Discovery of arylamide-5-anilinoquinazoline-8-nitro derivatives as VEGFR-2 kinase inhibitors: Synthesis, in vitro biological evaluation and molecular docking

Article abstract of DOI:10.1016/j.bmcl.2019.126711

Herein, we embarked on a structural optimization campaign aiming at the discovery of novel anticancer agents with our previously reported XL-6f as a lead compound. A library of 23 compounds has been synthesized based on the highly conserved active site of VEGFR-2. Several title compounds exhibited selective inhibitory activities against VEGFR-2, which also displayed selective anti-proliferation potency against HepG2 cell. All synthesized compounds were evaluated for anti-angiogenesis capability. Compound 7o showed the most potent anti-angiogenesis ability, the efficient cytotoxic activities (in vitro against HUVEC and HepG2 cell lines with IC₅₀ values of 0.58 and 0.23 μM, respectively). The molecular docking analysis revealed 7o is a Type-II inhibitor of VEGFR-2 kinase. In general, these results indicated these arylamide-5-anilinoquinazoline-8-nitro derivatives are promising inhibitors of VEGFR-2 for the potential treatment of anti-angiogenesis.

Full text of DOI:10.1016/j.bmcl.2019.126711

Journal Pre-proofs
Discovery of arylamide-5-anilinoquinazoline-8-nitro derivatives as VEGFR-2
kinase inhibitors: synthesis, invitro biological evaluation and molecular docking
Yongqiang Zhao, Feifei Liu, Guojing He, Ke Li, Changcheng Zhu, Wei Yu,
Conghai Zhang, Mingjin Xie, Jun Lin, Jihong Zhang, Yi Jin
PII:
S0960-894X(19)30669-9
DOI:
https://doi.org/10.1016/j.bmcl.2019.126711
BMCL 126711
Reference:
Bioorganic & Medicinal Chemistry Letters
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Accepted Date:
25 June 2019
23 August 2019
19 September 2019
Please cite this article as: Zhao, Y., Liu, F., He, G., Li, K., Zhu, C., Yu, W., Zhang, C., Xie, M., Lin, J., Zhang, J.,
Jin, Y., Discovery of arylamide-5-anilinoquinazoline-8-nitro derivatives as VEGFR-2 kinase inhibitors: synthesis,
in vitro biological evaluation and molecular docking, Bioorganic & Medicinal Chemistry Letters (2019), doi: https://
doi.org/10.1016/j.bmcl.2019.126711
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Discovery of arylamide-5-anilinoquinazoline-8-nitro derivatives as
VEGFR-2 kinase inhibitors: synthesis, in vitro biological evaluation
and molecular docking
Yongqiang Zhao,a‡ Feifei Liu,b‡ Guojing He,a‡ Ke Li,c* Changcheng Zhu,d Wei Yu,e Conghai
Zhang,a Mingjin Xie,a Jun Lin,a* Jihong Zhangb* and Yi Jina*
a. Key Laboratory of Medicinal Chemistry for Natural Resource, Ministry Education and Yunnan
Province, School of Chemical Science and Technology, Yunnan University, Kunming, 650091, P.
R. China.
b. Laboratory of Molecular Genetics of Aging and Tumor, Medical School, Kunming University of
Science and Technology, Kunming, 650500, P. R. China.
c. Biomedical Department, Yunnan Cancer Hospital, the Third Affiliated Hospital of Kunming
Medical University, Kunming, 650118, P. R. China.
d. Institute of Drug Research and Development, Kunming Pharmaceutical Corporation, Kunming,
650100, P. R. China.
e. Pharmaceutical Department, Kunming General Hospital of Chengdu Military Command,
Kunming, 650118, P. R. China.
‡ the authors contributed equally to this work.
٭ Corresponding author. Tel./fax: +86-871-6503-3119. E-mail: likelikelike@126.com (K. Li);
linjun@ynu.edu.cn (J. Lin); zhjihong2000@126.com (JH. Zhang); jinyi@ynu.edu.cn (Y. Jin).
Keywords: quinazoline; anticancer agents; Antiangiogenesis; VEGFR-2 kinase inhibitors
1

