Design, synthesis, and molecular modelling of pyridazinone and phthalazinone derivatives as protein kinases inhibitors

Article abstract of DOI:10.1016/j.bmcl.2013.02.027

The design and synthesis of pyridazinone and phthalazinone derivatives are described. Newly synthesized compounds were tested on a panel of four kinases in order to evaluate their activity and potential selectivity. In addition, the promising compounds were tested on four cancer cell lines to examine cytotoxic effects. The compounds inhibited DYRK1A and GSK3 with different activity. SAR analysis and docking calculations were carried out to aid in the interpretation of the results. Taken together, our findings suggest that pyridazinone and phthalazinone scaffolds are interesting starting points for design of potent GSK3 and DYRK1A inhibitors.

Full text of DOI:10.1016/j.bmcl.2013.02.027

Bioorganic & Medicinal Chemistry Letters 23 (2013) 2007–2013
Contents lists available at SciVerse ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Design, synthesis, and molecular modelling of pyridazinone and
phthalazinone derivatives as protein kinases inhibitors
Mohamed Elagawany a,b,c, , , Mohamed A. Ibrahim a,b,d, , Hany Emary Ali Ahmed c,e, A. Sh. El-Etrawy b,
⇑
Adel Ghiaty c, Zakaria K. Abdel-Samii d, Said A. El-Feky d, Jürgen Bajorath f
a Laboratoire d’innovation thérapeutique, UMR 7200, Faculté de Pharmacie, Université de Strasbourg, 74-route du Rhin, BP 60024, 67401 ILLKIRCH Cedex, France
b Organic Chemistry Department, College of Pharmacy, Misr University for Science and Technology, Al-Motamayez District, 6th of the October, PO Box 77, Egypt
c Organic Chemistry Department, Faculty of Pharmacy, Al-Azhar University, Cairo 11884, Egypt
d Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Zagazig University, Zagazig-44519, Egypt
e Pharmacognosy and Pharmaceutical Chemistry Department, Pharmacy College, Taibah University, Al-Madinaha Al-Munawaraha, Saudi Arabia
f Department of Life Science Informatics, B-IT, LIMES Program Unit Chemical Biology and Medicinal Chemistry, Rheinische Friedrich-Wilhelms-Universität Bonn, Dahlmannstr. 2,
D-53113 Bonn, Germany
a r t i c l e i n f o
a b s t r a c t
Article history:
The design and synthesis of pyridazinone and phthalazinone derivatives are described. Newly synthe-
sized compounds were tested on a panel of four kinases in order to evaluate their activity and potential
selectivity. In addition, the promising compounds were tested on four cancer cell lines to examine cyto-
toxic effects. The compounds inhibited DYRK1A and GSK3 with different activity. SAR analysis and dock-
ing calculations were carried out to aid in the interpretation of the results. Taken together, our findings
suggest that pyridazinone and phthalazinone scaffolds are interesting starting points for design of potent
GSK3 and DYRK1A inhibitors.
Received 21 December 2012
Revised 24 January 2013
Accepted 2 February 2013
Available online 13 February 2013
Keywords:
Pyridazinone
Phthalazinone
Kinases
Ó 2013 Elsevier Ltd. All rights reserved.
Docking
GSK3
Large numbers of protein kinases are involved in controlling the
phosphorylation of protein in cells. This process plays an important
role in the regulation of various cellular processes.1–3 Alterations of
this kinase signalling are found in numerous human pathologies.4
Accordingly, kinase inhibitors continue to be of high interest for
therapeutic intervention. Currently, large numbers of small mole-
cule kinase inhibitors are undergoing clinical trials for the treat-
ment of cancer and other diseases, showing that kinases
constitute important therapeutic targets.
The role of cyclin-dependent kinases (CDKs) to regulate the cell
cycle and apoptosis have been well explored.5–8 They are involved
in several diseases, including cancer, Alzheimer’s disease, Parkin-
son’s disease, stroke, diabetes, polycystic kidney disease, glomeru-
lonephritis, inflammation, and AIDS.5,9 Glycogen synthase kinase-3
(GSK-3) plays an important role in a large number of cellular pro-
cesses, apoptosis control, neurodegenerative disorders (Alzhei-
mer’s disease) and cardiovascular diseases.9 Furthermore, casein
kinase 1 (CK1) plays an important role in controlling cell differen-
tiation, proliferation, apoptosis, circadian rhythms and has been
implicated in neurodegenerative diseases.10,11 Dual specificity,
tyrosine phosphorylation regulated kinase 1A (DYRK1A) plays a
key role in Alzheimer’s disease and Down syndrome.12
Several structurally diverse ligands were previously reported to
inhibit GSK-3. Examples include thiadiazolidindiones (TDZD), hyd-
antoins, triazoles, thiazoles, maleimides, dithiazolidindiones, and
pyrazolepyridines.13–19 Many current efforts toward the develop-
ment of novel kinase inhibitors concentrate on structure-based li-
gand design. A large number of X-ray structures of kinase-inhibitor
complexes are deposited in the Protein Data Bank with resolutions
in the range of 1.95–2.8 Å that provide a basis for compound design
and optimization. We have explored pyridazinone and phthalazi-
none scaffolds as potentially novel kinase inhibitors. Herein, we re-
port the design, synthesis and evaluation of novel pyridazinone
and phthalazinone derivatives.
The synthesized compounds were tested for kinase inhibitory
activity against four protein kinases including DYRK1A, CK1,
CDK5, and GSK3 types and, in addition, for cytotoxic activity
against four different human cancer cell lines. Structure–activity
relationships and the potential contribution of kinase inhibition
to anti-tumor properties are discussed.
⇑
Corresponding author. Tel.: +20 1001231305.
E-mail
addresses:
alfath_tours@yahoo.com,
drmmonem@yahoo.com
(M. Elagawany).
These authors equally contributed to this work.
0960-894X/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.bmcl.2013.02.027

