Novel thioureido-benzenesulfonamide derivatives with enaminone linker as potent anticancer, radiosensitizers and VEGFR2 inhibitors

Article abstract of DOI:10.1016/j.bmcl.2018.03.089

In this study, novel series of thioureido-benzenesulfonamide derivatives bearing an enaminone linker either meta or para oriented and having terminal linear or substituted aromatic or heteroaromatic ring system 5–16a,b were designed and synthesized based on the general pharmacophoric features of type II VEGFR2 inhibitors. Evaluation of the synthesized compounds against HEPG2 hepatocellular carcinoma cells in vitro identified compounds 5b, 6b and 10–13b as most active anticancer agents with IC₅₀ equal to 0.12, 0.29, 0.58, 0.44, 0.42 and 0.66 μM, respectively. These compounds were evaluated for their ability to in vitro inhibit VEGFR2 kinase enzyme. The results demonstrated highly potent dose-related VEGFR2 inhibition with IC₅₀ values in nanomolar range (33, 57, 210, 37, 37 and 220 nM, respectively). The radiosensitizing ability of the most promising compounds was studied which showed an increase in the cell killing effect of radiation after combination with the synthesized compounds which revealed lowered IC₅₀ by nearly 50%. Molecular docking for the most potent compounds was performed to predict their possible binding mode within VEGFR2 active site and they showed binding affinity in a similar way to sorafenib.

Full text of DOI:10.1016/j.bmcl.2018.03.089

Accepted Manuscript
Novel Thioureido-Benzenesulfonamide Derivatives with Enaminone Linker as
Potent Anticancer, Radiosensitizers and VEGFR2 inhibitors
Mostafa M. Ghorab, Fatma A. Ragab, Helmy I. Heiba, Marwa G. El-Gazzar,
Mostafa G.M. El-Gazzar
PII:
S0960-894X(18)30294-4
https://doi.org/10.1016/j.bmcl.2018.03.089
BMCL 25743
DOI:
Reference:
To appear in:
Bioorganic & Medicinal Chemistry Letters
Received Date:
Revised Date:
Accepted Date:
30 December 2017
26 March 2018
30 March 2018
Please cite this article as: Ghorab, M.M., Ragab, F.A., Heiba, H.I., El-Gazzar, M.G., El-Gazzar, M.G.M., Novel
Thioureido-Benzenesulfonamide Derivatives with Enaminone Linker as Potent Anticancer, Radiosensitizers and
VEGFR2 inhibitors, Bioorganic & Medicinal Chemistry Letters (2018), doi: https://doi.org/10.1016/j.bmcl.
2
018.03.089
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Novel Thioureido-Benzenesulfonamide Derivatives with Enaminone Linker as
Potent Anticancer, Radiosensitizers and VEGFR2 inhibitors
a
b
a
a*
Mostafa M. Ghorab , Fatma A. Ragab , Helmy I. Heiba , Marwa G. El-Gazzar , Mostafa
G. M. El-Gazzar
a
a
Department of Drug Radiation Research, National Center for Radiation Research and
Technology (NCRRT), Egyptian Atomic Energy Authority (EAEA), Nasr City, P.O. Box 29,
Cairo, Egypt.
b
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Cairo University,
Cairo, Egypt.
*
Correspondence author; E-Mail: marwagalalgazzar@yahoo.com ; Tel.: +2-012-
7
7448742.
Abstract
In this study, novel series of thioureido-benzenesulfonamide derivatives bearing an
enaminone linker either meta or para oriented and having terminal linear or substituted aromatic
or heteroaromatic ring system 5-16a,b were designed and synthesized based on the general
pharmacophoric features of type II VEGFR2 inhibitors. Evaluation of the synthesized
compounds against HEPG2 hepatocellular carcinoma cells in vitro identified compounds 5b, 6b
and 10-13b as most active anticancer agents with IC equal to 0.12, 0.29, 0.58, 0.44, 0.42 and
5
0
0
.66 µM, respectively. These compounds were evaluated for their ability to in vitro inhibit
VEGFR2 kinase enzyme. The results demonstrated highly potent dose-related VEGFR2
inhibition with IC values in nanomolar range (33, 57, 210, 37, 37 and 220 nM, respectively).
5
0
The radiosensitizing ability of the most promising compounds was studied which showed an
increase in the cell killing effect of radiation after combination with the synthesized compounds
which revealed lowered IC by nearly 50%. Molecular docking for the most potent compounds
5
0
was performed to predict their possible binding mode within VEGFR2 active site and they
showed binding affinity in a similar way to sorafenib.
Keywords: Benzenesulfonamides, HEPG2, VEGFR2.
Cancer remains to be one of the lethal diseases in the world; hepatocellular carcinoma
1
(
HCC) is considered the third type of cancer causing death . The use of the common
chemotherapeutic agents, although effective in cancer eradication, but also suffer from severe
2
side effects arising from the lack of selectivity . Therefore, finding new drugs that selectively
3
, 4
target cancer cells is a today’s goal . Inhibition of the VEGFR-2 signaling pathway was proved
to have an antiangiogenic effect on human cancers as they exist predominately in vascular
endothelial cells and hematopoietic stem cells and appears to mediate almost all of the known
1

