Synthesis and antidepressant activity of 5-(benzo[b]furan-2-ylmethyl)-6-methylpyridazin-3(2H)-one derivatives

Article abstract of DOI:10.1007/s00044-015-1490-x

A new series of pyridazin-3-one derivatives were designed, synthesized and evaluated for their preclinical antidepressant effect on Swiss mice. Among the series, compounds 6c, 6d and 6f exhibited significant activity profile in forced swimming test. Compounds 6c and 6d were most efficacious, which at dose of 50 mg kg^-1 reduced the time of immobility by 42.85 and 38.09 %, respectively, as compared to the standard drug fluoxetine which reduced the immobility time by 45.23 % at the dose of 32 mg kg^-1. All the test and standard compounds were administered orally 60 min before the test. Interestingly, all active compounds did not cause any significant alteration of locomotor activity in mice as compared to control, indicating that the hybrids did not produce any motor impairment effects. The results indicate that pyridazin-3(2H)-one derivatives may have potential therapeutic value for the management of mental depression.

Full text of DOI:10.1007/s00044-015-1490-x

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res
DOI 10.1007/s00044-015-1490-x
ORIGINAL RESEARCH
Synthesis and antidepressant activity of 5-(benzo[b]furan-2-
ylmethyl)-6-methylpyridazin-3(2H)-one derivatives
Youness Boukharsa1 Bouchra Meddah2 Ramata Yvette Tiendrebeogo2 Azeddine Ibrahimi4
•
•
•
•
Jamal Taoufik1 Yahia Cherrah2 Ali Benomar3 My El Abbes Faouzi2 M’hammed Ansar1
•
•
•
•
Received: 1 June 2015 / Accepted: 15 December 2015
Ó Springer Science+Business Media New York 2016
Abstract A new series of pyridazin-3-one derivatives
were designed, synthesized and evaluated for their pre-
clinical antidepressant effect on Swiss mice. Among the
series, compounds 6c, 6d and 6f exhibited significant
activity profile in forced swimming test. Compounds 6c
and 6d were most efficacious, which at dose of 50 mg kg-1
reduced the time of immobility by 42.85 and 38.09 %,
respectively, as compared to the standard drug fluoxetine
which reduced the immobility time by 45.23 % at the dose
of 32 mg kg-1. All the test and standard compounds were
administered orally 60 min before the test. Interestingly, all
active compounds did not cause any significant alteration
of locomotor activity in mice as compared to control,
indicating that the hybrids did not produce any motor
impairment effects. The results indicate that pyridazin-
3(2H)-one derivatives may have potential therapeutic value
for the management of mental depression.
Keywords Pyridazin-3(2H)-one derivatives Á
Antidepressant activity Á Forced swimming test (FST) Á
Locomotor activity
Abbreviations
1H NMR 1H nuclear magnetic resonance
CDCl3
CHCl3
CNS
Deuterated chloroform
Chloroform
Central nervous system
Dimethylformamide
DMF
DMSOd6 Deuterated dimethylsulfoxide
ESI
Electrospray ionization
Forced swimming test
FST
HCl
Chlohydric acid
IR
Infrared
KBr
Potassium bromide
LD
Lethal dose
MAOIs
MDD
NaOH
SNRIs
SSRIs
TCAs
TMS
TRI
Monoamine oxidase inhibitors
Major depression disorder
Potassium hydroxide
Serotonin–norepinephrine reuptake inhibitors
Selective serotonin reuptake inhibitors
Tricyclic antidepressants
Tetramethylsilane
& M’hammed Ansar
ansarmhammed@gmail.com
1
Laboratory of Therapeutic Chemistry, Faculty of Medicine
and Pharmacy, BP 6203, Rabat Institutes, Mohammed V
University, Rabat, Morocco
Triple reuptake inhibitors
United States Food and Drug Administration
World Health Organization
USFDA
WHO
2
Laboratory of Pharmacology and Toxicology,
Pharmacokinetic Research Team, Faculty of Medicine and
Pharmacy, Rabat Institutes, Mohammed V University, Rabat,
Morocco
3
Faculty of Medicine and Pharmacy, Research Center for
Clinical Epidemiology and Therapeutic Trials, Mohammed V
University, Rabat Institutes, Rabat, Morocco
Introduction
Major depression disorder (MDD) is described as a
depressive state of mind, which is associated with faulty
mood, loss of interest, disruption in sleep patterns, fatigue
4
Biotechnology Laboratory, Faculty of Medicine and
Pharmacy, Rabat Institutes, Mohammed V University, Rabat,
Morocco
123

Med Chem Res
and sometimes suicidal tendencies. It is a chronic and life-
threatening mental illness, which remains hidden and
untreated at most of the times (Hampton, 2012). World
Health Organization (WHO) had estimated that ‘at least
350 million people live with depression and it is the leading
cause of disability worldwide’ (WHO, 2012). Epidemio-
logical studies have indicated that about 2/3 of people who
commit suicide are depressed at the time of their death (Al-