2008
M. Elagawany et al. / Bioorg. Med. Chem. Lett. 23 (2013) 2007–2013
Cl
A detailed literature survey revealed that the majority of cur-
O
R2
R1
R2
R2
R1
N
N
rently available kinase inhibitor scaffolds consist of planar hetero-
cycles that carry both hydrogen bond donors and acceptor
moieties.20–22 The analysis of cyclin-dependent kinase inhibitors
and comparison with pyridazinone and phthalazinone cores sug-
gested that derivatives of these scaffolds should merit consider-
ation as potential kinase inhibitors (Fig. 1). Hence, we
synthesized pyridazinone and phthalazinone derivatives and eval-
uated their kinase inhibitor property.
Heating 3-phenylmaleic anhydride 1 under reflux with hydra-
zine sulfate in water yielded intermediate 2.23,24 Further treatment
of 2 with POCl3 gave the dichloro derivatives 3.24 Similarly, 1,4-
dichlorophthalazine 525 was synthesized from the commercially
available 2,3-dihydrophthalazine-1,4-dione 4 by treating with
POCl3 (Scheme 1).
POCl3
Reflux
NH
NH
H2SO4
NH2NH2
R1
H2O, Reflux
O
O
O
R1=H, R2=Ph
Cl
O
3
2
1
Cl
O
N
N
NH
NH
POCl3
Reflux
Cl
5
O
4
Scheme 1. Synthesis of the dichloro derivatives 3 and 5.
achieved by heating the same reaction mixture in microwave at
120 °C for 5 min.
Amination of intermediates 3 and 5 was carried out with vari-
ous amines (Scheme 2a and b). The use of excess amine with inter-
mediate 3 leads to the formation of two isomers 6a–h. The two
isomers can be separated easily using flash chromatography to give
each isomer in pure form except in the cases of 6g and 6h where
close rf resulted in poor separation and yielded only a small
amount of pure 6g. The use of the microwave was found to accel-
erate the reaction rate and reduce the reaction time dramatically
from 3 h to 30 min.26 Compounds 7a–g were obtained by heating
6a–g with acetic acid in presence of sodium acetate under reflux
overnight using conventional heating.27 The same result was
The use of excess amine in the case of intermediate 5 gives the
diamine 8e. Mono-substitution of intermediate 5 was achieved
using an equimolar quantity of the appropriate amine in presence
of base to afford 8a–d as single isomers. Hydrolysis of 8a–d was
achieved using the above mentioned method to afford 9a–d.
Simple amino substituted compounds 10a, 10b and 16 were
synthesised by the direct amination of chloro aromatics 3 and 5
with NH4OH either under reflux overnight or microwave irradia-
tion for 30 min (see Scheme 3a and b).
Hydrolysis of compound 10a with acetic acid in the presence of
sodium acetate for 3 h, gave two products 11a and 11b, which
Reference Compounds
HRM
H
N
N
O
BRW1383
Hymenialdisine
H2N
NH
HN
O
N
OH
N
O
Br
N
H
N
H
Br
NH
O
Target Compounds
R
R
NH
O
NH
O
N
N
NH
NH
Phthalazinone
Pyridazinone
Key Features
Planar hydrophobic fragment Hydrogen bonding fragments
Figure 1. Structural similarity of cyclin-dependent kinase inhibitors and pyridazinone and phthalazinone scaffolds. HRM, a selective DYRK1A inhibitor, hymenialdisine, an
inhibitor of different kinases, and BRW1383, a selective GSK3 inhibitor, are compared to pyridazinone and phthalazinone. These compounds display pharmacophoric
resemblance. Key structural features are highlighted in red or bold lines.

