98 (d, 1H, 4-benzothiazole H, J ¼ 6 Hz), 8.09e8.14
(m,2H, 7-benzothiazole H þ 2-pyridyl CH), 8.52 (s, 2H, D2O-
exchangeable NH2); MS m/z (%) 319 (Mþ1 12.92), 318 (Mþ, 79.63),
301 (10.85), 292 (4.07), 276 (7.64), 235 (13.41), 184 (6.39), 108
(35.42). Anal. Calcd for C17H10N4OS: C, 64.14; H, 3.17; N, 17.60.
Found: C, 64.00; H, 2.99; N, 17.91.
3.6.7. 6-Amino-5-(5,6-dimethyl-1H-benzimidazol-2-yl)-4-phenyl-
pyridine-3-carbonitrile (17a)
Yellow powder (44%) mp > 350 ꢁC. IR (KBr) cmꢀ1 3467 (NH),
3368 (NH2), 2227 (C^N), 1639, 1586, (C]N, C]C); 1H NMR
(DMSO-d6)
d
2.42 (d, 6H, 2CH3, J ¼ 9 Hz), 7.21e7.35 (m, 6H, 5
ArH þ 1H, D2O-exchangeable NH), 7.60 (d, 2H, 4,7 benzimidazole H,
3.6.2. 6-Amino-5-(1,3-benzothiazol-2-yl)-4-(thiophen-2-yl)pyri-dine-
3-carbonitrile (5b)
J ¼ 9 Hz), 8.43 (s,1H, 2-pyridyl CH), 8.57 (s, 2H, D2O-exchangeable
NH2); 13C NMR (DMSO-d6)
d 19.84, 114.43, 115.76, 118.69, 126.33,
Brown powder (40%) mp 158e160 ꢁC. IR (KBr) cmꢀ1 3300 (NH2),
128.60, 129.92,131.08,134.80, 135.38, 143.00,146.39,151.59,152.02;
MS m/z (%) 340 (Mþ1 3.8), 339 (Mþ, 11.8), 337 (100), 323 (2.6), 313
(0.7), 145 (2.1). Anal. Calcd for C21H17N5: C, 74.32; H, 5.04; N, 20.63.
Found: C, 74.00; H, 5.38; N, 20.60.
2212 (C^N),1608 (C]N, C]C); 1H NMR (DMSO-d6)
d 7.30 (d, 1H, 5-
thiohenyl CH, J ¼ 9 Hz), 7.41e7.47 (m,1H, 4-thiohenyl CH), 7.50e7.55
(m, 1H, 3-thiohenyl CH), 7.98e8.02 (m, 2H, 5, 6-benzothiazole H),
8.08e8.10 (m, 4H, 4, 7-benzothiazole H þ D2O-exchangeable NH2);
8.58 (s, 1H, 2-pyridyl CH); 13C NMR (DMSO-d6)
d
101.06, 116.17,
3.6.8. 6-Amino-4-(4-chlorophenyl)-5-(5,6-dimethyl-1H-benzimida-
zol-2-yl)pyridine-3-carbonitrile (17b)
122.23,122.79,125.91,126.92,128.53,134.20,135.04,136.30,138.07,
140.67, 152.90, 162.71; MS m/z (%) 334 (Mþ 1.59), 202 (6.36), 184
(8.25),173 (3.66),134 (63.13),117 (23.07),108 (72.00),102 (5.92),101
(5.92), 90 (15.76). Anal. Calcd for C17H10N4S2: C, 61.06; H, 3.01; N,
16.75. Found: C, 61.22; H, 3.33; N, 16.62.
Yellow powder (34%); mp >350 ꢁC. IR (KBr) cmꢀ1 3426 (NH),
3270 (NH2), 2214 (C^N), 1646,1584 (C]N, C]C); 1H NMR (DMSO-
d6)
d
2.42 (d, 6H, 2CH3, J ¼ 12 Hz), 7.64e7.66 (m, 7H, 4 Ar H þ 2H, 4,7
benzimidazole H þ 1H, D2O- exchangeable NH), 8.46 (s,1H, 2-
pyridyl CH), 8.57 (s, 2 D2O- exchangeable NH2); MS m/z (%) 373
(Mþ, 8.0), 372 (25.3), 371 (19.5), 290 (100), 289 (60.9), 256 (32.2),
147 (54), 145 (39.1), 91 (40.2), 77 (42.5). Anal. Calcd for C21H16ClN5:
C, 67.47; H, 4.31; N, 18.73. Found: C, 67.30; H, 4.28; N, 19.10.