Habeeb et al., 2013). Exact cause of depression is not
clearly known, but it is believed that imbalance of neuro-
transmitters in brain, genetic vulnerability, stressful life
events and medical problems are the main factors leading
to depression (DeWeerdt, 2013). Currently available
antidepressant treatments are selective serotonin reuptake
inhibitors (SSRIs), monoamine oxidase inhibitors (MAO
Is), tricyclic antidepressants (TCAs), serotonin–nore-
pinephrine reuptake inhibitors (SNRIs) and some non-
medication therapeutic options (Chancellor, 2011). Even
though wide range of conventional therapies is available,
nearly 15 % of depressed people are still refractory to the
current existing therapies (Anderson et al., 2012). In
addition, most of the people suffer from relapse and
experience serious side effects after treatment with current
therapies (Check, 2004; Licinio and Wong, 2005). In
February 2007, the USFDA displayed ‘black box’ label on
currently available antidepressants indicating that their use
may increase the risk of suicidal thinking behavior in few
cases of children, adolescents and adults (Friedman and
Leon, 2007). Hence, there is an urgent need to develop new
class of prototypes that are more effective, tolerable and
safe in depressed individuals against this deadly disorder.
Considerable interest has been paid to derivatives con-
taining 5-arylpyridazinone moieties, because of their
effects on the central nervous system (CNS) (Bosc et al.,
1990; Mokrosz et al., 1992; Perregaard et al., 1992;
Sladowska, 1993). However, two pyridazine derivatives,
5-benzyl-6-methyl-2-[4-(3-trifluoromethylphenyl)piperazin-
1-yl] methylpyridazin-3-one and 5-benzyl-6-methyl-2-
[4-(3-chlorophenyl)piperazin-1-yl] methylpyridazin-3-one,
were evaluated for their potential antidepressant effects,
using classical psychopharmacological tests in mice. The
intraperitoneal LD50 values of these compounds were,
respectively, 1125.8 and 429.6 mg kg-1. Both compounds
(5–20 mg kg-1, i.p.) reduced the duration of immobility of
mice in the FST, antagonized reserpine (2.5 mg kg-1, i.p.)-
derivatives, as new generation of triple reuptake inhibitors
(TRI) and observed significant antidepressant effects
(Castro et al., 1994).
Based on these observations, we were interested in
evaluating the pharmacological properties of a new series
of 5-(benzo[b]furan-2-ylmethyl)-6-methylpyridazin-3(2H)-
one derivatives.
This report describes the chemical synthesis and bio-
logical evaluation of 5-(benzo[b]furan-2-ylmethyl)-6-
methylpyridazin-3(2H)-one derivatives as antidepressant
agents.
Materials and methods
Chemistry
The synthesis of 5-(benzo[b]furan-2-ylmethyl)-6-methylpyri-
dazin-3(2H)-one derivatives is outlined in Scheme 1. Salicy-
laldehydes 2a-g, which are not commercially available, were
synthesized via Reimer-Thieman (Thoer et al., 1988) formy-
lation of the appropriate substituted phenols 1 with CHCl3 and
NaOH. Aldehydes 2a–g have been previously synthesized
with very low yield. Briefly, reaction of intermediates 2a–g
with bromacetaldehyde diethylacetal in the presence of
potassium carbonate in DMF (dimethylformamide) yielded
compounds 3a–g. These compounds 3 were cyclized to
Benzo[b]furan-2-ylcarboxaldehydes 4a–g by heating in con-
centrated acetic acid. Benzo[b]furanaldehydes 4 were pre-
pared according to the methods described in the literature
(Hirota et al., 1986). Treatment of substituted aldehydes 4 with
levulinic acid in the presence of acetic acid gave products 5a–g,
which were treated by hydrazine hydrate in ethanol at reflux
temperature to afford the pyridazin-3(2H)-ones 6a–g (Ben-
moussa et al., 2012).
Antidepressant activity
Antidepressant activity was measured with fluoxetine as
standard drug using the FST in Swiss mice. Swiss mice
were placed in a vertical Plexiglas cylinder filled with
water, maintained at 25 °C, for 15 min. Five to 6 min later
immobility reached a plateau, where the mice remained
immobile for approximately 80 % of the time. After
15 min in the water, the mice were removed and allowed to
dry in a heated enclosure (32 °C) before being returned to
their home cages. They were again placed in the cylinder
for 24 h later, and the total duration of immobility was
measured during a 5 min test (Table 1). After solubilizing
the product in vegetable oil, the solution was administered
directly into the stomach of mice via a technique called
oral gavage (0.2 mL of solution/20 g of animals). The
newly synthesized compounds were administered at a dose
induced ptosis and potentiated reserpine (2.5 mg kg-1
,
i.p.)-induced hypothermia (Rubat et al., 1995).
