Synthesis and biological evaluation of 3-amino-, 3-alkoxy- and 3-aryloxy-6-(hetero)arylpyridazines as potent antitumor agents

Article abstract of DOI:10.1016/j.bmcl.2018.12.050

Various 3-amino-, 3-aryloxy- and alkoxy-6-arylpyridazines have been synthesized by an electrochemical reductive cross-coupling between 3-amino-, 3-aryloxy- or 3-alkoxy-6-chloropyridazines and aryl or heteroaryl halides. In vitro antiproliferative activity

Full text of DOI:10.1016/j.bmcl.2018.12.050

Accepted Manuscript
Synthesis and biological evaluation of 3-amino-, 3-alkoxy- and 3-aryloxy-6-
(hetero)arylpyridazines as potent antitumor agents
Stéphane Sengmany, Mathilde Sitter, Eric Léonel, Erwan Le Gall, Gervaise
Loirand, Thierry Martens, Didier Dubreuil, Florian Dilasser, Morgane
Rousselle, Vincent Sauzeau, Jacques Lebreton, Muriel Pipelier, Rémy Le
Guével
PII:
S0960-894X(18)30997-1
https://doi.org/10.1016/j.bmcl.2018.12.050
BMCL 26219
DOI:
Reference:
Bioorganic & Medicinal Chemistry Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
4 October 2018
29 November 2018
3 December 2018
Please cite this article as: Sengmany, S., Sitter, M., Léonel, E., Le Gall, E., Loirand, G., Martens, T., Dubreuil, D.,
Dilasser, F., Rousselle, M., Sauzeau, V., Lebreton, J., Pipelier, M., Le Guével, R., Synthesis and biological
evaluation of 3-amino-, 3-alkoxy- and 3-aryloxy-6-(hetero)arylpyridazines as potent antitumor agents, Bioorganic
& Medicinal Chemistry Letters (2018), doi: https://doi.org/10.1016/j.bmcl.2018.12.050
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Synthesis and biological evaluation of 3-amino-, 3-alkoxy- and 3-aryloxy-6-
(hetero)arylpyridazines as potent antitumor agents
Stéphane Sengmanya, Mathilde Sittera, Eric Léonela*, Erwan Le Galla, Gervaise Loirandc, Thierry Martensa,
Didier Dubreuilb, Florian Dilasserc, Morgane Roussellec, Vincent Sauzeauc, Jacques Lebretonb, Muriel
Pipelierb, Rémy Le Guéveld
a Electrochimie et Synthèse Organique, Université Paris Est, ICMPE (UMR 7182), CNRS, UPEC, 2 rue Henri Dunant, F-94320 Thiais, France
b Laboratoire de - de
, BP 92208, F-44322 Nantes Cedex 3, France
c INSERM, UMR1087, CNRS, UN V ’ x, 8 quai Moncousu - BP 70721, F-44007 Nantes Cedex 1, France
d Plate-forme ImPACcell, Structure Fédérative de Recherche BIOSIT, Université de Rennes 1, Campus de Villejean 2 Avenue du Pr. Leon
Bernard CS34317, F-35043 Rennes cedex, France
 Corresponding author. Tel.: +33-149781136; fax: +33-149781148; e-mail: leonel@icmpe.cnrs.fr
Keywords: Electrosynthesis; Nickel catalysis; Arylpyridazines; Biological evaluation; Cytotoxic activity
ABSTRACT: Various 3-amino-, 3-aryloxy- and alkoxy-6-arylpyridazines have been synthesized by an
electrochemical reductive cross-coupling between 3-amino-, 3-aryloxy- or 3-alkoxy-6-chloropyridazines and aryl or
heteroaryl halides. In vitro antiproliferative activity of these products was evaluated against a representative panel of
cancer cell lines (HuH7, CaCo-2, MDA-MB-231, HCT116, PC3, NCI-H727, HaCaT) and oncogenicity prevention of
the more efficient derivatives was highlighted on human breast cancer cell line MDA-MB 468-Luc prior establishing
their interaction with p44/42 and Akt-dependent signaling pathways.
The pyridazine ring system can currently be considered as a privileged scaffold in medicinal chemistry due to its
widespread distribution in active compounds displaying significant and varied biological properties.1 Pyridazines also
represent interesting phenyl surrogates due to possible secondary electrostatic interactions with proteins’ receptors
and exhibit modified ADME profile. Among these, very important subclasses are 3-amino-6-arylpyridazines, and to a
lesser extent, 3-aryloxy- and 3-alkoxy-6-arylpyridazines, which prove to display diverse biological activities
including analgesic,2 anti-inflammatory,3-6 anti-hypertensive,7-10 and anti-depressant activities.11-13 They have also
found applications in the treatment for obesity,14-17 neurodegenerative diseases,18-24 and were additionally used as
GABA-A receptor antagonists.25-27 Interestingly, whereas fused pyridazinic rings are also privileged in numerous
potential anticancer drugs acting either as DNA chelators, angiogenesis inhibitors, or protein kinase inhibitors,28 only
few examples of simple 3,6-disubstituted pyridazine derivatives exhibiting cytotoxic properties have been
documented yet (Fig. 1). Therefore, in 2002, general screening using the rat aortic ring assay (in vitro functional
model of angiogenesis) led to the discovery of a thiadiazole pyridazinic derivative (R 90324) with nanomolar in vitro
anti-angiogenic potency.29 A few years ago, George described the pyrazoline derivatives bearing phenyl pyridazine
core as new apoptosis inducers.30 IC50 up to 1.67 M are reported against HepG-2, MCF-7 and CaCo-2 cancer cell
lines. Although limited, these activities have to be balanced with a remarkable selectivity, normal cell lines remaining
safe until 300 M. In 2013, Ahmed described the synthesis and biological evaluation of a series of novel 3,6-
disubstituted pyridazines based on vatalanib’s (PTK787) structure.31 One of the tested compounds proved five times
more active on HT-29 cancer cell lines than the reference drug. More recently, Ahmed reported the synthesis of new
pyridazinic analogues of imatinib targeting VEGFR kinase.32 Biological assays revealed that one compound shows
improved cytotoxic activity compared to the reference drug imatinib on colon cancer cell line (HCT-116). It was also
demonstrated that the antitumor activity of some compounds is greater in vivo than that of imatinib against Ehrlich’s
ascites carcinoma (EAC) solid tumors in mice.
Fig. 1. Aminopyridazine derivatives described as potential antitumor agents.

