Schiff's base derivatives bearing nitroimidazole and quinoline nuclei: New class of anticancer agents and potential EGFR tyrosine kinase inhibitors

Article abstract of DOI:10.1016/j.bmcl.2014.02.041

New Schiff's base derivatives 5a-j have been synthesized by reaction between 2-phenoxyquinoline-3-carbaldehydes 3a-j and 2-(2-methyl-5-nitro-1H- imidazol-1-yl)acetohydrazide 4 in presence of nickel(II) nitrate as a catalyst in ethanol under reflux in good

Full text of DOI:10.1016/j.bmcl.2014.02.041

Bioorganic & Medicinal Chemistry Letters 24 (2014) 1734–1736
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Schiff’s base derivatives bearing nitroimidazole and quinoline nuclei:
New class of anticancer agents and potential EGFR tyrosine kinase
inhibitors
⇑
Jigar A. Makawana, Chetan B. Sangani, Lin Lin, Hai-Liang Zhu
State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing 210093, People’s Republic of China
a r t i c l e i n f o
a b s t r a c t
Article history:
New Schiff’s base derivatives 5a–j have been synthesized by reaction between 2-phenoxyquinoline-3-
carbaldehydes 3a–j and 2-(2-methyl-5-nitro-1H-imidazol-1-yl)acetohydrazide 4 in presence of nickel(II)
nitrate as a catalyst in ethanol under reflux in good yield (78–92%). All compounds were tested for anti-
cancer and inhibition of EGFR. Of the compounds studied, majority of the compounds showed effective
antiproliferation and inhibition of EGFR and HER-2 activities. Compound 5h showed most effective inhi-
Received 25 December 2013
Revised 6 February 2014
Accepted 14 February 2014
Available online 28 February 2014
bition (IC50 = 0.12 0.05
energy (
Gb = À58.3691 kcal/mol). The binding was stabilized by two hydrogen bonds, two
one –sigma interactions. Compound 5d showed most effective inhibition (IC50 = 0.37 0.04
l
M) by binding in to the active pocket of EGFR receptor with minimum binding
–cation and
M).
Keywords:
Schiff’s base
Nitroimidazole
Quinoline
D
p
p
l
Ó 2014 Elsevier Ltd. All rights reserved.
EGFR inhibition
Anticancer activity
Epidermal growth factor receptor (EGFR) is a kind of tyrosine ki-
nase firstly reported in the literature.1,2 It has become one of the
targets of anticancer drug research and development because of
its widely distribution in the cell and important role in cell life.
EGFRs are distributed in mammalian epithelial cell membranes
and have relationships with cell proliferation, death, and differen-
tiation. They are junctions to deliver extracellular growth signals
intracellular. EGFR family comprise four members, including: EGFR
(HER1/ErbB-1), ErbB-2 (HER2/neu), ErbB-3 (HER3), and ErbB-4
(HER4).3 EGFR tyrosine kinase-mediated cell growth signaling
pathway plays an important role in the formation and develop-
ment of many types of solid tumors, such as nonsmall cell lung
cancer,4 head and neck cancer,5 and glioblastomas.6 Over expres-
sion of EGFR family receptors have always been observed in these
tumors, approximately in 60% of all tumors.4 EGFR and ErbB-2 are
the hottest targets in current research and their over expression or
abnormal activation often cause cell malignant transformation.
Also they have relationship with postoperative adverse, radiother-
apy and chemotherapy resistance and tumor angiogenesis.7
Further, Schiff’s bases constitute an important class of biologi-
cally active drug molecules which has attracted attention of medic-
inal chemists due to their wide range of pharmacological
properties. These compounds are being synthesized as drugs by
many researchers in order to combat diseases with minimal
toxicity and maximal effects. These predictions has provided
therapeutic pathway to develop new effective biologically active
Schiff’s base derivatives. A number of Schiff’s base derivatives
have been reported to exert notably antibacterial,8 antimycobacte-
rial,9 antitumor,10 antileishmanial activity,11 DNA-binding activi-
ties, etc.
Encouraged by potential clinical applications of Schiff’s base
derivatives and our previous investigations on EGFR inhibitory
activity of nitroimidazole derivatives12 and other literature survey
on quinoline having the same activity,13 we report herein, the syn-
thesis and anticancer activity as well as EGFR inhibitory activity of
Schiff’s base derivatives having nitroimidazole and quinoline moi-
eties in a single scaffold with the goal to develop more effective
target molecule for EGFR.
Schiff’s base derivatives 5a–j have been synthesized by reaction
between 2-phenoxyquinoline-3-carbaldehydes14 3a–j and 2-(2-
methyl-5-nitro-1H-imidazol-1-yl)acetohydrazide15 4 in presence
of nickel(II) nitrate as a catalyst in ethanol under reflux in good
yield (78–92%) (Scheme 1). The reaction was also attempted using
AcOH,16,17 and conc. H2SO4,18 however, some shortcomings was
observed such as incompletion of reaction, long reaction time; lose
of yield and purification problems. Therefore, we applied Ni(NO3)2-
Á6H2O as a catalyst12a for this reaction to avoid such drawbacks as
well as to develop easy and efficient method for the synthesis of
new Schiff’s base derivatives 5a–j.
The structures of all the new synthesized compounds were
⇑
Corresponding author. Tel.: +86 25 8359 2572; fax: +86 25 8359 2672.
E-mail address: zhuhl@nju.edu.cn (H.-L. Zhu).
established by 1H NMR, 13C NMR, FT-IR, elemental analysis, and
http://dx.doi.org/10.1016/j.bmcl.2014.02.041
0960-894X/Ó 2014 Elsevier Ltd. All rights reserved.