3.6.3. 6-Amino-5-(1,3-benzothiazol-2-yl)-4-(4-hydroxyphenyl)-
pyridine-3-carbonitrile (8a)
Brown powder (84%) mp > 333e335 ꢁC. IR (KBr) cmꢀ1 3432
(OH), 3377 (NH), 3347 (NH2), 2203 (C^N), 1609, 1547, (C]N, C]C);
1H NMR (DMSO-d6)
d
5.82 (s, D2O-exchangeable OH), 7.14e7.18 (m,
3.6.9. 6-Amino-5-(5,6-dimethyl-1H-benzimidazol-2-yl)-4-(4-
hydroxy- phenyl)pyridine-3-carbonitrile (17c)
2H, 2, 6 ArH), 7.31e7.36 (m, 2H, 3, 5 ArH), 7.39e7.58 (m, 2H, 5, 6-
benzothiazole H), 7.77 (d, 1H, 7-benzothiazole H, J ¼ 6 Hz), 7.96
(d, 1H, 4-benzothiazole H, J ¼ 6 Hz), 8.69 (s, 1H, (s,1H, 2-pyridyl CH);
Brown powder (88%); mp >350 ꢁC. IR (KBr) cmꢀ1 3437 (NH),
3346 (NH2), 2196 (C^N), 1646,1585 (C]N, C]C); 1H NMR (DMSO-

4034
H.S.A. Elzahabi / European Journal of Medicinal Chemistry 46 (2011) 4025e4034
[27] A.K. Piskin, A. Zeynep, F.B. Atac, Y. Musdal, E. Buyukbingol, Turk. J. Biochem. 34
d6)
d
2.35 (s, 6H, 2CH3), 7.52e7.62 (m, 3H, 2, 6 ArH þ 1 D2O-
(2009) 39.
exchangeable NH), 7.77e7.82 (m, 4H, 3, 5 ArH þ 4,7 benzimidazole
H), 8.30 (s,1H, 2-pyridyl CH), 8.55 (s, 2 D2O- exchangeable NH2);
10.76 (s, 1 D2O-exchangeable OH); MS m/z (%) 355 (Mþ, 3.3), 354
(21.6), 353 (100), 352 (33.3), 327 (14.9), 177 (15), 145 (3.3), 91 (9.2),
77 (9). Anal. Calcd for C21H17N5O: C, 70.98; H, 4.82; N, 19.71. Found:
C, 70.52; H, 4.89; N, 19.31.
[28] T.A. Heba, A.F.R. Fatma, M.R. Mostafa, I.E. Hoda, Eur. J. Med. Chem. 45 (2010)
2336.
[29] Sh. Mohammad, M.M. Abdullah, M.A. Bakht, M. Jaseela, Eur. J. Med. Chem. 45
(2010) 114.
[30] N. Boufatah, A. Gellis, J. Maldonado, P. Vanelle, Tetrahedron 60 (2004) 9131.
[31] M. Boiani, M. Gonzalez, Mini Rev. Med. Chem. 5 (2005) 409.
[32] S. Alper, O. Temiz, E. Sener, I. Yalcin, Il Farmaco 58 (2003) 497.
[33] S. Neidle, J. Mann, E.L. Rayner, A. Baron, Y. Opoku-Boahen, I.J. Simpson,
N.J. Smith, K.R. Fox, J.A. Hartley, L.R. Kelland, Chem. Commun. (1999) 929.
[34] K. Wong, Recent Patents on Anti-Cancer Drug Discovery, 4, (2009) 28.
[35] N.K. Haass, K. Sproesser, T.K. Nguyen, R. Contractor, A. Medina, K.L. Nathanson,
M. Herlyn, K.S.M. Smalley, Clin. Cancer Res. 14 (2008) 230.
[36] www.chem-x-infinity.com Benzimidazole nucleotide interacting library.
[37] Z. Ates, B.C. Eke, S. Suzen, E. Buyukbingol, M. Iscan, Il Farmaco 52 (1997) 703.
[38] Z. Ates-Alagoz, E. Buyukbingol, Heterocyclic Commun. 7 (2001) 455.
[39] Z. Ates-Alagoz, B.C. Eke, T. Coban, M. Iscan, E. Buyukbingol, Arch. Pharm. 337
(2004) 188.
[40] S. Budow, M. Kozlowska, A. Gorska, Z. Kazimierczuk, H. Eickmeier, P. La Colla,
G. Gosselin, F. Seela, Arkivoc (2009) 225e250.
[41] M.T. Migawa, J. Girardet, J.A. Walker, G.W. Koszalka, S.D. Chamberlain,
J.C. Drach, L.B. Townsend, J. Med. Chem. 41 (1998) 1242e1251.
[42] A.R. Porcari, R.V. Devivar, L.S. Kucera, J.C. Drach, L.B. Townsend, J. Med. Chem.
41 (1998) 1252e1262.