cellular responses to VEGF, which stimulate multiplication of vascular endothelial cells and
5
, 6
growth of blood vessels
. Among the well-known VEGFR2 inhibitors, we should mention
sorafenib, a diphenylurea that is approved for first-line treatment of renal cell carcinoma (RCC)
7
-9
and hepatocarcinoma (HCC) . Sorafenib, trade name Nexavar, was the only current standard of
1
0, 11
care for HCC
until the recent FDA approval of regorafenib (Stivarga, Bayer) as a second-
line treatment for patients with hepatocellular carcinoma (HCC) who have previously received
1
2, 13
sorafenib
. Sorafenib is an oral kinase inhibitor targeting both tumor cells and the tumor
vasculature, also, it has multikinase inhibitory abilities (serine/threonine, Raf, and receptor
tyrosine kinases), and targets receptor tyrosine kinase signaling. It inhibits vascular endothelial
growth factor receptor (VEGFR) and platelet-derived growth factor receptor (PDGFR).
Moreover, an oxidative stress mechanism was proved for Sorafenib through generation of
1
4
reactive oxygen spices (ROS) in HCC leading to cell death . The development of cytotoxic and
anti-angiogenic agents for HCC treatment are still limited, therefore, there is a must that
medicinal chemists pay more attention to develop more potent and effective drugs.
Moreover, sulfonamide derivatives belong to the most important structural classes of
1
5-18
drug molecules. Sulfonamides possess many biological activities such as anticancer
antibacterial
,
1
9-21
, and many other activities. Sulfonamide is incorporated in many potent
anticancer agents as SLC-0111, a biarylurea-benzenesulfonamide, currently completed phase I
22
clinical trials for the treatment of solid tumors . On the other hand, enaminones are important
organic intermediates used to synthesize various heterocyclic and biologically active analogues
2
3-26
.
Combining sulfonamide and enaminone moieties led to potent anticancer agents. In 2016,
Ghorab et. al. designed novel chromene derivatives bearing sulfonamide as potent aromatase
2
7
inhibitors for breast cancer suppression , also chloroquinoline benzenesulfonamide derivatives
2
8
showed high potency against various human tumor cell lines .
By studying the structure activity relationships (SAR) and common pharmacophoric
features of various VEGFR2 inhibitors, as well as the binding modes of sorafenib, three main
2
9, 30
requirements were reported
. 1) The core scaffold of most inhibitors consists of a flat hetero
aromatic ring system that occupies the ATP binding region and binds to the hinge region via an
essential hydrogen bond with the backbone NH of Cys919 residue. 2) Most inhibitors have
hydrogen bond donor-acceptor linker interacting with Glu885 and Asp1046 residues. 3) In all
inhibitors, there is a terminal aryl moiety that occupies the allosteric hydrophobic binding region.
Moreover, the X-ray structure of various inhibitors bound to VEGFR2 showed that there is
sufficient space available for various substituents around the terminal aromatic ring allowing a
3
1, 32
diversity of substituents to be accommodated in this region
.
Based on the above study, a novel series of thioureido-benzenesulfonamide derivatives
bearing an enaminone linker were designed and synthesized. In previous work, the combination
1
8, 33
of sulfonamide and thiourea derivatives have produced promising anticancer agents
. We
selected sulfapyridine as starting benzenesulfonamide aiming to maintain the same binding
interactions with the Cys919 NH in the hinge region. The hydrogen bond donor-acceptor pair is
represented in the designed compounds by the enaminone moiety which is either meta or para
oriented to the adjacent benzene ring to explore the different binding modes of such both
orientations. In addition, the terminal linear, aromatic or heteroaromatic ring substituted with
2