J. A. Makawana et al. / Bioorg. Med. Chem. Lett. 24 (2014) 1734–1736
1735
Scheme 1. Synthetic pathway for the compounds 5a–j.
molecular weight of compounds confirmed by mass spectrometry.
Mass spectroscopy of compounds showed molecular ion peak
[M+H]+ corresponding to the exact mass.
All compounds were tested against EGFR and HER-2 kinases as
well as against A549 adenocarcinomic human alveolar basal
epithelial cell line and Hep G2 liver cancer cell line (Table 1).
Upon investigation of antiproliferative activity of compounds
5a–j, it has been observed that against A549, compounds 5h
5c (IC50 = 0.27 0.10
(IC50 = 0.42 0.02
other compounds and less comparable to the positive control erl-
otinib (IC50 = 0.032 0.02 M). Compounds 5d (IC50 = 0.37 0.04 M),
(IC50 = 0.43 0.09 M) and 5i showed excellent activity as compared
l
M), 5g (IC50 = 0.18 0.03
l
M) and 5i
l
M) showed excellent activity as compared to
l
l
l
to other compounds of the series.
Structure activity relationship (SAR) was carried out from EGFR
inhibitory and anticancer activities. According to the activity data,
it has been observed that the change in R1 and R2 substitution may
lead to change in the activity against employed cancer cells as well
as EGFR. Compounds having R1 = –CH3 and/or R2 = –OCH3 have
proved as most effective members against EGFR and A549, while
against HepG2, compounds having electron withdrawing groups
such as –F and –Cl have proved as effective members of the series.
Moreover, reviewing and comparing the activity data, it is worthy
to mention that the anticancer and activity against EGFR of the tar-
get compounds depends not only on the bicyclic heteroaromatic
pharmacophore, but also on the nature of the substituents.
Molecular docking study: To gain better understanding on the
potency of all compounds and guide further SAR studies, we pro-
ceeded to examine the interaction of those with EGFR (PDB code:
1M17) by molecular docking, which was performed by simulation
of compounds into the ATP binding site in EGFR. The binding en-
ergy of all the compounds is mentioned in Table 2. Of the com-
pounds studied, compound 5h was nicely bound into the active
(IC50 = 0.16 0.03
potent as well as compounds 5c (IC50 = 0.92 0.14
(IC50 = 1.23 0.10 M) and 5g (IC50 = 1.19 0.02 M) showed good
activity as compared to other compounds of the series. Compounds
5d (IC50 = 0.18 0.05 M), 5e (IC50 = 0.22 0.01 M) and 5i
(IC50 = 1.56 0.16 M) against Hep G2 showed most effective
activity as compared to other compounds. As shown in Table 1,
against EGFR, compound 5h (IC50 = 0.12 0.05 M) displayed
l
M) and 5i (IC50 = 0.19 0.07
lM) showed most
lM), 5j
l
l
l
l
l
l
the most potent inhibitory activity as well as compounds
Table 1
Inhibition of EGFR and HER-2 kinases as well as antiproliferative activity of
compounds 5a–j
IC50
(l
M
SD)
Compound
EGFR
HER-2
A549
Hep G2
5a
5b
5c
5d
5e
5f
5g
5h
10.35 0.54
23.13 0.12
0.27 0.10
21.02 0.21
5.12 0.33
3.17 0.02
0.18 0.03
0.12 0.05
0.42 0.02
8.66 0.13
0.032 0.002
15.3 11.47
7.67 0.36
12.02 0.07
0.37 0.04
4.10 1.07
1.58 0.58
17.0 40.66
2.18 0.08
0.43 0.09
19.0 11.23
0.16 0.02
9.45 0.23
21.51 0.01
0.92 0.14
3.12 0.09
9.03 0.06
7.18 0.14
1.19 0.02
0.16 0.03
0.19 0.07
1.23 0.10
0.13 0.01
13.28 0.09
27.12 0.10
4.13 0.07
0.18 0.05
0.22 0.01
15.09 0.08
21.90 0.13
3.15 0.14
1.56 0.16
3.18 0.04
0.12
site of EGFR with minimum binding energy
D
Gb = À58.3691 kcal/
mol. The binding model of compound 5h and EGFR is depicted in
Figures 1 and 1A. The amino acid residues which had interaction
with EGFR were labeled. In the binding mode, compound 5h was
nicely bound to the ATP binding site of EGFR through hydrophobic
interaction and the binding was stabilized by two hydrogen bonds,
5i
5j
two
p–cation and one p–sigma interactions. Among two hydrogen
Erlotinib
bonds, one formed between O-atom of carbonyl and THR766 with