3.6.10. 6-Amino-5-(5,6-dimethyl-1H-benzimidazol-2-yl)-4-(4-
methoxy-phenyl)pyridine-3-carbonitrile (17d)
Buff powder (50%); mp 319e322 ꢁC. IR (KBr) cmꢀ1 3435 (NH),
3296 (NH2), 2213 (C^N), 1641, 1613, 1581 (C]N); 1H NMR (DMSO-
d6) d 2.40 (s, 6H, 2CH3), 3.82 (s, 3H, OCH3), 7.-7.14 (d, 2H, 3", 5" ArH,
J ¼ 8.7 Hz), 7.55 (d, 2H, 2", 6" ArH, J ¼ 8.4 Hz), 7.61(s, 2H, 4,7
benzimidazole H), 8.4 (s,1H, 2-pyridyl CH), 8.53 (brs, 3 D2O-
exchangeable NH þ NH2); MS m/z (%) 370 (Mþ1 0.4), 369 (Mþ, 3.4),
367 (100), 353 (6.1), 338 (0.4), 145 (1.2). Anal. Calcd for C22H19N5O:
C, 71.53; H, 5.18; N, 18.96. Found: C, 71.40; H, 5.38; N, 18.72.
[43] M. Andrzejewska, L. Yépez-Mulia, R. Cedillo-Rivera, A. Tapia, L. Vilpo, J. Vilpo,
Z. Kazimierczuk, Eur. J. Med. Chem. 37 (2002) 973e978.
[44] A. Pinar, P. Yurdakul, I. Yildiz, O. Temiz-Arpaci, N.L. Acan, E. Aki-Sener,
I. Yalcin, Biochem. Biophys. Res. Commun. 317 (2004) 670e674.
[45] H.M. Refaat, Eur. J. Med. Chem. 45 (2010) 2949e2956.
[46] T.D. Bradshaw, S. Wrigley, D.F. Shi, R.J. Schulz, K.D. Paull, M.F.G. Stevens, Br. J.
Cancer 77 (1998) 745.
Acknowledgements
Author thank the members of Drug Research and Development,
Division of Cancer Research, National Cancer Institute, Bethesda, for
the in-vitro anticancer screening.
[47] E. Kashiyama, I. Hutchinson, M.S. Chua, S.F. Stinson, L.R. Phillips, G. Kaur,
E.A. Sausville, T.D. Bradshaw, A.D. Westwell, M.F.G. Stevens, J. Med. Chem. 42
(1999) 4172.
References
[48] I. Hutchinson, M.S. Chua, H.L. Browne, V. Trapani, T.D. Bradshaw,
A.D. Westwell, M.F.G. Stevens, J. Med. Chem. 44 (2001) 1446.
[49] C.K. Lau, C. Dufresne, Y. Gareau, R. Zamboni, M. Labelle, R.N. Young,
K.M. Metters, C. Rochette, N. Sawyer, D.M. Slipetz, L. Charette, T. Jones,
M. McAuliffe, C. McFarlane, A.W. Ford-Hutchinson, Bioorg. Med. Chem. 5
(1995) 1615.
[1] E. Sener, I. Yalcin, O. Temiz, I. Oren, A. Akin, N. Ucarturk, IL Farmaco 52 (1997) 99.
[2] P. Sharma, A. Kumar, M. Sharma, Eur. J. Med. Chem. 41 (2006) 833.
[3] P. Lindberg, P. Nordberg, T. Alminger, A. Brandstrom, B. Wallmark, J. Med.
Chem. 29 (1986) 1327.
[4] R. Mannhold, Drugs Future 10 (1985) 570.
[50] A. Mishra, R.K. Behera, P.K. Behera, B.K. Mishra, G.B. Behera, Chem. Rev. 100
(2000) 1973.
[5] S. Nakamura, Chem. Pharm. Bull. 3 (1955) 379.
[6] R.S. Verma, S.A. Immam, Def. Sci. J. 25 (1975) 67.
[51] A.S. Michaelidou, D. Hadjipavlou-Litina, Chem. Rev. 105 (2005) 3235.
[52] S. Aiello, G. Wells, E.L. Stone, H. Kadri, R. Bazzi, D.R. Bell, M.F.G. Stevens,
C.S. Matthews, T.D. Bradshaw, A.D. Westwell, J. Med. Chem. 51 (2008) 5135.
[53] Y. Cho, T.R. Ioerger, J.C. Sacchettini, J. Med. Chem. 51 (2008) 5984.
[54] S. Prachayasittikul, L. Treeratanapiboon, S. Ruchirawat, V. Prachayasittikul,
Excli J. 8 (2009) 121.
[7] A. Zeynep, A. Mehmet, K. Canan, Y. Sulhiye, B. Erdem, G. Hakan, Arch. Pharm.
Chem. Life Sci. 339 (2006) 74.
[8] T. Meral, G. Hakan, E. Rahmiye, E. Recep, K. Engin, A. Nurten, Arch. Pharm.
Pharm. Med. Chem. 330 (1997) 372.