M. Elagawany et al. / Bioorg. Med. Chem. Lett. 23 (2013) 2007–2013
2009
R3
NH
in situ hydrolysis with acetic acid and sodium acetate produced
20f in a single step.
All synthesized compounds were evaluated for their inhibitory
activities against different kinases including DYRK1A, CK1, CDK5,
and GSK3 (Table 1). Three compounds showed promising initial
R3
NH
Cl
Cl
R2
R1
R2
R1
R2
R1
R2
R1
R3NH2
N
NH
N
N
CH3COOH
CH3COONa
N
N
N
N
O
HN
R3
Cl
6a,c,e,g
Cl
7a-g
3
6b,d,f,h
activity with IC50 values ranging from 2.2 to 8.1 lM. Two com-
1
2
3
pounds 12 and 20e exhibited good differential inhibitory activity
against GSK3 and DYRK1A enzymes and displayed a selective ten-
dency. In contrast, compound 13 was active against DYRK1A and
GSK. In our study, compounds were considered inactive if IC50 val-
6a,7a
6b,7b
6c,7c
6d,7d
; R =Ph, R =H, R =Benzyl
1
2
3
; R =Ph, R =H, R =Benzyl
; R =Ph, R =H, R3=Propyl
1
2
; R =Ph, R =H, R3=Propyl
1
2
6e,7e; R1=Ph, R2=H, R3=(2-(piperidin-1-yl)ethyl)
6f,7f ; R1=Ph, R2=H, R3=(2-(piperidin-1-yl)ethyl)
6g,7g; R1=Ph, R2=H, R3=(1-Methyl piperidin-4-yl)
6h ; R1=Ph, R2=H, R3=(1-Methyl piperidin-4-yl)
ues were 10 lM or larger.
The compounds 12, 13 and 20e were evaluated against four tu-
mour cell lines, and found to be active (Table 2). All three com-
pounds were active against all four cell lines, with IC50 values of
less than 15 lM over all the cell lines. The potency of all three com-
Scheme 2a. Synthesis of pyridazinone derivatives 7a–g.
pounds against cell line SF-295 was comparable. Furthermore,
compound 13 was most potent against all cell lines. Given the
activity of 13 for GSK3 and DYRK1A, these kinases might play an
important role in these four different types of cancer cells.
Regarding Kinases activity, only three compounds exhibited
promising activity, two phenyl pyridazine and one phthalazine
analogs. 5-Substitution of phenyl pyradazine with amino function
group results a compound 13 with modest activity (6 and 8.1 lM)
towards only DYRKA and GSK-3 kinases respectively. However,
acetylation of such compound revealed a potent compound 12
were separated by flash chromatography. By hydrolysis of 10b
with acetic acid under reflux conditions overnight compound 12
was obtained as a single product. Compound 13 was prepared by
removal of the acetyl group of 12 using a mixture of NaHCO3 in
H2O-dioxan under reflux for 48 h. Benzoylation of compound 10b
using benzoyl chloride in the presence of DIPEA gave compound
14, which was hydrolyzed by acetic acid and sodium acetate to
produce 15.
For the phthalazine derivatives, reaction of the NH2 with acid
chlorides or anhydrides using microwave heating gave clean reac-
tions of mixtures of mono, di-substituted amines which can be re-
solved by hydrolysis to give the desired compounds 20a–d.
Reaction of compound 16 with acetic acid and sodium acetate
produced a mixture of 20c and 20e, which was confirmed by HPLC.
Heating the resulting reaction mixture with water gave the 20e.
Reaction of compound 16 with benzoyl chloride followed by
(IC50 2.2 lM) with GSK-3 kinase selectivity and lost of the activity
towards the others. This proved that the substitution in the 5-pos-
tion of phenyl pyridazine scaffold affected and trapped the activity
between only DYRKA and GSK-3 enzymes. The other derivative of
phthalazine scaffold 20e showed a promising degree of activity and
hence selectivity (4.1 lM) against DYRKA enzyme through the
4-amino substitution. Taken all together, we can conclude that, (1)
all target compounds have only activity against two enzymes from
R
NH
Ph
Ph
NH
Cl
Cl
NH
Ph
(3eq)
NH2
(1eq)
R4 NH2
N
NH
N
N
CH3COOH
CH3COONa
N
N
N
N
O
NH
8e
Cl
9a-d
8a-d
5
8a,9a; R=benzyl
8b,9b; R=propyl
8c,9c
; R=(2-(piperidin-1-yl)ethyl)
8d,9d; R=(1-Methyl piperidin-4-yl)
Scheme 2b. Synthesis of phthalazinone derivatives 9a–d.
NH2
N
NH
O
Ph
NH
NH2
Ph
Ph
CH3COOH
CH3COONa
N
NH
N
N
O
11b
O
11a
Cl
Cl
10a
Ph
N
N
NH4OH
O
O
Cl
Ph
Cl
3
Ph
NH
N
Ph
Dioxane
NaHCO3
CH3COOH
CH3COONa
NH
N
N
N
NH2
13
HN
12
O
NH2
10b
O
O
Cl
Ph
Ph
NH
N
Cl
Ph
CH3COOH
CH3COONa
N
N
Ph NH
15
Ph NH
14
O
O
Scheme 3a. Synthesis of pyridazinone substituted amide 11–15.