Abstract
Herein, we embarked on a structural optimization campaign aiming at the discovery of novel
anticancer agents with our previously reported XL-6f as a lead compound. A library of 23
compounds has been synthesized based on the highly conserved active site of VEGFR-2. Several
title compounds exhibited selective inhibitory activities against VEGFR-2, which also displayed
selective anti-proliferation potency against HepG2 cell. All synthesized compounds were evaluated
for anti-angiogenesis capability. Compound 7o showed the most potent anti-angiogenesis ability,
the efficient cytotoxic activities (in vitro against HUVEC and HepG2 cell lines with IC50 values of
0.58 and 0.23 µM, respectively). The molecular docking analysis revealed 7o is a Type-II inhibitor
of VEGFR-2 kinase. In general, these results indicated these arylamide-5-anilinoquinazoline-8-nitro
derivatives are promising inhibitors of VEGFR-2 for the potential treatment of anti-angiogenesis.
2

The tumors metastasis, growth and survival depend on the cell differentiation, proliferation,
angiogenesis, and apoptosis, which are regulated by a variety of signal transduction pathways and
protein kinases.1-3 Receptor tyrosine kinases (RTKs) have become important targets for tumor
therapy, and a growing number of RTKs inhibitors have been designed and synthesized.4, 5 Among
these kinases, vascular endothelial growth factor receptors (VEGFR-1, VEGFR-2, and VEGFR-3)
was confirmed as key intermediates in tumor angiogenesis and in the formation of new blood vessel
network required for tumor growth.6-8 In particular, VEGFR-2 is expressed in endothelial cells and
at abnormally high levels in various tumor cells. There are many pieces of evidence that
over-activation of VEGFR-2 is correlated with metastasis in the majority of solid tumor patients.9-11
Due to the vital roles of VEGFR-2 in tumor angiogenesis, inhibition of VEGFR-2 is an attractive
strategy in the treatment of tumors.12, 13 At present, a number of small molecule targeting agents are
acknowledged as promising therapeutic drugs for treatment against a wide variety of human cancers,
such as pazopanib,14 sorafenib,15 regorafenib16 and sunitinib17 (Figure 1.).
NH2
O
S
O
CF3
O
Cl
O
N
O
NH
N
N
N
N
N
N
N
N
H
H
H
Pazopanib
Sorafenib
O
H
N
H
N
F
N
H
CF3
Cl
N
H
N
N
HN
O
O
O
F
N
O
H
Regorafenib
Sunitinib
Figure 1. Representative VEGFR-2 inhibitors currently approved.
Quinazolines are a highly significant type of biological molecules that are widely found in bioactive
agrochemicals, pharmaceuticals, synthetic drugs, and natural products.18-25 Many of its derivatives
are used to display anticancer,26-28 anti-virus,29-32 antifungal,33-35 antimicrobial,36-38
40, 42
44
anti-inflammatory,39-41 analgesic,39,
or immunotropic43,
activities. Anilinoquinazoline
structure provides the necessary binding properties for inhibition of the VEGFR kinase.45-50 In our
previous work, a series of anilinoquinazoline analogs were synthesized and evaluated.51-55 An
arylurea quinazoline (XL-6f in Figure 2.) exhibited the efficient VEGFR-2 inhibition in the
submicromolar level but showed weak inhibitory activity on cancer cells, such as hepatocellular
carcinoma cells (HepG2), breast cancer cells (MCF-7) and ovarian cancer cells (SK-OV-3).51
Molecular docking calculations demonstrate that the binding mode of XL-6f with the active site of
VEGFR-2 (Figure 2.) presents a pharmacophore model in which the central arylurea moiety
occupied the linker region of the kinase, and the quinazoline core occupied the adenine pocket,
3