In the last years, our group focused on electroreductive cross-couplings of diazinic rings with aryl halides using a
sacrificial anode process.33,34 As such experimental conditions are well mastered in the laboratory, we desired to
highlight the efficiency of the electrochemical process for the synthesis of a wide range of compounds embedding a
3,6-subtituted pyridazinic ring. In addition, as this subunit is a common feature of some scaffolds exhibiting
promising anti-cancer activities, we were prompted to undertake the biological assessment of this series of
compounds against various cancer cell lines. Therefore, we report herein the easy access to various 3-amino-, 3-
aryloxy- and 3-alkoxy-6-arylpyridazines and their biological evaluation as potent antitumor agents.
The synthesis of 3-amino-, 3-aryloxy- and 3-alkoxy-6-(hetero)arylpyridazines 3 and 5 was undertaken from the
corresponding chloropyridazines 1 and 4, in the presence of aryl or heteroaryl halide partners 2 following the general
and effective electrochemical reductive cross-coupling process developed in our laboratory (Scheme 1).33
Scheme 1. Overview of the electrochemical couplings.
Electrolyses were performed in an undivided cell, under galvanostatic mode, using an iron/nickel (64/36) anode
and a nickel foam cathode, until consumption of the starting materials. Thus, after a short optimization of the general
reaction parameters, it was found that under a constant current intensity of 0.2 A, the cross-coupling between
chloropyridazines 1 or 4 (1 equiv.) proceeded better with (hetero)aryl halides 2 (2 equiv.) in N,N-dimethylformamide
(DMF) at room temperature, in the presence of NiBr2bpy (10 mol%) as a pre-catalyst and tetrabutylammonium
bromide as supporting electrolyte.
The synthesis of 3-amino-6-(hetero)arylpyridazines 3 from 3-amino-6-chloropyridazines 1 was examined first.35
Results are reported in Table 1.
Table 1
Synthesis of 3-amino-6-(hetero)arylpyridazines 3a,b.
3a (X=I, 44%)
3b (X=Br, 48%)
3f (X=Br, 28%)
3c (X=Br, 68%)
3g (X=Br, 48%)
3d (X=Br, 65%)
3h (X=Br, 60%)
3e (X=Br, 38%)
3i (X=Br, 61%)
3m (X=Br, 58%)
3q (X=I, 58%)
3j (X=Br, 62%)
3n (X=Br, 70%)
3r (X=I, 64%)
3k (X=Br, 55%)
3o (X=Br, 30%)
3s (X=I, 46%)
3l (X=I, 62%)
3p (X=Br, 70%)
3t (X=Br, 71%)