Many reports suggest that pyridazinones and their syn-
thetic analogues can be considered as anti-inflammatory
¨
agents (Ozadali et al., 2012), anticancer agents (Lattmann
et al., 2003) and also possess an anti-feedant activity
(Huang et al., 2003). On the other hand, Castro and col.
have synthesized a series of substituted pyridazine
123

Med Chem Res
R
H
C O
R
R
H
C O
6
3
6
2
1
1
4
5
a
b
5
4
H
OC2
5
2
3
H
C
2
O
H
C
H
O
H
O
1a-g
2a-g
3a-g
H
OC2
5
c
H
C
COO
H
2C
H
3
C
R
R
C
H
4'
4'
3'
3'
5'
6'
5'
6'
d
O
H
C O
C
2'
2'
1'
1'
7'
7'
O
O
5a-g
4a-g
e
O
NH
3
2
4
1N
6
5
R
4'
3'
5'
6'
H
C
H
C
3
2
2'
1'
7'
O
6a-g
Compound
R
a
b
c
d
e
f
H
CH3
CH2CH3
CH(CH3)2
OCH3
OCH2CH2CH3
Cl
g
Scheme 1 Synthesis of target compounds 6a-g. Reagents: a CHCl3/NaOH 10 N, reflux 2 h; b BrCH2CH(OC2H5)2/K2CO3/DMF, reflux 4 h;
c CH3COOH, reflux 24 h; d H3CCOCH2CH2COOH/CH3COOH, reflux 24 h; e H2NNH2/EtOH, reflux 2 h
123

Med Chem Res
of 50 mg kg-1, orally 60 min before the test. The fluox-
etine was administered at a dose of 32 mg kg-1, orally
60 min before the test. (Porsolt et al., 1977, 1978; Petit-
Demouliere et al., 2005).
(0.4 mmHg); IR (KBr mmax cm-1), 1655 (C=O); 1H NMR
(CDCl3, 400 MHz), d = 7.00–8.10 (m, 4H, H3, H4, H5,
H6), 9.85 (s, 1H, –CHO), 10.85 (s, 1H, exch D2O, –OH).
2-Hydroxy-5-methylbenzaldehyde 2b. This compound
was obtained as white solid, yield 95 %, mp 48–50 °C
(petroleum ether); IR (KBr mmax cm-1), 1650 (C=O),
2900–3000 (C–H); 1H NMR (CDCl3, 400 MHz), d = 2.37
(s, 3H, –CH3), 6.90 (d, 1H, J = 8.60 Hz, H3), 7.25–7.50
(m, 2H, H4, H6), 9.80 (s, 1H, –CHO), 10.75 (s, 1H, exch
D2O, –OH).
Results and discussion
Chemistry
Melting points were determined on a Bu¨chi SMP 20
apparatus and are not corrected. Infrared (IR) spectra were
recorded with an IR VERTEX 70 FT-IR (Bruker Optics)
2-Hydroxy-5-ethylbenzaldehyde 2c. This compound
was obtained as yellow oil, yield 36 %, bp 74–76 °C
(0.3 mmHg); IR (KBr mmax cm-1), 1651 (C=O),
2900–3000 (C–H); 1H NMR (CDCl3, 400 MHz), d = 1.25
(t, 3H, j = 7.41 Hz, –CH2–CH3), 2.70 (q, 2H, j = 7.41 Hz,
–CH2–CH3), 6.83 (d, 1H, J = 9.50 Hz, H3), 7.26–7.52 (m,
2H, H4, H6), 9.87 (s, 1H, –CHO), 10.88 (s, 1H, exch D2O,
–OH).
1
spectrometer. H Nuclear magnetic resonance (1H NMR)
spectra were recorded on a Bruker Avance (400 MHz)
spectrometer, using tetramethylsilane (TMS) as internal
standard and CDCl3 and DMSOd6 as solvent. Mass spectra
were recorded on a API 3200 LC/MS/MS mass spec-
trometer using electrospray ionization (ESI) in positive
polarity.