meanwhile the terminal 2-chloro-5-(trifluoromethyl)-benzene moiety was buried in the hydrophobic
pocket with the H-bond acceptor (C=O) of the urea moiety directed to Asp1044 and H-bond
donator (N-H) directed to Gly883.51 As the antiproliferative activities of most VEGFR-2 inhibitors
containing arylamide unit (e.g., Ponatinib,56 and Apatinib57 in Figure 1.) were better than that of
arylurea compounds (e.g., sorafenib), we reasoned that the arylamide substituent may improve the
bioavailability of 5-anilinoquinazoline-8-nitro derivatives. To achieve this ability, the central
arylurea linker of compound XL-6f was changed with the arylamide linker (Figure 2.). New
5-anilinoquinazoline-8-nitro derivatives were designed and synthesized. Interestingly, these
compounds showed much more potent cytotoxic and antiangiogenic activities than XL-6f in HepG2,
MCF-7, and SK-OV-3 cancer cell lines. Molecular docking analysis of the most efficient compound
with VEGFR-2 enzyme was described in this paper.
linker
region
linker
region
hydrophobic
pocket
adenine
pocket
Cl
H
H
H
N
N
NO2
N
N
N
O
N
O
N
H
N
N
CF3
N
CF3
HO
N
Ponatinib
XL-6f
linker
region
hydrophobic
pocket
adenine
pocket
O
R
NO2
N
H
N
N
H
HO
N
7a-7w
Figure 2. Design of arylamide-5-anilinoquinazoline-8-nitro based on XL-6f and arylamide derivatives.
The general synthetic methods for arylamide-5-anilinoquinazoline-8-nitro derivatives are
demonstrated in Scheme 1. First, the readily available starting material 1,3-benzenediamine or
1,4-benzenediamine (1) was reacted with BOC anhydride under 0oC to convenient afford single
N-Boc protected diamines (2), which were then amidated by various benzoyl chloride (3) under
mild conditions to produce intermediates (4) with high yield. Subsequently, arylamides (5) were
obtained by facile deprotection of Boc in DCM solvent, which then carried out nucleophilic
substitution reaction with compound 6 to generate target products 7.55 Initially, the yield of this
nucleophilic substitution reaction was not ideal, therefore, we used N-(3-aminophenyl)benzamide
(5a) as a template to optimize the reaction conditions. Using 1,4-dioxane as a solvent, the proper
increasing temperature was effective for yield increment (SI, Table S1. entry 1-4), while excessive
4

temperature rise is not conducive to obtain products. On the other hand, the improvement of the
yield is not obvious by changing the common solvents (e.g., DMF, DMSO, CH3CN, toluene, and
ethyl acetate). However, it is noteworthy that when a mixture of ethyl acetate and DMF is used as a
solvent, the yield can be significantly increased to about 50%, thus a mixture solvent of DMF and
ethyl acetate was screened. When the ratio of DMF to ethyl acetate is 1:8, the yield is optimized to
reach about 80%. Meanwhile, in this step, the use of different base did not significantly change the
yield of the reaction (entry 18-21). Thereby, under the optimum conditions, a total of 23 compounds
with different arylamide substituents on 5-anilinoquinazoline-8-nitro scaffold were synthesized. All
newly synthesized compounds were systematically characterized by melting points and
1
13
spectroscopic techniques (high-resolution HPLC-MS, H NMR, and C NMR). The purity of the
compounds was determined by HPLC and was found to be in the range of 95% to 100% pure. The
inhibitory activities against kinases and tumor cells were determined in the bioassay by using these
purified compounds.
O
DCM
triethylamine
b).
a). (Boc)2O,DCM
X
Cl
X
Boc
+
H2N
NH2
R
H2N
N
H
2-3 h, rt
60-150min, 0℃
1
2
3
Yield=45-60%
H
H
R
R
c). TFA
1-2h
NHBoc
NH2
N
N
X
X
O
O
4
5
Yield>95%
Yield=75-90%
O
Cl
OH
X=
R
N
HN
X
HN
NO2
N
N
6
d).
NO2
HO
7
R=H,Cl,F,CH3,OCH3
N
EtOAc:DMF=8:1, 8-72h,
Yield=58-85%
45℃
7a (65%)
7b (75%)
7c (58%)
7d (78%)
7e (81%)
7l (69%)
:
7m (73%)
7n (69%)
7o (58%)
7p (74%)
7q (83%)
: R = 4-H,
: R = 4-Me,
: R = 4-Cl,
: R = 4-F,
: R = 2-Me,
X = 1,3-aniline
X = 1,3-aniline
X = 1,3-aniline
X = 1,3-aniline
X = 1,3-aniline
R = 4-H,
: R = 4-Me,
: R = 4-Cl,
: R = 4-F,
: R = 2-Me,
X = 1,4-aniline
X = 1,4-aniline
X = 1,4-aniline
X = 1,4-aniline
X = 1,4-aniline
7f (67%)
:
R = 2-OMe, X = 1,3-aniline
: R = 2-OMe, X = 1,4-aniline
7g (52%)
7h (68%)
7r (75%)
:
: R = 2-Cl,
: R = 2-F,
R = 3-Me,
R = 3-Cl,
X = 1,3-aniline
X = 1,3-aniline
X = 1,3-aniline
X = 1,3-aniline
X = 1,3-aniline
R = 2-Cl,
X = 1,4-aniline
X = 1,4-aniline
X = 1,4-aniline
7s (85%)
: R = 2-F,
7i (83%)
7j (76%)
7t (68%)
7u (82%)
7v (65%)
7w (73%)
:
:
: R = 3-Me,
: R = 3-OMe, X = 1,4-aniline
: R = 3-Cl,
: R = 3-F
7k (74%)
: R = 3-F,
X = 1,4-aniline
X = 1,4-aniline
Scheme 1. Synthesis of intermediates and products. Reagents and conditions: a) Boc anhydride (1.1 equiv.), DCM
as solvent, 0 oC, 60-150 min (yield=45-60%); b) Aryl chloride (1.2 equiv.), TEA (1.2 equiv.), DCM as solvent, rt,
2-3 h (yield=80-95%); c) TFA (3-4 equiv.), rt, 1-2 h (yield=95-100%); d) 6 (0.9 equiv.), EtOAc:DMF (8:1) as
solvent, 8-72 h, (yield=65-83%).
The synthesized compounds were evaluated for their inhibitory potency against VEGFR-2 and
5