2010
M. Elagawany et al. / Bioorg. Med. Chem. Lett. 23 (2013) 2007–2013
O
O
O
HN
O
O
N
CH3COOH
N
N
N
Cl
NH
CH3COONa
17a
17b
Cl
20a
18a
Cl
Cl
N
N
O
HN
O
HN
O
O
N
O
N
5
CH3COOH
N
Cl
N
N
N
N
NH
CH3COONa
NH4OH
O
20b
Cl
Cl
18c
18b
NH2
N
N
O
O
O
O
O
HN
O
O
N
O
CH3COOH
N
NH
16
Cl
NH
CH3COONa
17c
O
19a O
20c
CH3COOH\
Cl CH3COONa
O
O
O
Ph
O
HN
O
O
N
HN
N
O
O
O
CH3COOH
N
NH
N
NH
N
N
N
N
HN Ph
CH3COONa
17d
N
NH
20d
O
O
19b
Cl
Cl
18d
18e
O
20f
HN
O
NH2
N
NH
NH2
H2O
CH3COOH
N
N
NH
NH
CH3COONa
20e
O
O
20c
20e
O
Scheme 3b. Synthesis of phthalazinone substituted amide 20a–f.
Table 1
Table 2
Kinases activity
Cytotoxic activity of compounds 12, 13 and 20e against four cell lines
Cancer cell lines (IC50, l
M)*
Compound
IC50 (l
M)*
Compounds
DYRK1A
CK1
CDK5
GSK3
OVCAR-8
SF-295
HCT-116
HL-60
7a–g
9a–d
11a–b
12
>10
>10
>10
10
>10
>10
>10
>10
>10
>10
>10
>10
>10
>10
>10
>10
>10
>10
>10
>10
>10
>10
>10
>10
>10
>10
>10
>10
>10
>10
>10
2.2
12
13
20e
14.00
4.86
11.78
7.66
5.71
6.06
15.44
4.40
12. 71
11.61
3.64
8.87
*
All measurements were determined in triplicate, and mean values are reported.
Data are presented as IC50 values, with 95% confidence intervals obtained by non-
linear regression for all cell lines.
13
14
15
6
8.1
>10
>10
>10
>10
>10
4.1
>10
>10
>10
>10
>10
>10
>10
>10
18a–c
19a–b
20a–d
20e
ulated annealing. We compared newly active compounds to crys-
tallographic reference inhibitors to derive hypothetical binding
modes and study structural features implicated in activity. Figures
2 and 3 show the crystallographic binding modes of these two
inhibitors. First, crystallographic inhibitors were redocked to
reproduce their structure and adjust docking parameters accord-
ingly. Only 6-amino phenyl pyradazinone 13 was active against
DYRK1A and GSK3. Introduction of an acetyl amino group instead
of the amine rendered the compound 12 selective for GSK3.
Hence, modifications at this site modulated the activity of pyr-
adazinone ligands. The new inhibitors were docked into the active
sites of DYRK1A and GSK3. Figures 4 and 5 show preferred docking
poses of compound 13 in complex with DYRK1A and GSK3.
In addition, Figure 6 shows the hypothetical binding mode of
compound 12 in the active site of GSK3 and Figure 7 the hypothet-
ical binding mode of compound 20e in the active site of DYRK1A.
From the docking studies, preliminary SAR trends are beginning
to emerge.
20f
*
All measurements were determined in triplicate, and mean values are reported.
The standard error of determination in all cases does not exceed 10%. IC50 value
reported as >10
l
M indicates that the compound did not display any inhibitory
activity at the highest concentration tested (10
lM).
the kinase panel, (2) two factors affect activity/selectivity towards
these enzymes, that is, scaffolds and distinct substitution patterns.
In addition, molecular docking was carried out for further SAR
analysis.
To explore possible SAR characteristics of the newly identified
inhibitors, docking analysis was carried out using the Molecular
Operating Environment (MOE 2008.10)28 on the basis of high res-
olution crystal structures of DYRK1A in complex with HRM (PDB
code 3ANR) and GSK3 in complex with BRW1383 (PDB code
1UV5).29 Target proteins and ligands were energy-minimized using
MOE. The following parameters were used for energy minimiza-
tion; gradient: 0.01, force field: MMFF94X, chiral constraint: cur-
rent geometry; total runs = 50, cycles/run = 15, iteration
limit = 10,000, potential energy grid: on, annealing algorithm: sim-
The binding mode of the crystallographic inhibitor HRM and the
putative binding mode of compound 13 in the active site of DYR-
K1A are very similar involving interactions with Leu241 and
Glu239. As indicated in Figure 8, compound 20e may form three