2-Hydroxy-5-isopropylbenzaldehyde 2d. This com-
pound was obtained as yellow oil, yield 32 %, bp 78–80 °C
(0.3 mmHg); IR (KBr mmax cm-1), 1650 (C=O),
2900–3000 (C–H); 1H NMR (CDCl3, 400 MHz), d = 1.25
(d, 6H, j = 6.70 Hz, H3C–CH–CH3), 2.95 (h, 1H,
j = 6.70 Hz, H3C–CH–CH3), 6.88–7.38 (m, 3H, H3,H4,
H6), 9.87 (s, 1H, –CHO), 10.88 (s, 1H, exch D2O, –OH).
2-Hydroxy-5-methoxybenzaldehyde 2e, 2-Hydroxy-5-
propoxybenzaldehyde 2f and 5-chloro-2-Hydroxyben-
zaldehyde 2g, products commercially available.
General procedures for the formylation of phenols 2a–g:
Method A
A solution of the substituted phenols 1 (0.5 mol) in
300 mL of 10 N NaOH (3 mol) was heated to 65 °C. Then
80 mL of CHCl3 was added in three portions over 15 min.
The mixture was heated at reflux in chloroform for 2 h.
After cooling, the mixture was acidified to pH 1 with 12 N
HCl, the organic layer collected and the aqueous layer
extracted with chloroform. The combined chloroform
solution was dried and evaporated to give a crude product
which was distilled or recrystallized from an appropriate
solvent.
General procedures for the synthesis of 2-
formylphenoxyacetadehyde diethyl acetals 3a–g: Method B
To a stirred suspension containing substituted 2-hydroxy-
benzaldehydes 2 (0.15 mol) and potassium carbonate
(0.16 mol) in 100 mL of DMF, bromoacetaldehyde diethyl
acetal (0.16 mol) was added drop wise. The mixture was
2-Hydroxybenzaldehyde 2a. This compound was
obtained as yellowish oil, yield 20 %, bp 75–77 °C
Table 1 Representation of percentage change in immobility duration in FST after administration of different compounds and standard drug
fluoxetine to mice
Compound
Dose (mg/kg)
Immobility time SEM
% Immobility
Control
–
210 10
145 25
175 20
90 25
80 24
150 15
125 20
155 25
95 10
100
6a
50
50
50
50
50
50
50
32
69.04
6b
83.33
6c
42.85***
38.09***
71.42
6d
6e
6f
59.52***
73.81
6g
Fluoxetine
45.23***
*** P \ 0.0001, when compared with the control (vegetable oil)
123

Med Chem Res
refluxed for 4 h. After cooling, the precipitate was filtered
off and the solvent evaporated under reduced pressure. The
oily residue was distilled.
(2-Formyl-4-propoxyphenoxy)acetaldehyde diethylac-
etal 3f. This compound was obtained as yellow oil, yield
67 %, bp 180–183 °C (0.5 mmHg); IR (KBr mmax cm-1),
1700 (C=O), 2900–3000 (C–H); 1H NMR (CDCl3,
400 MHz), d = 1.01 (t, 3H, j = 7.21 Hz, –OCH2–CH2–
CH3), 1.24 (t, 6H, j = 6.91 Hz, (–OCH2–CH3)2), 1.78 (m,
2H, –OCH2–CH2–CH3), 3.69 (m, 4H, (–OCH2–CH3)2),
3.90 (t, 2H, j = 6.21 Hz, –OCH2–CH2–CH3), 4.07 (d, 2H,
j = 5.11 Hz, –CH2–CH), 4.83 (t, 1H, j = 5.11 Hz, –CH2–
CH), 6.76–7.31 (m, 3H, H3, H5, H6), 10.46 (s, 1H, –CHO).
(4-Chloro-2-formylphenoxy)acetaldehyde diethylacetal
3g. This compound was obtained as yellow oil, yield 90 %,
bp 140–143 °C (0.3 mmHg); IR (KBr mmax cm-1), 1690
2-Formylphenoxy acetaldehyde diethylacetal 3a. This
compound was obtained as yellowish oil, yield 85 %, bp
181–183 °C (5 mmHg); IR 1700 (C=O), 2900–3000 (C–
H); 1H NMR (CDCl3, 400 MHz), d = 1.23 (t, 6H,
j = 6.42 Hz, (–OCH2–CH3)2), 3.51–4.12 (m, 4H,
(–OCH2–CH3)2), 4.14 (d, 2H, j = 5.13 Hz, –CH2–CH),
4.89 (t, 1H, j = 5.13 Hz, –CH2–CH), 6.95–7.82 (m, 4H,
H3, H4, H5, H6), 10.48 (s, 1H, –CHO).