EGFR kinases using sorafenib and XL-6f as a reference control. According to the results (Table 1.),
it is obvious that all compounds showed the selectively inhibition against VEGFR than EGFR at 1
µM, although some compounds exhibited moderate inhibitory activity against EGFR, such as 7m
(VEGFR-2: 83.7% vs. EGFR: 57.2%), 7n (VEGFR-2: 97.9% vs. EGFR; 64.1%), and 7o (VEGFR-2:
101.5% vs. EGFR: 69.2%). The most active compound is 7o (64.8 nM) which inhibitory activity
against VEGFR-2 is slightly lower than XL-6f (15.4 nM). As for the structure-activity relationship
(SAR) of 5-(N-arylamides)-quinazoline-8-nitro analogs against VEGFR-2 kinase: first,
aryl-1,4-diamine linker afforded the better inhibitory activities against kinase than that of
aryl-1,3-diamine linker, for example 7d (R=4-F, X=1,3-dianiline, 41.9% inhibition) compared with
7o (R=4-F, X=1,4-dianiline, 101.5% inhibition), which suggested that linear molecule structure can
better match the active site of VEGFR-2 than that of curved molecule. In addition, the
electron-withdrawing group can significantly improve kinase inhibitory potency than the
electron-donating group, for example, compound 7h (3-F, 35.8%) compared with 7e (3-Me, 21.6%),
and compound 7r (4-Cl, 76.9%) compared with 7q (4-OMe, 60.3%). Lastly, the inhibitory activities
of the compounds with 4-substituted arylamide (e.g., 7b-7d, and 7m-7o with inhibitions of 32.7-
41.9%, and 83.7-101.5%, respectively) are better than that of 2, or 3-substituted arylamide (e.g.,
7e-7k, and 7p-7w with inhibitions of 18.0-38.1%, and 47.6-76.9%, respectively), which suggested
that the position of substituents on aryl amides also had a certain effect on the kinase inhibitory
activities. Based on the VEGFR-2 kinase activity evaluation, a preliminary structure-activity
relationship (SAR) in this work was summarized in Figure 3.
hydrophobic
pocket
O
Hinge region
Cl, F > H, Me, OMe
4-R > 2-R, or 3-R
NH
X
R
NH OH
N
adenine
pocket
N
HN
NO2
NH
NH
7
HN
Figure 3. Preliminary structure-activity relationships of synthesized compounds against VEGFR-2 kinase.
All synthesized compounds were also evaluated for the cell growth inhibitory activities against
6