various groups was designed to occupy the hydrophobic pocket. (Figure 1). First, the synthesized
compounds were evaluated against HEPG2 cell line to investigate their anticancer activity, next,
the most potent conpounds were further subjected to in vitro VEGFR2 inhibitory evaluation in
order to study their ability to affect the tumor vasculature, docking study and radiosensitizing
evaluation were performed.
Figure 1. Essential pharmacophoric features of VEGFR2 inhibitors of the designed compounds revealing
the main scaffolds in blue, the hydrogen bond donor-acceptor linker are presented in pink color and finally the
terminal substituted aromatic or heteroaromatic moiety occupying the allosteric hydrophobic pocket is presented
in green color.
The target compounds were synthesized according to the general pathways described in
3
4
scheme 1. 4-Isothiocyanato-N-pyridin-2-yl-benzenesulfonamide 2 was prepared by treating an
aqueous solution of N-pyridin-2-yl-benzenesulfonamide 1 hydrochloride with thiophosgene
3
5
according to the reported method . 4-Isothiocyanato-N-pyridin-2-yl-benzenesulfonamide 2 was
used to prepare different sulfonamide derivatives by incorporating different biologically active
moieties. The orientation and binding affinity of different compounds within their targets active
sites varies greatly according to the position of substituents, therefore, compound 2 was allowed
to react with either O- or P-aminoacetophenone to yield the corresponding acetyl derivatives
3
a,b which were further reacted with dimethylformamide-dimethyl acetal DMF/DMA in xylene
2
3, 36 1
to give the enaminones 4a,b in good yields following the reported method
. H-NMR spectra
of the enaminones 4a,b showed the presence of a singlet signal at 2.91 and 2.93 ppm,
respectively corresponding to N-dimethyl, while, the two olefinic protons were represented by
1
3
two doublets around 5 and 8 ppm. C-NMR spectra showed significant signals at 40.37 and
0.33 ppm, respectively representing the two methyl groups. The presence of the good leaving
4
group, the dimethyl amino, in 4a,b, prompted us to undergo different substitution reactions with
different heterocyclic amines yielding the enaminones 5-16a,b with substitutions either on O- or
P- positions of the adjacent benzene ring. (scheme 1). All the synthesized compounds were
3

1
13
characterized by IR, H-NMR, C-NMR, mass spectra and microanalytical data and were in
conformity with the assigned structures as listed in the material and methods section in details.
Scheme 1. Synthetic pathways for compounds 5-16a,b.
In an initial screening, All the synthesized compounds were subjected to in vitro
anticancer evaluation against HEPG2 hepatocellular carcinoma cells using MTT assay with five
molar concentrations (0.01, 0.1, 1.0, 10 and 100 µM) for each compound in triplicates, the
4