(2-Formyl-4-methylphenoxy)acetaldehyde diethylacetal
3b. This compound was obtained as yellow oil, yield 80 %,
bp 192–194 °C (5 mmHg); IR (KBr mmax cm-1), 1700
1
(C=O), 2900–3000 (C–H); H NMR (CDCl3, 400 MHz),
1
(C=O), 2900–3000 (C–H); H NMR (CDCl3, 400 MHz),
d = 1.26 (t, 6H, j = 7.60 Hz, (–OCH2–CH3)2), 3.50–4.00
(m, 4H, (–OCH2–CH3)2), 4.10 (d, 2H, j = 5.71 Hz, –CH2–
CH), 4.87 (t, 1H, j = 5.71 Hz, –CH2–CH), 6.95 (d, 1H,
j = 8.50 Hz, H6), 7.48 (dd, 1H, j1 = 2.81, j2 = 8.50 Hz,
H5), 7.79 (d, 1H, j = 2.81 Hz, H3), 10.43 (s, 1H, –CHO).
d = 1.25 (t, 6H, j = 6.40 Hz, (–OCH2–CH3)2), 2.30 (s,
3H, –CH3), 3.50–4.00 (m, 4H, (–OCH2–CH3)2), 4.12 (d,
2H, j = 5.10 Hz, –CH2–CH), 4.87 (t, 1H, j = 5.10 Hz,
–CH2–CH), 6.90 (d, 1H, j = 8.20 Hz, H6), 7.40 (dd, 1H,
j1 = 2.11, j2 = 8.20 Hz, H5), 7.62 (d, 1H, j = 2.11 Hz,
H3), 10.50 (s, 1H, –CHO).
General procedures for the synthesis of substituted
(2-Formyl-4-ethylphenoxy)acetaldehyde diethylacetal
3c. This compound was obtained as yellow oil, yield 81 %,
bp 198–200 °C (5 mmHg); IR (KBr mmax cm-1), 1690
(C=O); 2900–3000(C–H); 1H NMR (CDCl3, 400 MHz),
d = 1.00–1.38 (m, 9H, (–OCH2–CH3)2, –CH2–CH3), 2.62
(q, 2H, j = 7.61 Hz, –CH2–CH3), 3.50–4.00 (m, 4H,
(–OCH2–CH3)2), 4.08 (d, 2H, j = 4.70 Hz, –CH2–CH), 4.88
(t, 1H, j = 4.70 Hz, –CH2–CH), 6.88 (d, 1H, j = 8.50 Hz,
H6), 7.57 (dd, 1H, j1 = 8.50 Hz, j2 = 3.20 Hz, H5), 7.64 (d,
1H, j = 3.20 Hz, H3), 10.50 (s, 1H, –CHO).
Benzo[b]furan-2-yl carboxaldehydes 4a–g: Method C
A stirred solution of compounds 3 (0.1 mol) in 35 mL of
concentrated acetic acid was refluxed for 24 h. After cooling,
the solution was evaporated to dryness. The crude product
was distilled or recrystallized from an appropriate solvent.
2-Formylbenzo[b]furan 4a. This compound was
obtained as yellow oil, yield 75 %, bp 121–123 °C
1
(3 mmHg); IR (KBr mmax cm-1), 1680 (C=O); H NMR
0
0
0
(CDCl3, 400 MHz), d = 7.26–7.74 (m, 5H, H3 , H4 , H5 ,
0
H6 , H7 ), 9.84 (s, 1H, –CHO).
0
(2-Formyl-4-isopropylphenoxy)acetaldehyde diethylac-
etal 3d. This compound was obtained as yellow oil, yield
80 %, bp 160–162 °C (0.3 mmHg); IR (KBr mmax cm-1),
1700 (C=O), 2900–3000 (C–H); 1H NMR (CDCl3,
400 MHz), d = 1.00–1.30 (m, 12H, (–OCH2–CH3)2, H3C–
CH–CH3), 2.92 (h, 1H, j = 6.41 Hz, H3C–CH–CH3),
3.50–3.90 (m, 4H, (–OCH2–CH3)2), 4.10 (d, 2H,
j = 5.30 Hz, –CH2–CH), 4.88 (t, 1H, j = 5.30 Hz, –CH2–
CH), 6.90 (d, 1H, j = 8.51 Hz, H6), 7.40 (dd, 1H,
j1 = 2.70, j2 = 8.50 Hz, H5), 7.70 (d, 1H, j = 2.70 Hz,
H3), 10.50 (s, 1H, –CHO).
2-Formyl-5-methylbenzo[b]furan 4b. This compound
was obtained as yellow solid, yield 66 %, mp 26–27 °C
(ehanol/water 9/1); IR (KBr mmax cm-1), 1680 (C=O),
2900–3000 (C–H); 1H NMR (CDCl3, 400 MHz), d = 2.38
0
(s, 3H, –CH3), 7.40–7.77 (m, 4H, H3 , H4 , H6 ,H7 ), 9.87 (s,
0
0
0
1H, –CHO).