3u (X=Br, 31%)
3y (X=I, 72%)
3v (X=Br, 26%)
3z (X=Br, 67%)
3w (X=I, 67%)
3x (X=Br, 66%)
3ab (X=Br, 36%)
3aa (X=Br, 58%)
3ac (X=I, 52%)
Typical reaction conditions: iron/nickel (64/36) rod anode, nickel foam cathode, DMF (50 mL), tetrabutylammonium
a
bromide (1.2 mmol), 1,2-dibromoethane (2.5 mmol), NiBr2bpy complex (10 mol%), chloropyridazine 1 (4 mmol), aryl
or heteroaryl halide 2 (8 mmol), I = 0.2 A. b Isolated yields.
Coupling products were prepared using either aryl bromides or iodides36 in limited to good yields (26 to 72%),
depending on the substitution pattern of the organic halide. It was also observed that substituted phenyl bromides are
more efficient as partners for the coupling reaction when the substituent is electron-withdrawing whereas iodides
react better in the presence of electron-donating groups (compounds 3a, 3l, 3q-s, 3w, 3y and 3ac). The position of the
substituent has a non-negligible influence on the coupling efficiency as variable yields are obtained with ortho, meta,
and para-substituted aryl halides (compounds 3m, 3n and 3o). Both electronic effects and steric hindrance can
explain low yields with aryl bromides or heteroaromatic partners substituted at the ortho-position of an electron-
withdrawing group like CO2Et (compound 3o).37 The nature of the amino group at the para-position shows notable
influence on the coupling yield, as a pyrrolyl group (compound 3ab) leads to worst results than aliphatic amino
groups like diethylamino or morpholino groups (compounds 3i and 3n). However, amino groups like piperazines are
well tolerated, with some yields close to 70% (compounds 3w, 3x and 3y).
Encouraging biological results obtained with para-amino esters 3g and 3h (see biological part below) prompted us
to prepare the amino acid mimic 3g’ derived from 3g (Scheme 2). Indeed, the hydrolysis of the ester group prior to
biological assessment would likely anticipate potential hydrolysis that often occurs in physiological medium. It was
thus considered relevant to compare the in vitro cytotoxic activity of a genuine amino ester to that of the
corresponding hydrolysed species.
Scheme 2. Synthesis of amino acid 3g’.
Going further through this work, the synthesis of the oxygenated counterparts 3-alkoxy- and 3-aryloxy-6-
(hetero)arylpyridazines 5 from 3-alkoxy- and 3-aryloxy-6-chloropyridazines 4 was undertaken. Results are reported
in Table 2.
Table 2
Synthesis of 3-aryloxy- and 3-alkoxy-6-(hetero)arylpyridazines 5a,b.
5a (X=Br, 55%)
5b (X=Br, 58%)
5c (X=Br, 63%)
5d (X=Br, 86%)