results were expressed as IC (concentration required for 50% inhibition of cell viability) and
5
0
compared to the reference drug sorafenib.
This screening identified compounds 5b, 6b and 10-13b, all incorporating the terminal
substituted aromatic ring in para position to the adjacent ring, as the most active compounds
with IC in the range of 0.12-0.66 µM. Table 1.
5
0
Structure activity relationship for the newly synthesized compounds was closely
investigated. A relatively weak activity was observed for the starting isothiocyanate 2 (IC =
5
0
5
.50 µM) as well as the four intermediates 3 and 4a,b (IC = 5.50 µM). Incorporating terminal
50
linear or substituted aromatic or heteroaromatic to the enaminone linker ameliorated the activity
to different extends, but the main observation is that the para- oriented substituents 3-16b were
more active than the meta- substituents 3-16a underlining the importance of the para- orientation
of the donor-acceptor group and the terminal hydrophobic substituents for the activity as in
sorafenib (IC = 1.06 µM).
5
0
Further comparison of the anticancer activity among compounds 3-16b revealed that
introduction of linear ester terminal substituents greatly increased the activity in compounds 5b
(
IC = 0.12 µM) and 6b (IC = 0.29 µM) which were the most potent compounds in this study. A
50 50
relatively weaker activity was observed in case of compounds 7-9b (IC = 1.40-3.90 µM) which
5
0
contain terminal phenyl, benzyl, hydroxy phenyl substituents. While, incorporation of terminal
aromatic ring with carboxylic, ester or halide substituents led to an increase in the activity for
compounds 10-13b (IC = 0.42-0.66 µM).
5
0
Finally, introduction of terminal heterocyclic ring system as pyridine 14b (IC = 3.10
5
0
µM), or thiophene 15b (IC = 6.20 µM), or substituted pyrazole moiety 16b (IC = 8.00 µM),
5
0
50
decreased the activity.
From the SAR of the most potent compounds, we can conclude that para-orientation of
the enaminone moiety with respect to the adjacent aromatic ring is optimum for activity, the ester
or carboxylic groups are important either on an aliphatic chain or attached to a benzene ring as in
compounds 5b, 6b, 10b and 13b may be by providing a better orientation of the compounds
within the active site. Moreover, the two halogen-containing compounds 11b and 12b exhibited
high activity, they were nearly equipotent, the position of the fluorine or chlorine atoms on the
aromatic didn’t affect the activity.
Table 1. In-vitro anticancer screening of the synthesized compounds 2-16a,b against HEPG-2
hepatocellular carcinoma cells.
a
a
Compound No.
2
IC (µM)
Compound No.
IC (µM)
5
0
50
5.50 ± 0.12
5.00 ± 0.11
5.50 ± 0.20
1.90 ± 0.09
1.50 ± 0.08
3
4
5
6
a
a
a
a
3b
4b
5b
6b
6.90 ± 0.21
3.50 ± 0.22
0.12 ± 0.01
0.29 ± 0.01
5

7
8
9
1
1
1
1
1
1
1
a
a
a
0a
1a
2a
3a
4a
5a
6a
4.70 ± 0.22
2.50 ± 0.09
2.90 ± 0.16
1.60 ± 0.07
0.50 ± 0.01
1.20 ± 0.06
1.50 ± 0.07
4.70 ± 0.11
10.80 ± 0.56
11.40 ± 0.76
1.06 ± 0.05
7b
8b
9b
10b
11b
12b
13b
14b
15b
16b
3.90 ± 0.11
2.30 ± 0.09
1.40 ± 0.09
0.58 ± 0.03
0.44 ± 0.02
0.42 ± 0.02
0.66 ± 0.04
3.10 ± 0.11
6.20 ± 0.32
8.00 ± 0.43
Sorafenib
a
Each value is the mean of three experiments ± standard error.
The most potent six compounds from the previous study 5b, 6b and 10-13b were chosen
to be tested in vitro for their inhibitory activity against VEGRR2 kinase enzyme. Sorafenib was
included in the experiments as a reference drug. The results were reported as a 50% inhibition
concentration value (IC , determined in triplicate) Table 2. The tested compounds displayed a
5
0
noticeable high inhibitory activity in Nano molar range with IC values from 33 to 220 nM.
5
0
In this study, The SAR results depends on the comparison between the inhibitory activity
against VEGFR2 and structural variations resulted from incorporating a terminal substituted
linear or aromatic moiety on the para- oriented enaminone linker which were proved to be more
active than the corresponding meta- ones. The linear ester substituent had a greater impact on the
activity than the aromatic substitution, where, the ethyl ester derivative 5b (IC = 33 nM) had
5
0
more inhibitory activity than the methyl propene ester derivative 6b (IC = 57 nM). On the other
5
0
hand, when focusing on the aromatic substituents, the type of the substitution on the aromatic
ring greatly affected the activity. Introducing a carboxylic group at position 2 yielded an
inhibitory activity of 210 nM, the two halide substituents were equipotent with IC of 37 nM.
5
0
Finally, the ester substituent at position 4 resulted in inhibitory activity of 220 nM. Overall,
compounds 6b, 11b and 12b showed nearly similar inhibitor activity as the reference drug
sorafenib (IC = 30 nM).
5
0
Table 2. In-vitro enzymatic inhibition of VEGFR-2 for compounds 5b, 6b, 10b-13b.
a
Compound No.
IC (nM)
5
0
5
6
1
1
1
1
b
b
0b
1b
2b
3b
33 ± 0.01
57 ± 0.01
210 ± 0.12
37 ± 0.02
37 ± 0.01
220 ± 0.01
30 ± 0.01
Sorafenib
a
Each value is the mean of three experiments ± standard error.
6