5-Ethyl-2-formylbenzo[b]furan 4c. This compound was
obtained as yellowish oil, yield 80 %, bp 130–132 °C
(3 mmHg); IR (KBr mmax cm-1), 1680 (C=O), 2900–3000
(C–H); 1H NMR (CDCl3, 400 MHz), d = 1.30 (t, 3H,
j = 7.90 Hz, –CH2–CH3), 2.76 (q, 2H, j = 7.90 Hz,
(2-Formyl-4-methoxyphenoxy)acetaldehyde diethylac-
etal 3e. This compound was obtained as yellow oil, yield
68 %, bp 154–156 °C (0.3 mmHg); IR (KBr mmax cm-1),
1700 (C=O), 2900–3000 (C–H); 1H NMR (CDCl3,
400 MHz), d = 1.25 (t, 6H, j = 6.40 Hz, (–OCH2–CH3)2),
2.38 (s, 3H, –OCH3), 3.45–4.30 (m, 4H, (–OCH2–CH3)2),
4.42 (d, 2H, j = 5.10 Hz, –CH2–CH), 4.97 (t, 1H,
j = 5.10 Hz, –CH2–CH), 6.95 (d, 1H, j = 8.21 Hz, H6),
7.45 (dd, 1H, j1 = 2.11, j2 = 8.21 Hz, H5), 7.65 (d, 1H,
j = 2.11 Hz, H3), 10.56 (s, 1H, –CHO).
0
0
0
0
–CH2–CH3), 7.25–7.70 (m, 4H, H3 , H4 , H6 , H7 ), 9.86 (s,
1H, –CHO).
2-Formyl-5-isopropylbenzo[b]furan 4d. This compound
was obtained as yellowish oil, yield 56 %, bp 131–133 °C
(3 mmHg); IR (KBr mmax cm-1), 1700 (C=O), 2900–3000
(C–H); 1H NMR (CDCl3, 400 MHz), d = 1.28 (d, 6H,
j = 6.30 Hz, H3C–CH–CH3), 3.00 (h, 1H, j = 6.30 Hz,
0
H3C–CH–CH3), 7.48–7.63 (m, 4H, H3 , H4 , H6 , H7 ), 9.85
0
0
0
(s, 1H, –CHO).
123

Med Chem Res
0
j2 = 1.21 Hz, H6 ), 7.36 (d, 1H, j = 1.21 Hz, H4 ), 7.40 (d,
0
2-Formyl-5-methoxybenzo[b]furan 4e. This compound
was obtained as yellow solid, yield 70 %, mp 82–84 (di-
isopropyl ether); IR (KBr mmax cm-1), 1700 (C=O),
2900–3000 (C–H); 1H NMR (CDCl3, 400 MHz), d = 2.41
0
1H, j = 8.41 Hz, H7 ), 12.74 (ls, 1H, NH). MS m/z; 255.1
[M ? H]?, 253.3 [M ? H]-, 276.9 [M ? Na]?.
5-(5-Ethylbenzo[b]furan-2-ylmethyl)-6-methylpyridazin-
3(2H)-one 6c. This compound was obtained as brown solid,
yield 73 %, mp 180–181 °C (ethanol); IR (KBr mmax
0
0
0
0
(s, 3H, –OCH3), 7.43–7.80 (m, 4H, H3 , H4 , H6 , H7 ), 9.89
(s, 1H, –CHO).
1
2-Formyl-5-propoxybenzo[b]furan 4f. This compound
was obtained as yellow solid, yield 85 %, mp 65–67 °C
(diisopropyl ether); IR (KBr mmax cm-1), 1700 (C=O),
2900–3000 (C–H); 1H NMR (CDCl3, 400 MHz), d = 0.97
(t, 3H, j = 7.20 Hz, –OCH2–CH2–CH3), 1.73 (m, 2H,
–OCH2–CH2–CH3), 3.94 (t, 2H, j = 6.60, –OCH2–CH2–
cm-1), 1605 (C=N), 1661 (C=O), 2900–3000 (C–H); H
NMR (DMSOd6, 400 MHz), d = 1.18 (t, 3H,
j = 7.50 Hz, –CH2–CH3), 2.21 (s, 3H, –N=C–CH3), 2.65
(q, 2H, j = 7.50 Hz, –CH2–CH3), 4.05 (s, 2H, –CH2–),
0
6.56 (s, 1H, H4), 6.64 (s, 1H, H3 ), 7.08 (dd, 1H,
0
j1 = 8.40 Hz, j2 = 1.80 Hz, H6 ), 7.37 (d, 1H,
0
CH3), 7.15 (dd, 1H, j1 = 9.10 Hz, j2 = 2.70 Hz, H6 ), 7.31
0
0
j = 1.80 Hz, H4 ), 7.41 (d, 1H, j = 8.40 Hz, H7 ), 12.76
(ls, 1H, NH). MS m/z; 269.5 [M ? H]?, 267.1 [M ? H]-,
291.3 [M ? Na]?.