5e (X=Br, 51%)
5f (X=Br, 51%)
5g (X=Br, 36%)
5h (X=Br, 79%)
5i (X=I, 57%)
5j (X=I, 52%)
a
Typical reaction conditions: iron/nickel (64/36) rod anode, nickel foam cathode, DMF (50 mL), tetrabutylammonium
bromide (1.2 mmol), 1,2-dibromoethane (2.5 mmol), NiBr2bpy complex (10 mol%), chloropyridazine 4 (4 mmol), aryl or
heteroaryl halide 2 (8 mmol), I = 0.2 A. b Isolated yields.
Electrosyntheses worked fairly well and afforded cross-couplings products in 36 to 86% yields. In a general
manner, results of cross-couplings in oxygenated series are comparable to those obtained from aminated pyridazinic
substrates, whatever the nature of the substituents on the phenyl ring. It can be noted that the coupling is also efficient
with heteroaryl halide such as 3-bromothiophene (compound 5h). Due to the possible presence of an aryloxy
substituent linked to the pyridazinic moiety, it was envisaged to additionally assess to effect of substituents connected
to the O-Ar moiety through the preparation of compounds 5i and 5j embedding para-fluoro and -cyano substituent,
respectively.
The antiproliferative activity of these 3-substituted-6-(hetero)aryl-pyridazine derivatives 3 and 5 were then
evaluated in vitro in seven human cancer cell lines HuH7 (hepatocellular carcinoma), Caco-2 (colorectal
adenocarcinoma), MDA-MB-231 (breast carcinoma), HCT116 (colorectal carcinoma), PC3 (prostate carcinoma),
NCI-H727 (lung carcinoid) and HaCaT (skin carcinoma) with roscovitine (cyclin-dependent kinase inhibitor),
doxorubicin (DNA topoisomerase inhibitors), Taxol (mitotic inhibitor) and Pi103 (dual PI3Kα/mTOR inhibitor) as
the reference compounds (see 2.1. and 2.2. of supplementary data). IC50, reported in Table 3, was defined as the drug
concentration causing 50% inhibition of cell proliferation (values between parentheses indicate the maximum cell
death percentage induced by the pyridazine derivatives).
Table 3
IC50 for compounds 3 and 5 on cancer cell lines.
Cell lines
Compound
MDA-MB-
HuH7
CaCo-2
HCT116
>25
PC3
NCI-H727 HaCaT
Fibroblast
231
DMSO
>25
>25
>25
>25
>25
>25
>25
Rosco (µM)
Doxo (µM)
Taxol (µM)
Pi103 (µM)
20 (90%)
10 (90%)
12 (80%)
9 (100%)
12 (8%)
20 (40%)
12 (80%)
12 (40%)
0.005 (40%)
0.03 (40%)
0.09 (60%)
0.012 (50%) 0.05 (80%)
0.08 (80%)
0.03 (60%) 0.03 (70%)
0.012 (50%) 0.02 (60%)
0.06 (60%)
8 (40%)
<0.001 (90%) <0.001 (60%) n.d.
0.002 (70%) <0.001 (30%)
6 (40%)
0.8 (60%)
3 (80%)
1.2 (60%)
>25
2 (70%)
>25
3a-3e (µM)
3f (µM)
>25
>25
>25
>25
>25
>25
>25
>25
>25
25 (80%)
0.09 (60%)
>25
15 (80%)
0.25 (80%)
>25
5 (60%)
6 (100%)
25 (80%)
20 (80%)
>25
3g (µM)
3g' (µM)
3h (µM)
3i (µM)
0.14 (60%) 0.06 (100%) 0.09 (72%)
0.09 (60%) 0.08 (85%)
>25 >25
1.5 (60%) 0.5 (80%)
0.10 (40%)
>25
>25
>25
>25
9 (60%)
>25
4 (80%)
>25
1.5 (70%)
>25
0.5 (90%)
>25
1 (80%)
>25
3 (40%)
>25
30 (40%)
>25
>25
-
3j (µM)
>25
>25
>25
>25
>25
>25
3k (µM)
3l-3v (µM)
>25
>25
>25
>25
>25
>25
-
>25
>25
>25
>25
>25
>25
>25
>25
>25
>25
>25
3w-3ac (µM) 30 (75%)
5a-5j (µM) >25
50 (80%)
>25
>25
>25
>25
>25
>25
>25
>25
>25
>25
>25