[9] Z.M. Nofal, H.H. Fahmy, H.S. Mohamed, Arch. Pharm. Res. 25 (2002) 28.
[10] A.C. Cuckler, K.C. Mezey, Arzneim. Forsch 16 (1966) 411.
[11] A.C. Hollinshead, P.K. Smith, J. Pharmacol. Exp. Ther. 123 (1958) 54.
[12] D.C. O’Sullivan, A.K. Wallis, J. Med. Chem. 15 (1972) 103.
[13] B. Simone, K. Mariola, G. Agata, K. Zygmunt, E. Henning, L. Paolo, G. Gilles,
S. Frank, Arkivoc iii (2009) 225.
[55] E. Nassar, J. Am. Sci. 6 (2010) 338.
[56] S. Koji, K. Satoshi, N. Yukihiro, Synthesis 3 (1983) 210.
[57] Y. Ch. Richard, D. Mei-Fang, Ch. Jhao-Yu, L. Chuan-Chen, L. Shaw-Tao, J. Chin.
Chem. Soc. 57 (2010) 213.
[58] F.S. Babichev, V.K. Patratii, Yu. M. Volovenko, N.G. Prodanckuk, V.G. Sinchenko,
A.G. Nemazanyi, Khim. Farm. Zh. 22 (1988) 1223 Chem. Abstr., 111, (1989) 7285.
[59] M.E.A. Zaki, A.A. Fadda, K. Samir, F.A. Amer, Chem. Heterocycl. Comp. 39
(2003) 1242.
[60] P.A. Thakurdesai, S.G. Wadodkar, Ch. T. Chopade, Pharmacology- Online 1
(2007) 314.
[14] R. Zou, K. Ayres, J. Drach, L. Townsend, J. Med. Chem. 39 (1996) 3477.
[15] W.W. Kilgore, E.R. White, Bull. Environ. Contam. Toxicol. 5 (1970) 67.
[16] B. Maxwell, Appl. Microbiol. 21 (1971) 944.
[17] N.A. Tikhonova, N.L. Poznanskaya, V.A. Rusakova, S.N. Ivanova, Yu. N. Fadeev,
Yu. N. Ivanchenko, N.I. Skvetsov-Shilkovskii, N.N. Melnikov, G.I. Zhilsova,
Mikol. Fitopatol. 7 (1973) 450.
[61] K. Bogdanowicz-Szwed, A. Czarny, J. Prakt Chem. 335 (1993) 279.
[62] S.N. Kovalenko, M.V. Vasil’ev, I.V. Sorokina, V.P. Chernykh, A.V. Turov,
S.A. Rudnev, Chem. Heterocycl. Comp. 34 (1998) 1412.
[63] S.M. Rida, S.A.M. El-Hawash, H.T.Y. Fahmy, A.A. Hazzaa, M.M.M. El-Meligy,
Arch. Pharm. Res. 29 (2006) 826.
[64] A. Monk, D. Scudiero, P. Skehan, R. Shoemaker, K. Paull, D. Vistica, C. Hose,
J. Langley, P. Cronise, A. Viagro-Wolff, M. Gray-goodrich, H. Campbell, J. Mayo,
M. Boyd, J. Natl. Cancer Inst. 83 (1991) 757.
[65] S. Kuo, H. Lee, J. Juang, Y. Lin, T. Wu, J. Chang, D. Lednicer, K. Paull, C.M. Lin,
E. Hmel, K. Lee, J. Med. Chem. 36 (1993) 1146.
[18] K.A.M. Walker, A.C. Braemer, S. Hitt, R.E. Jones, T.R. Mathews, J. Med. Chem 21
(1978) 840.
[19] C.J. Going, V.W. Mayer, Mut. Res. 343 (1995) 185.
[20] C. Tomlin, The Pesticide Manual, tenth ed. (1994).
[21] G. Kamlesh, B. Jamie, P. Austin, B. Julie, W. Leslie, P. Dulal, Biochemistry 43
(2004) 6645.
[22] O. Seckin, A. Dilek, Y. Sulhiye, G. Hakan, Bioorg. Med. Chem. 13 (2005) 1587.
[23] G. Hakan, M. Tuncbilek, G. Ayhan, N. Altanlar, Farmaco 53 (1998) 415.
[24] T. Hisano, M. Ichikawa, K. Tsumoto, M. Tasaki, Chem. Pharm. Bull. 30 (1982)
2996.
[66] F. Leteurtre, G. Kohlhagen, K. Paull, Y.J. Pommier, J. Natl. Cancer Inst. 86 (1994)
1239.
[25] M. Tuncbilek, T. Kiper, N. Altanlar, Eur. J. Med. Chem. 44 (2009) 1024.
[26] E.A. Ibrahim, A.M.E. Omar, M.A. Khalil, J. Pharm. Sci. 69 (1980) 1348.