0
(d, 1H, j = 2.70 Hz, H4 ), 7.61 (d, 1H, j = 9.10 Hz, H7 ),
0
0
7.86 (s, 1H, H3 ), 9.79 (s, 1H, –CHO).
5-Chloro-2-formylbenzo[b]furan 4g. This compound
was obtained as yellow solid, yield 60 %, mp 126–127 °C
(ethyl acetate); IR (KBr mmax cm-1), 1670 (C=O); 1H
5-(5-Isopropylbenzo[b]furan-2-ylmethyl)-6-methylpyri-
dazin-3(2H)-one 6d. This compound was obtained as
brown solid, yield 82 %, mp 185–186 °C (ethanol); IR
(KBr mmax cm-1), 1605 (C=N), 1682 (C=O), 2900–3000
(C–H); H NMR (DMSOd6, 400 MHz), d = 1.24 (d, 6H,
j = 6.90 Hz, H3C–CH–CH3), 2.10 (s, 3H, –N=C–CH3),
0
0
NMR (CDCl3, 400 MHz), d = 7.25–7.75 (m, 4H, H3 , H4 ,
1
0
H6 , H7 ), 9.86 (s, 1H, CHO).
0
General procedures for the synthesis of substituted
3-benzo[b]furan-2-ylmethylene-levulinic acids 5a–g:
Method D
2.99 (h, 1H, j = 6.90 Hz, H3C–CH–CH3), 3.90 (s, 2H,
0
0
0
0
–CH2–), 7.30–7.76 (m, 5H, H4, H3 , H4 , H6 , H7 ), 12.32 (ls,
1H, NH). MS m/z; 283.4 [M ? H]?, 281.2 [M ? H]-,
337.4 [M ? Na]?.
A stirred solution of compounds 4 (0.1 mol) in 35 mL of
concentrated acetic acid was refluxed for 24 h. After
cooling, the solution was evaporated to dryness. The
obtained residue was used crude for the continuation.
5-(5-Methoxybenzo[b]furan-2-ylmethyl)-6-methylpyri-
dazin-3(2H)-one 6e. This compound was obtained as yel-
low solid, yield 78 %, mp 190–192 °C (ethanol); IR (KBr
1
mmax cm-1), 1650 (C=O), 2950–3000 (C–H); H NMR
(DMSOd6, 400 MHz), d = 2.25 (s, 3H, –N=C–CH3), 3.74
(s, 3H, –OCH3), 4.04 (s, 2H, –CH2–), 6.55 (s, 1H, H4), 6.64
General procedures for the synthesis of substituted
5-(benzo[b]furan-2-ylmethyl)-6-methylpyridazin-3(2H)-
ones 6a–g: Method E
0
0
(s, 1H, H3 ), 6.82 (dd, 1H, j = 8.70 and 2.71 Hz, H6 ), 7.08
0
0
(d, 1H, j = 2.71 Hz, H4 ), 7.40 (d, 1H, j = 8.70 Hz, H7 ),
12.75 (ls, 1H, NH). MS m/z; 299.4 [M ? H]?, 297.1
[M ? H]-, 321.4 [M ? Na]?.
The mixture of acids 5 and hydrazine hydrate solution in
ethanol was refluxed for 2 h; the precipitate formed is fil-
tered and recrystallized from an appropriate solvent.
5-(Benzo[b]furan-2-ylmethyl)-6-methylpyridazin-3(2H)-
one 6a. This compound was obtained as yellow solid, yield
69 %, mp 181–183 °C (ethanol); IR (KBr mmax cm-1),
5-(5-Propoxybenzo[b]furan-2-ylmethyl)-6-methylpyri-
dazin-3(2H)-one 6f. This compound was obtained as brown
solid, yield 87 %, mp 194–196 °C (ethanol); IR (KBr mmax
cm-1), 1652(C=O), 2940–3000(C–H); 1H NMR (DMSOd6,
400 MHz), d = 0.96 (t, 3H, j = 6.90 Hz, –OCH2–CH2–
CH3), 1.71 (m, 2H, –OCH2–CH2–CH3), 2.21 (s, 3H,
–N=C–CH3), 3.90 (t, 2H, j = 6.90 Hz, –OCH2–CH2–CH3),
1
1604 (C=N), 1662 (C=O), 2900–3000 (C–H); H NMR
(DMSOd6, 400 MHz), d = 2.22 (s, 3H, –N=C–CH3), 4.08
0
(s, 2H, –CH2–), 6.97 (s, 1H, H4), 6.71 (s, 1H, H3 ),
0
4.04 (s, 2H, –CH2–), 6.55 (s, 1H, H4), 6.62 (s, 1H, H3 ),
0
0
0
0
0
6.81 (dd, 1H, j = 9.00 and 2.71 Hz, H6 ), 7.06 (d, 1H,
7.19–7.58 (m, 4H, H4 , H5 , H6 , H7 ), 12.71 (ls, 1H, NH).