HUVEC cell and hepatocellular carcinoma HepG2 cell lines highly expressing the VEGFR-2
protein as well as non-small cell lung cancer A549 cell and human breast cancer MDA-MB-231 cell
lines highly expressing the EGFR protein by the standard MTT assay, using sorafenib and XL-6f as
the reference control (Table 1.). It was found that these samples also selectively inhibited the
growth of HUVEC cell and HepG2 cancer cells, and all samples were weak or inactive against
A549 and MDA-MB-231 cancer cells. In general, the compounds containing aryl-1,4-diamine
linker also afforded the better anti-proliferation activities against HUVEC and HepG2 cell lines
than that of aryl-1,3-diamine linker compounds, for example, 7a-7k (1,3-dianiline linker) showed
moderate to weak inhibitory potency, but 7l-7w (1,4-dianiline linker) displayed moderate to strong
anti-proliferation activities. This result is consistent with the result of kinase assay, suggesting that
the linear compounds have a good inhibitory potency against the cell lines expressing high levels of
VEGFR-2 kinase. To our delighted, the most potent compound 7o, although has a slightly lower
inhibitory activity against VEGFR-2 than compound XL-6f, its anti-proliferation activity in vitro
against both HUVEC (0.58 µM) and HepG2 (0.23 µM) cells is almost one or two orders of
magnitude higher than that of XL-6f (2.1 and 13.7 µM, respectively). This change may be due to
the difference in hydrophobicity between the two compounds. The calculated hydrophobic
parameters (ClogP) of 7o and XL-6f are 4.70 and 6.38, respectively, which indicate that compound
7o may have better solubility and better cell absorption in bioavailability. Moreover, 7o showed the
same inhibitory activity against HepG2 cell line as ponatinib and was superior to sorafenib.
Therefore, these results confirmed that it is feasible to use amide moiety instead of urea moiety to
improve the medicinal properties of compounds.
Finally, we evaluated the cytotoxicities of some synthesized compounds (7l-7o) on the LO2 cell
line (normal human hepatocytes cells) in vitro. Compared with three control samples (XL-6f,
sorafenib, and ponatinib), no compounds showed obvious cytotoxicity against this cell line.
Table 1. The kinase inhibitory activities and in vitro antiproliferative effects of synthesized compounds.
O
NH
R
X
NH OH
N
N
NO2
7
7

kinase inhibitory activities a
in vitro anti-proliferative effects (IC50, µM) c
X
R
H
Cpd
7a
7b
7c
7d
7e
7f
VEGFR2
37.8±1.4
EGFR
15.4±1.7
12.8±0.9
9.4±0.4
HUVEC
79.1±3.2
80.5±3.7
73.8±1.7
63.2±1.8
89.6±2.5
82.0±2.2
74.6±1.2
70.4±2.1
93.6±3.5
86.53±2.4
74.2±1.9
5.7±2.4
HepG2
75.2±2.6
74.0±1.6
76.3±2.4
68.5±1.1
90.3±1.3
90.3±3.1
71.9±1.9
69.6±1.5
>100
A549
>100
MDA-MB-231
>100
LO2
NT d
1,3-aniline
1,3-aniline
1,3-aniline
1,3-aniline
1,3-aniline
1,3-aniline
1,3-aniline
1,3-aniline
1,3-aniline
1,3-aniline
1,3-aniline
1,4-aniline
1,4-aniline
1,4-aniline
1,4-aniline
1,4-aniline
1,4-aniline
1,4-aniline
1,4-aniline
1,4-aniline
1,4-aniline
1,4-aniline
1,4-aniline
32.7±0.5
>100
>100
NT
4-Me
4-Cl
38.5±2.6
>100
>100
NT
41..9±0.7
18.5±1.4
6.4±1.3
95.0±3.5
>100
>100
NT
4-F
21.6±0.4
>100
NT
2-Me
2-OMe
2-Cl
26.9±1.5
12.4±0.5
22.5±1.6
17.2±0.5
11.3±1.2
26.3±1.5
27.3±2.1
53.8±2.5
57.2±1.7
64.1±2.4
69.22.1
>100
>100
NT
30.1±1.4
>100
>100
NT
7g
7h
7i
35.8±2.4
>100
>100
NT
2-F
18.0±0.7
>100
>100
NT
3-Me
3-Cl
29.2±2.4
93.0±2.7
72.1±3.2
7.41±2.5
18.5±1.5
0.9±0.1
0.2±0.1
30.1±2.4
40.7±1.1
28.0±0.8
21.0±1.8
40.8±1.8
64.2±2.5
42.0±1.5
36.1±0.7
13.7±0.3
3.6±0.4
0.6±0.2
>100
>100
NT
7j
38.1±1.4
>100
>100
NT
7k
7l
3-F
92.4±2.4 (734.9±4.7)b
83.7±1.8
87.4±1.7
>100
86.3±2.3
94.68±3.7
95.1±2.5
58.4±2.4
>100
65.3±2.5
93.2±4.1
73.5±1.5
63.2±2.7
NT
H
14.3±0.7
1.6±0.3
7m
7n
7o
7p
7q
7r
7s
4-Me
4-Cl
97.9±2.6 (362.7±9.5)b
101.5±5.2 (64.8±2.4)b
65.8±2.5
83.0±2.6
69.0±0.9
91.6±3.8
>100
0.5±0.1
4-F
41.7±1.1
43.6±1.9
50.3±2.7
42.1±1.6
37.8±2.7
36.7±1.4
27.7±0.8
36.9±2.8
21.8±1.5
(43.5±0.8)b
NT.
37.2±0.9
36.3±2.1
26.5±1.9
23.8±2.6
47.0±2.1
57.8±1.1
36.7±1.5
38.9±1.1
2.1±0.2
2-Me
2-OMe
2-Cl
60.3±1.5
95.8±3.2
96.1±1.4
93.2±2.8
>100
NT
76.9±1.9
90.3±2.5
85.8±2.4
>100
NT
73.8±2.4
NT
2-F
58.2±1.5
NT
7t
3-Me
3-OMe
3-Cl
47.6±1.6
>100
>100
NT
7u
7v
7w
63.2±1.7
>100
>100
NT
69.4±2.4
83.27±3.2
>100
>100
NT
3-F
102.2±3.5(15.4±1.1)b
104.2±2.7(25.7±0.9)b
NT.d
>100
84.2±3.1
72.9±1.2
64.7±3.6
XL-6f
sorafenib
ponatinib
4.1±0.7
8.1±0.3
5.3±0.2
15.8±1.1
10.5±0.3
0.5±0.1
a The kinase inhibition % at 1 µM are the average of two independent experiments.
b IC50 (nM) values are the average of two independent experiments in the parentheses.
8