1736
J. A. Makawana et al. / Bioorg. Med. Chem. Lett. 24 (2014) 1734–1736
Table 2
cluded that the every important parts of the molecule is taking part
in the interaction with EGFR and it might be responsible for the
effective activity of compound 5h against EGFR.
Binding energy of synthesized compounds 5a–j
Compounds
CDOCKER interaction energy—DGb (kcal/mol)
In the conclusion, new series of Schiff’s base derivatives having
nitroimidazole and quinoline nuclei has been synthesized by reac-
tion between 2-phenoxyquinoline-3-carbaldehydes and 2-(2-
methyl-5-nitro-1H-imidazol-1-yl)acetohydrazide in presence of
nickel(II) nitrate as a catalyst in ethanol under reflux in good yield.
This synthetic strategy allows the assimilation of two promising
bioactive nuclei in a single scaffold through an easy way. Review-
ing the biological activity data, it has been concluded that com-
pounds 5c, 5d, 5e, 5g, 5h and 5i are found to be most effective
compounds of the series. Compound 5h showed most effective
inhibition by binding in to the active pocket of EGFR receptor with
minimum binding energy may be because of substitution nature
and position as well as spatial relation. According to this, it is wor-
thy to mention that the Schiff’s base derivatives having nitroimi-
dazole and quinoline nuclei have become vital spot of anticancer
as well as EGFR and HER-2 inhibition medicine research.
5a
5b
5c
5d
5e
5f
5g
5h
5i
51.0943
48.0622
53.7634
48.9263
51.1701
51.2811
58.1884
58.3691
53.3504
51.1685
5j
Acknowledgment
This work was supported by Natural Science Foundation of
Jiangsu Province (No. BK20130554).
Supplementary data
Supplementary data associated with this article can be found,
in the online version, at http://dx.doi.org/10.1016/j.bmcl.2014.
02.041.
References and notes
Figure 1. 2D binding model of compound 5h into the active site of EGFR.
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distance = 1.97376 Å, DHA angle = 147.7° and HAY angle = 114.4°,
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while another one formed between phenoxy ring of quinoline nu-
cleus and LYS721 with distance = 6.76259 Å. One p–sigma interac-
tion formed between quinoline ring and LEU694 with distance =
2.72184 Å. Based on the favorable EGFR inhibitory activity of Schiff’s
base derivatives having nitroimidazole moiety, it could be con-