MS m/z; 241.2 [M ? H]?, 238.9 [M ? H]-, 263.3
[M ? Na]?.
0
j = 2.71 Hz, H4 ), 7.38 (d, 1H, j = 9.00 Hz, H7 ), 12.74 (ls,
0
1H, NH).
5-(5-Methylbenzo[b]furan-2-ylmethyl)-6-methylpyri-
dazin-3(2H)-one 6b. This compound was obtained as yel-
low solid, yield 80 %, mp 183–184 °C (ethanol); IR (KBr
mmax cm-1), 1603 (C=N), 1666 (C=O), 2900–3000 (C–H);
1H NMR (DMSOd6, 400 MHz), d = 2.23 (s, 3H, –N=C–
CH3), 2.37 (s, 3H, Ar–CH3), 4.07 (s, 2H, –CH2–), 6.58 (s,
5-[(5-Chlorobenzo[b]furan-2-yl)methyl]-6-methylpyri-
dazin-3(2H)-one 6g. This compound was obtained as yel-
low solid, yield 70 %, mp 198–200 °C (ethanol); IR (KBr
1
mmax cm-1), 1649(C=O); H NMR (DMSOd6, 400 MHz),
d = 2.23 (s, 3H, –N=C–CH3), 4.11 (s, 2H, –CH2–), 6.60 (s,
0
1H, H4), 6.74 (s, 1H, H3 ), 7.29 (dd, 1H, j = 8.71 and
0
1H, H4), 6.64 (s, 1H, H3 ), 7.07 (dd, 1H, j1 = 8.41 Hz,
0 0
2.16 Hz, H6 ), 7.58 (d, 1H, j = 8.71 Hz, H4 ), 7.66 (d, 1H,
123

Med Chem Res
butyrophenone derivatives of 6-phenylpyridazine. Eur J Med
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Chancellor D (2011) The depression market. Nat Rev Drug Discov
10(11):809–810
0
j = 2.16 Hz, H7 ), 12.76 (ls, 1H, NH). MS m/z; 275.0
[M ? H]?, 272.7 [M ? H]-, 297.0 [M ? Na]?.
Antidepressant activity
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To evaluate the structure–activity relationship, the effects
of the substituents on C5 of the benzofuran ring were
considered. As shown in Table 1, we noticed that the
increase in the aliphatic chain size in the C5 of benzofuran
reduced the immobility time of the mice. Among all the
pyridazinone compounds tested at a dose of 50 mg kg-1
orally in adult mice in FST (Hirota et al., 1986), com-
pounds 6c and 6d were found to be the most active
structures, compared to fluoxetine tested at a dose of
32 mg kg-1
.
In conclusion, through our drug design and discovery
program, we were able to develop a new series of pyri-
dazinone derivatives as potential antidepressant agents.
Our ongoing studies are directed toward the detailed
mechanistic and pharmacokinetic studies on compound 6d
so as to advance this molecule into a therapeutic option.
Interestingly, all active compounds did not cause any sig-
nificant alteration of locomotor activity in mice as com-
pared to control, indicating that the hybrids did not produce
any motor impairment effects. The results indicate that
pyridazin-3(2H)-one derivatives may have potential thera-
peutic value for the management of mental depression.
´
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Structure-activity relationship studies of central nervous system
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4-substituted 1-(3-chlorophenyl)piperazines for 5-HT1A recep-
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¨
¨
´
´
Ozadalı K, Ozkanlı F, Jain S, Rao PP, Velazquez-Martınez CA (2012)
Synthesis and biological evaluation of isoxazolo[4,5-d]pyri-
dazin-4-(5H)-one analogues as potent anti-inflammatory agents.
Bioorg Med Chem 20(9):2912–2922
Acknowledgments The authors are grateful to the University
Mohammed V and Laboratory of control of drugs, Rabat-Morocco,
for, IR, RMN and MASS spectra and the studies of antidepressant
activity.
´
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