Among all evaluated 1-amino-6-(hetero)arylpyridazines in series 3, three derivatives 3f, 3g and 3h showed a
noticeable proliferation inhibition on selected cancer cells lines with a lower impact on healthy cells (i.e. fibroblast)
which shown almost 60% of survival cells, albeit with a similar IC50. While 3-N,N-diethylamino-6-para-
acetophenone-pyridazine (3f) showed a modest antiproliferative activity with IC50 ranging between 5 and 25 µM, the
two alkyl 4-(6-(diethylamino)pyridazin-3-yl)benzoate derivatives 3g and 3h exhibited significant IC50 with mean
ranges of 0.1 µM for 3g and 3 µM for 3h. Antiproliferative activity of 3g, in which a methyl ester group substitutes
the aryl moiety in para position, appeared to be the most efficient with ten-fold increase on CaCo-2, MDA-MB231,
HCT116, and HaCaT cell lines, and hundred-fold on HuH7 and PC3, compared to the ethyl ester homologue 3h.
Increasing the electron-withdrawing effect by the introduction of a cyano group (compound 3e) resulted in a total
loss of antiproliferative activity (IC50 > 25 µM). The presence of either electron-donating or electron-withdrawing
groups at meta-position of the phenyl did not restore the activity (compounds 3a-3d and 3i, IC50 > 25 µM). A similar
result was observed with a cyclic amino group at 3-position of pyridazines instead of the 3-N,N-dialkylamino
residues, as shown with the morpholino derivatives 3l-3v. None of other modifications performed at 3- and 6-
positions of pyridazines 3w-3ac, using various combinations of cyclic amino residues (substituted piperazine,
pyrrolidine) and aryl or hetetoaryl moieties, respectively, were able to restore proliferation inhibition activity.
These data seem to highlight a surprising selective behavior of the alkyl 4-(6-(dialkylamino)pyridazin-3-
yl)benzoate scaffold that would be ascribed, with caution, to a possible electronic delocalization, occurring from the
electron-donating dialkylamino residue to the electron-withdrawing aromatic ring, through the pyridazine moiety.
This subtle contribution of a polarized form in the activity of such pyridazine backbone is widened by the
antiproliferative inefficiency of all other analogues including compounds in series 5 designed to establish this
hypothesis further. In this latter series 5a-5j, the N,N-dialkylamino group at 3-position of the pyridazine derivatives
has been replaced by less electron-donating ether linkages or electron-withdrawing groups, giving IC50 values over
25 µM on all tested cancer cell lines.
More intriguing, ethyl 4-(6-(dimethylamino)pyridazin-3-yl)benzoate 3j and its methyl ester homologue 3k, also
appeared inactive under 25 µM in all cancer cell lines. These two analogues 3j and 3k only differ from pyridazines
3h and 3g by N,N-dialkylamino residue, which could counterbalance the electronic hypothesis made previously as
the only or main cause of their biological antiproliferative activity. As predictable, the amino acid 3g’ did not bring
more information due to a probable inability to cross cell membrane at physiological pH.
Thus, these previous results demonstrated that methyl 4-(6-(diethylamino)pyridazin-3-yl)benzoate 3g is able to
decrease cancer cells proliferation, albeit with low selectivity between lines. However, the cancer cells, regardless of
their origin, appear more sensitive to this new compound than healthy cells (i.e. fibroblasts). The results strongly
suggest a cytostatic activity on cell cycle rather than a cytotoxic effect from 3g that increase the interest of such novel
series of small molecules. Currently, the molecular mechanism allowing this activity is not identified inasmuch as a
slight change of substituent undergo a drastic decrease of their cancer cells antiproliferative effect.
The capacity of the selected molecules 3f, 3j, 3k, 3h and 3g to disrupt the phosphorylation level of p44/42 and
Akt, two enzymes involve in the cell cycle process, was then examined. However, instead of focusing the
investigation on widely studied HCT-116 tumor cells, the ability of these particular short aminoarylpyridazines to
inhibit these key enzymes on human triple-negative breast cancer cell line, one of the most aggressive cancers highly
associated with metastasis formation, was assessed. Only, few therapeutic solutions are currently available to prevent
oncogenicity of these particular cells and the discovery of simple molecules limiting their proliferation is off great
interest to design new therapeutic drugs. The breast cancer MDA-MB-468 cell line is characterized by the ability to
hyperactivate p44/42 and Akt-dependent signaling pathways promoting cell proliferation and linked to tumor
progression in triple-negative breast cancer.38,39 The capacity of the selected molecules 3f, 3j, 3k, 3h and 3g to
disrupt the phosphorylation level of p44/42 and Akt at a concentration of 10-5 M was examined first (Fig. 1A). By
western blot analysis (see 2.3. of supplementary data), it was observed that EGF-stimulated MDA-MB-468 cells
show potent decreased of P-p44/42 abundance (almost 70% of inhibition) after both 3h and 3g treatments, whereas 3f
exhibits less potency (50%) (Fig. 1B). However, 3g seems to maintain a potent effect on P-Akt inhibition (over 70%)
compared to 3h and, as observed in proliferation assays, no significant inhibitory effect was recorded with
compounds 3j and 3k upon both enzyme abundances.