Radiation therapy is employed extensively for treatment of almost all types of solid
tumors. Ionizing radiations do not discriminate between cancerous and normal cells. Thus,
normal tissue damage is still the dose limiting factor that diminishes tumor cells eradication in
radiation therapy. Application of tumor-specific drugs with radiation therapy has aimed to
improve the radiation therapy outcomes by inducing more toxicity for tumors and less for normal
tissues. These drugs could exert their tumor killing effect through ROS generation causing
37, 38
oxidative stress
effectiveness and reliability. Modern RT technologies has been developed, including image-
guided radiotherapy (IGRT), intensity-modulated radiotherapy (IMRT), and stereotactic
body radiotherapy, allowed more precise treatment without affecting normal surrounding
. The use of radiotherapy (RT) for HCC increased considerably due to its
39
tissues .
The ability of the most active compounds 5b, 6b, 10-13b to enhance the cell killing effect
of ɤ-irradiation was studied. From the results obtained in table 3, compound 5b showed an in
vitro anticancer activity with IC value of 0.12 µM, when the cells were subjected to different
5
0
concentrations of the compound alone. While, when the cells were subjected to the same
concentrations of compound 5b, and irradiated with a single dose of ɤ-radiation at a dose level of
8
Gy, the IC value was synergistically decreased to 0.07 µM. Similarly, compound 6b showed
50
IC value of 0.29 µM when used alone and the IC decreased to be 0.16 µM after radiation.
5
0
50
Similar observations for the rest of the tested compounds as shown in table 3. The results proved
the ability of the synthesized compounds to sensitize cancer cells to the lethal effects of ionizing
radiation in order to decrease the dose of the drug and decrease its toxicity.
Table 3. In-vitro anticancer activity of compounds 5b, 6b, 10b-13b against HEPG-2
hepatocellular carcinoma cells in combination with radiation (8Gy).
a
Compound No.
IC (µM)
5
0
5
6
1
1
1
1
b
b
0b
1b
2b
3b
0.07 ± 0.01
0.16 ± 0.01
0.30 ± 0.02
0.25 ± 0.01
0.23 ± 0.01
0.39 ± 0.02
a
Each value is the mean of three experiments ± standard error.
Docking simulation for compounds 5b, 6b, 10-13b was done to more understand their
binding mode in the VEGFR2 active site to interpret their observed in vitro inhibitory activity.
The docking results showed that they fit into the enzyme active site almost at the same position
of sorafenib with docking scores in the range of -12.31 to -11.57 kcal/mol. Table 4. Docking of
3
1
Sorafenib was performed and the binding pattern was found as reported with docking score
(S= -18.11 kcal/mol); N-methylpicolinamide is connected to Cys919 by two hydrogen bonds in
7

the ATP binding site, on the urea linker, the core scaffold, there are two important hydrogen
bonds with Glu885 and Asp1046 and the 3-chloro-4-trifluoromethyphenyl group shares as a
hydrophobic moiety embedded in the allosteric site. Inspection of the top docking poses of
compounds 5b, 6b, 10b, 11b and 13b (Figures 2-8, Table 4)) revealed that pyridinyl sulfonamide
moiety is embedded in the ATP binding site and evolved with Cys919 with hydrogen bond either
with the oxygen atom of SO group or with N-pyridinyl atom. While, the enaminone linker acted
2
as essential hydrogen bond donor and acceptor for binding with Glu885 and Asp1046. Moreover,
the binding of compounds 5b and 11b is stabilized by arene interaction with Phe1047. A
different binding mode is observed for compound 12b, where, the sulfonamide moiety is
connected by three hydrogen bonds with Glu885, Asp1046 and Lys868. The terminal ester of
compounds 5b and 6b, or the substituted aromatic moieties of compounds 10-13b were
accommodated within a lipophilic pocket comprised of the side chains of Ile888, Leu889, Ile892,
Val898 Val899, Leu1019, Cys1024 and Ile1044, the binding mode of the docked compounds
explains their superiority over the other synthesized derivatives in biological activity.
Figure 2. 2D interaction map of sorafenib in VEGFR-2 active site (PDB: 4ASD).
8

Figure 3. 2D interaction map of compound 5b in VEGFR-2 active site.
Figure 4. 2D interaction map of compound 6b in VEGFR-2 active site.
9

Figure 5. 2D interaction map of compound 10b in VEGFR-2 active site.
Figure 6. 2D interaction map of compound 11b in VEGFR-2 active site.
1
0