M. Elagawany et al. / Bioorg. Med. Chem. Lett. 23 (2013) 2007–2013
2011
Figure 2. Crystallographic binding mode of HRM in the active site of DYRK1A (PDB
code 3ANR).
Figure 5. Hypothetical binding mode of compound 13 in the active site of GSK3.
Figure 3. Crystallographic binding mode of BRW1383 in the active site of GSK3
(PDB code 1UV5).
Figure 6. Hypothetical binding mode of compound 12 in the active site of GSK3.
hydrogen bonding interactions via the amino group substituent
and, in addition, aromatic/hydrophobic interaction with the
Leu241 residue. This binding mode may results in a selective ten-
dency, although these interactions cannot be predicted with cer-
tainty. However, these putative interactions are quite different
from the reference ligand Figure 2 that may contribute to selectiv-
ity towards DYRK1A. Similar observations are made for compound
13 and crystallographic inhibitor BRW1383 in the active site of
GSK3, Figure 5. Taken together, these observations might rational-
ize the observed dual activity of compound 13. Also, the putative
interaction of compound 12 with GSK3 suggests that the pyrad-
azine ring might form two hydrogen bond interactions with the
backbone carbonyl group of Asp133 and the backbone amide of
Val135 respectively. Moreover, another hydrogen bond might be
formed through the acetamido NH with Val135 residue, different
from binding mode of compound 13 in Figure 6. In addition, the
fit of the aromatic ring into the hydrophobic pocket might support
selective binding, in addition to the orientation of the acetamido
group relative to the imide N in the inodolinoxime fragment of
the BRW reference compound in Figure 9.
Figure 4. Hypothetical binding mode of compound 13 in the active site of DYRK1A.

2012
M. Elagawany et al. / Bioorg. Med. Chem. Lett. 23 (2013) 2007–2013
Figure 7. Hypothetical binding mode of compound 20e in the active site of
DYRK1A.
Figure 9. 2D Interaction model of complex BRW-GSK3. Ligands BRW (red), 12
(green), and 13 (blue) are docked and shown with the residues of active site.
Hydrogen bonds are shown as dotted lines consistent with ligand colors.
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In conclusion, we have designed and synthesized a new series of
bicyclic heteroaromatic systems of fused or linked types containing
pyridazinone fragment. Structure–activity relationships of these
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Supplementary data
Supplementary data associated with this article can be found,
in the online version, at http://dx.doi.org/10.1016/j.bmcl.2013.
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