c IC50 values are the average of three independent experiments.
d NT means no test.
The CAM assay was selected to explore angiogenesis, which is an inexpensive, reliable, simple, and
convenient biological method. All twenty-three compounds (7a-7w) were screened for studying the
anti-angiogenic strength of the compounds (Figure 4). Compared with the normal saline group as
blank control and the sorafenib as a positive control, the results displayed that eight compounds (7l,
7m, 7n, 7o, 7r, 7s, 7v, and 7w) exhibited good anti-angiogenic activities. In particular, the
inhibition rates of 7n and 7o on angiogenesis were better than that of sorafenib. These results
confirmed that 5-(N-arylamides)-quinazoline-8-nitro analogs have the anti-angiogenic effect.
Figure 4. a) Quantification of the effect of twenty-three compounds on CAM blood vessel growth (10 nM/eggs) is
displayed in the bar graph. b) The effects of the best eight compounds on CAM assay.
The cell apoptosis and cell cycle analysis of compound 7o on HepG2 cell were explored by using
Flow Cytometer with dUPT-FITC/PI staining and PI staining, respectively. As shown in Figure 5a,
the percent of dUPT-FITC/PI-positive apoptotic cells was enhancement after HepG2 cells acted
9

with 7o in the concentration of 1 nM and 10 nM, only 2.6% (blank control), and the apoptotic ratio
increased up to 72.2% after treatment with 7o (10 nM) for 24 h. Additionally, after the treatment of
compound 7o with HepG2 cells in different concentration (1 nM and 10 nM), the cell cycle analysis
displayed the enhancement in the percentage of cells in G0/G1 phase in a concentration-dependent
manner. These results proved that compound 7o presented an important inhibitory effect on the
proliferation of HepG2 cells, which may be achieved by periodic blocking and apoptosis induction
in the G0/G1 phase.
Figure 5. a) The effect of compound 7o on HepG2 cells apoptosis using dUPT-FITC/PI staining; b) the effect of
compound 7o on HepG2 cells cycle using PI staining.
To better understand the SARs observed in the VEGFR-2 kinase inhibition assay, and for further
guidance of SARs studies, the optimized compound 7o was docked into the catalytic site of
VEGFR-2 protein (PDB code: 3WZE) using Gold 5.0 with the default parameters, i.e., pt_crosswt
(100), popsiz (100), niche_siz (2), n_islands (1). The lowest energy conformation was adopted as
the final binding conformation. As shown in Figure 6, the binding pattern of 7o revealed that
4-fulorobenzoyl moiety was buried in one hydrophobic sub-pocket of the allosteric site of
VEGFR-2, while quinazoline scaffold occupied the adenine region of the kinase, which assumed
the similar binding pattern with the protein as observed for XL-6f and sorafenib. Additionally, the
specific binding mode is as follows. First, six hydrogen-bonding interactions were observed: in the
hinge region of the kinase, amide oxygen and the nitrogen atom of benzoyl moiety H-bonded to
residues Cys1045 and Glu885, respectively; in adenine region, two nitrogen atoms of quinazoline
and one oxygen atom of the nitro group formed H-bonds with residues Cys919. Moreover, the
10