Figure 7. 2D interaction map of compound 12b in VEGFR-2 active site.
Figure 8. 2D interaction map of compound 13b in VEGFR-2 active site.
1
1

Table 4. Docking results expressed as binding scores, amino acid interactions and bond length of
compounds 5b, 6b and 10-13b within the active site of VEGFR-2.
Compound No.
Binding Scores (Kcal/mol)
Ligand Atom
Residue
Bond length (Å)
5
b
-12.31
O of SO2
O of CO
Benzene
O of SO2
H of NH
O of CO
O of SO2
O of CO
N pyridine
Benzene
H of NH
H of NH
O of SO2
O of SO2
H of NH
O of CO
O of CO
H of NH
O of CO
H of NH
N pyridine
H of NH
Cys919
Asp1046
Phe1047
Cys919
Glu885
Asp1046
Cys919
Asp1046
Cys919
Phe1047
Glu885
Glu885
Lys868
Asp1046
Cys919
Glu885
Lys868
Asp1046
Asp 1046
Glu 885
Cys 919
Cys 919
1.95
1.97
2.92
1.92
1.87
2.12
2.28
1.90
1.81
1.99
1.76
1.76
1.98
2.21
2.27
1.78
1.67
2.02
1.76
2.11
1.95
2.29
6
b
-12.02
1
1
0b
1b
-11.68
-11.98
1
1
2b
3b
-12.14
-11.57
Sorafenib
-18.11
In conclusion, a novel series of novel series of thioureido-benzenesulfonamide
derivatives bearing an enaminone linker either meta or para oriented and having terminal linear
or substituted aromatic or heteroaromatic ring system 5-16a,b were designed and synthesized.
SAR findings revealed that para- oriented enaminone linker was more successful and yielded
more active compounds 5-16b, while, terminal substitution with ester group in compounds 5b
and 6b were the most potent VEGFR2 inhibitors compared to sorafenib. Moreover, the most
active compounds 5b, 6b, 10-13b showed interesting radiosensitizing activity when evaluated
for their in vitro anticancer activity in combination with γ-irradiation. The IC of the most potent
5
0
compounds were plotted in a histogram for better comparing their activity on HEPG2
hepatocellular carcinoma cells before and after radiation and also in vitro VEGFR-2 inhibitory
activity. (Figure 9). These preliminary findings introduce a novel group of HCC promising
treatments targeting both the tumor cell and the tumor vascular system. More mechanistic
investigations regarding other kinase inhibitory evaluation, anti-angiogenic, anti-apoptotic and
toxicity studies are still ongoing.
1
2

0
0
0
0
0
0
0
.7
.6
.5
.4
.3
.2
.1
0
0.66
0
.58
0
.44
0
.42
0
.39
0
.3
0
.29
0
.25
0
.23
0
.22
0
.21
0.16
0.057
0
.12
0
.07
0
.033
0.037
0.037
5b
6b
10b
11b
12b
13b
Compound No.
HEPG2
HEPG2 + 8Gy
VEGFR2
Figure 9. Histogram showing IC of the most potent compounds 5b,6b and 10-13b on HEPG-2
50
hepatocellular carcinoma cells before and after radiation and in vitro VEGFR-2 inhibitory activity.
Acknowledgments
The authors appreciate the staff members of gamma irradiation unit at the National
Center for Radiation Research and Technology (NCRRT) for carrying the irradiation process.
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GRAPHICAL ABSTRACT
Novel Thioureido-Benzenesulfonamide Derivatives with Enaminone Linker as
Potent Anticancer, Radiosensitizers and VEGFR2 inhibitors
a,b
c
a
a*
Mostafa M. Ghorab , Fatma A. Ragab , Helmy I. Heiba , Marwa G. El-Gazzar ,
Mostafa G. M. El-Gazzar
a
Novel series of thioureido-benzenesulfonamide derivatives bearing an enaminone linker
either meta or para oriented and having terminal linear or substituted aromatic or heteroaromatic
ring system 5-16a,b were designed and synthesized based on the general pharmacophoric
features of type II VEGFR2 inhibitors.
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HIGHLIGHTS





Thioureido-benzenesulfonamide enaminone derivatives.
Synthesis and characterization.
In vitro anticancer screening on HEPG2.
In vitro VEGFR2 inhibitory activity.
Radiosensitizing evaluation.
1
7