Fig. 1. (A) Immunoblot analysis of P44/42 and Akt phosphorylation in MDA-MB-468-Luc cells treated with
indicated molecules. (B) Corresponding quantification of P44/42 and Akt phosphorylation.
Inhibition of clonogenic outgrowth of human breast cancer cells was then evaluated, showing a very good
correlation with their antiproliferative activity. MDA-MB 468-Luc cell line was cultured for 15 days in the presence
or not of molecules 3f, 3g, 3h, 3j and 3k. Then, cell cultures were stained with Giemsa to visualize and count the foci
of transformed cells (see 2.4. of supplementary data). As expected the two selected compounds 3g and 3h exhibited
markedly, whereas 3f, 3j and 3k displayed very poor or no significant effects. Increasing concentrations allowed to
establish IC50 (Fig. 2) and to confirm the higher activity of alkyl 4-(6-(diethylamino)pyridazin-3-yl)benzoate
analogues 3g and 3h (IC50 = 0.015 and 0.12 µM, respectively) compared to their dimethylamino counterparts 3j and
3k, respectively (IC50 = 26 for 3j and 3.5 µM for 3k). In this experiment, pyridazine 3f lacking ester function also
exhibited an unexpected activity with an IC50 of 0.65 µM.

Fig. 2. Focus formation assay. The human breast cancer cell line MDA-MB-468-Luc was treated with indicated
molecules (3f, 3g, 3h, 3j and 3k). Foci were photographed and counted after 2 weeks.
The toxicity of the most active molecules 3g and 3h was further evaluated in vitro on human hepatocytes,
HepaRG (see 4. of supplementary data) and in vivo on zebrafish assays (see 5. of supplementary data). Therefore,
HepaRG cells were incubated with 2.5 µM solutions of compounds 3g and 3h for 48 h (n = 3) without shown
toxicity. Furthermore, zebrafish embryos, incubated for 72 h with both molecules at two different concentrations
(0.8 and 2.5 µM), expressed toxicity only at a concentration of 2.5 µM, not observed at 0.8 µM. At this
concentration, the embryos remained alive, mobile, and their development was similar to the DMSO reference
without visible deformation. However, a reduced size of eyes observed in the presence of 3g at upper concentration
of 2.5 µM seemed to indicate a possible effect on this organ, undetectable at 0.8 µM.
In conclusion, several 3-amino-, 3-aryloxy- and alkoxy- 6-(hetero)arylpyridazines (series 3 and 5) have been
synthesized by an efficient electrochemical reductive cross-coupling process. All the prepared compounds were
tested for their in vitro antiproliferative activity against seven cancer cell lines and showed a very sensitive structural
effect depending of the nature of amino substituent and aryl ester group at positions 3 and 6 of the pyridazine anchor,
respectively. Only N,N-dialkylamino functions, with a preference for N,N-diethylamino vs N,N-dimethylamino, and
their exclusive association with a para-benzoate group at position 6, provided noticeable activity. Consequently, the
highest activity was found for compound 3g, exhibiting IC50 values at 10-1 µM range on several cancer cell lines
(MDA-MB231, HCT116, PC3, HaCaT, HuH7 and CaCo-2), albeit with a lack of selectivity. Regarding its ability to
inhibit key hyperactivated p44/42 and Akt-dependent signaling pathways, pyridazine 3g proved to be very interesting
with a potential tumor-selective mechanism of action. This compound also showed a potent ability to inhibit

clonogenicity of human breast cancer cell line, one of the most aggressive cancer, without inducing toxicity under
2.5 µM neither on human hepatocytes in vitro and in vivo on zebrafish thus paving the route for the design of novel
short pyridazine derivatives with therapeutic interest.
Acknowledgements
The authors are grateful to the CNRS and the Université Paris-Est Créteil for financial support on this work.
A. Supplementary data
Supplementary data associated to this article can be found, in the online version, at https://dx.doi.org/xxxx.
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