benzoyl ring and 1,4-dianiline ring were H-π stacked with the residues Asp1046 and Phe1047,
respectively, which enhanced the binding interaction to VEGFR-2 kinase. According to these
results, we assume that compound 7o is a Type II inhibitor of VEGFR-2 kinase.
Figure 6. Putative binding mode of compound 7o in VEGFR-2 kinase was predicted by molecular modeling. The
dashed lines illustrate atom pairs within hydrogen bonds.
In summary, we designed and synthesized a novel class of 5-anilinoquinazoline-8-nitro
derivatives that inhibit VEGFR-2 tyrosine kinase. The in-vitro cytotoxic activity assay and chick
chorioallantoic membrane assay showed that these compounds possess anti-tumor activity and
anti-angiogenesis. Compound 7o showed the greatest inhibitory activities against VEGFR-2 kinase,
HUVEC, and HepG2 cell with IC50 values of 64.8 nM, 0.58 µM, and 0.23 µM, respectively.
Molecular docking of the most potent inhibitor 7o into the active site of VEGFR-2 was performed
and the result suggested that compound 7o could bind well with the ATP-binding site of VEGFR-2
kinase. The above results demonstrated that compound 7o had emerged as a promising candidate
for further development.
Conflict of Interest
None of the authors of the above manuscript has declared any conflict of interest which
may arise from being named as an author on the manuscript.
Acknowledgments
This work was supported by the National Natural Science Foundation of China (Nos. 21662044,
11

81560601, 21262043, 81760621, and U1202221); Training Program for Young and Middle-aged
Academic and Technical Leaders in Yunnan Province (2015HB004); the Program for Changjiang
Scholars and Innovative Research Team in University (IRT17R94); the Foundation of “Yunling
Scholar” Program of Yunnan Province (C6183005); the 2017 Medical Oncology Academic
leader training program from the Health and Family Planning Commission of Yunnan province
(D-2017001); and thank the High Performance Computing Center at Yunnan University for use
of the high performance computing platform.
Author Contributions
Yi Jin, Jihong Zhang, Ke Li, and Jun Lin conceived and planned the experiments. Yongqiang Zhao,
Feifei Liu, Guojing He, and Changcheng Zhu carried out the experiments. Conghai Zhang and
Mingjin Xie carried out the computational simulations. Wei Yu contributed to biological sample
preparation. Yi Jin, Jihong Zhang, Ke Li, and Jun Lin contributed to the interpretation of the results.
Yi Jin took the lead in writing the manuscript. All authors provided critical feedback and helped
shape the research, analysis, and manuscript.
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Abstract
Discovery of arylamide-5-anilinoquinazoline-8-nitro derivatives as VEGFR-2 kinase
inhibitors: synthesis, in vitro biological evaluation and molecular docking
Yongqiang Zhao,‡a Feifei Liu,‡b Guojing He,‡a Ke Li,*c Changcheng Zhu,d Wei Yu,e Conghai Zhang,a
Mingjin Xie,a Jun Lin,*a Jihong Zhang*b and Yi Jin*a
Highlights
 The novel arylamide-5-anilinoquinazoline-8-nitro derivatives were synthesized.
 They showed selective inhibitions against VEGFR2 kinase and cancer cells.
 Compound 7o exerted the most excellent biological activities.
 Compound 7o was presumed to be as a Type II inhibitor of VEGFR-2 kinase.
16