Synthesis and antihepatotoxic activity of 5-(2,3-dihydro-1,4-benzodioxane- 6-yl)-3-substituted-phenyl-4,5-dihydro-1H-pyrazole derivatives

Article abstract of DOI:10.1016/j.bmcl.2011.10.056

In continuance of our search for newer antihepatotoxic agents some novel pyrazoline derivatives containing 1,4-dioxane ring system were synthesized starting from 3-(2,3-dihydro-1,4-benzodioxane-6-yl)-1-substituted-phenylprop-2- en-1-one. Some of the synthesized compounds were evaluated for antihepatotoxic activity against CCl₄-induced hepatotoxicity in rats. Among them some compounds have shown significant antihepatotoxic activity comparable to standard drug silymarin.

Full text of DOI:10.1016/j.bmcl.2011.10.056

Bioorganic & Medicinal Chemistry Letters 21 (2011) 7251–7254
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Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Synthesis and antihepatotoxic activity of 5-(2,3-dihydro-1,
4-benzodioxane-6-yl)-3-substituted-phenyl-4,5-dihydro-
1H-pyrazole derivatives
Habibullah Khalilullah a,b, , Shamshir Khan b, Mohamed Jawed Ahsan a, Bahar Ahmed b
⇑
a Department of Pharmaceutical Chemistry, Alwar Pharmacy College, Alwar 301030, Rajasthan, India
b Antihepatotoxic Research Laboratory, Faculty of Pharmacy, Jamia Hamdard, (Hamdard University), New Delhi 110062, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 2 July 2011
Revised 13 October 2011
Accepted 15 October 2011
Available online 20 October 2011
In continuance of our search for newer antihepatotoxic agents some novel pyrazoline derivatives
containing 1,4-dioxane ring system were synthesized starting from 3-(2,3-dihydro-1,4-benzodioxane-
6-yl)-1-substituted-phenylprop-2-en-1-one. Some of the synthesized compounds were evaluated for
antihepatotoxic activity against CCl4-induced hepatotoxicity in rats. Among them some compounds have
shown significant antihepatotoxic activity comparable to standard drug silymarin.
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
1,4-Benzodioxane
Pyrazoline
Antihepatotoxic activity
Liver is considered to be one of the most vital organs that func-
tions as a centre of metabolism of nutrients such as carbohydrates,
proteins and lipids and excretion of waste metabolites. Addition-
ally, it is also involved in the metabolism and excretion of drugs
and other xenobiotics from the body thereby providing protection
against foreign substances by detoxifying and eliminating them. Li-
ver pathologies affect hundreds of millions of patients worldwide.
The most common cause of hepatopathy are chronic hepatitis C
and alcoholism, nonalcoholic fatty liver diseases, autoimmune
and drug induced hepatic disorders. Many of these conditions
can be prevented or treated, but if not, they can lead to progressive
liver injury, liver fibrosis and ultimately cirrhosis, portal hyperten-
sion, liver failure, and in some instances cancer. Herbal-based ther-
apeutics for liver disorders have been in use in India for a long
time. Despite the significant popularity of several herbal medicines
in general, and for liver diseases in particular, they are still unac-
ceptable treatment modalities for liver diseases. The limiting fac-
tors that contribute to this eventuality are lack of standardization
of the herbal drugs, lack of identification of active ingredients/prin-
ciples, lack of randomized controlled clinical trials and lack of tox-
icological evaluation.1 Traditional drugs used in the treatment of
liver diseases are sometimes inadequate to cater the need of large
population. In spite of tremendous strides in the modern medicine,
there are not much drugs available for the treatment of liver disor-
ders. Many natural products of herbal origin are in use for the
treatment of liver ailments.2–5 The drug available in the modern
systems of medicine are mainly corticosteroids and immunosup-
pressive agents, which brings about only symptomatic relief and
in most of the cases have no influence on the disease process. Fur-
ther their use is associated with the risk of relapses and danger of
side effects.
Benzodioxane represents a series of synthetic and natural
compounds of considerable medicinal importance. Compounds
containing dioxane ring systems exhibited different biological
activities like antihepatotoxic,6–8
a
-adrenergic blocking agent,9
anti-inflammatory,10 and D2 antagonist/5-HT1A partial agonist
activity.11
Silymarin isolated from seeds of Silybum marianum commonly
known as ‘milk thistle’ has been found to be a potent antihepato-
toxic agent against a variety of toxicants. Silymarin has been found
to be a mixture of three isomers that is silybin, silychristin and
silydianin. The main component silybin, which usually makes up
20–30% of the total flavonolignans contains 1,4-benzodioxane ring
system and possess significant antihepatotoxic activity;6,7 other
constituents silychristin and silydianin do not possess 1,4-dioxan
ring system and thus do not display significant antihepatotoxic
activity. On the basis of the above hypothesis we taught that 1,4-
dioxane ring system plays an important role in exhibiting antihe-
patotoxic activity, and thus we have prepared some new pyrazo-
line derivatives bearing 1,4-dioxane ring system and evaluated
some of them for antihepatotoxic activity against CCl4-induced
hepatotoxicity in rats. Among them, compounds 3d and 3j have
shown significant antihepatotoxic activity as comparable to stan-
⇑
Corresponding author. Tel.: +91 0144 5121027; mobile: +91 8058790282.
E-mail address: shabib79@yahoo.co.in (H. Khalilullah).
0960-894X/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2011.10.056

7252
H. Khalilullah et al. / Bioorg. Med. Chem. Lett. 21 (2011) 7251–7254
O
O
2
3
7
3'
Br
Br
OH
O
(a)
OHC
CH2
CH2
a
(b)
5
(A)
+
1'
b
OHC
OH
O
(2a)
(1)
O
O
(c)
Reagent and conditions:
O
O
HB
a) K2CO3, dried acetone, stirring with reflux for 26 h, 67 % yield
HA
b) KOH / ethanol, stirring at room temprature for 11 h, 82% yield
c) Hydrazine hydrate, reflux for 12 h, 54% yield
(A)
NHH
(3a)
C
N
Scheme 1. Synthetic route for the preparation of 5-(2,3-dihydro-1,4-benzodioxane-6-yl)-3-phenyl)-4,5-dihydro-1H-pyrazole.
dard drug silymarin. Other compounds of the series showed
moderate antihepatotoxic activity.
than those substituted with the same functional group in the para
position.
The synthetic route used to prepare starting materials and the
title compounds is outlined in Scheme 1. The starting material
2,3-dihydro-1,4-benzodioxane-6-carbaldehyde was prepared12 by
reaction between 3,4-dihydroxybenzaldehyde and ethylene
dibromide in dry acetone in the presence of anhydrous potassium
carbonate, which on Claisen–Schmidt condensation with substi-
tuted acetophenone in absolute ethanol and 10% potassium
hydroxide afforded corresponding 3-(2,3-dihydro-1,4-benzodiox-
ane-6-yl)-1-substituted-phenylprop-2-en-1-one derivatives 2a–
o.13 The chalcones are considered to be useful intermediates in
several cyclization reactions to produce different types of hetero-
cyclic compounds of diverse biological importance. The titled
pyrazolines 3a–o (Table 1) were synthesized14 by cyclocondensa-
tion of chalcones 2a–o with hydrazine hydrate in absolute ethanol
and few drops of glacial acetic acid in presence of molecular sieve
(reaction time varies from 10 to 15 h). The highest yield (63%) was
observed for the compound 3d having 2,4-dihydroxy substitution
on the aromatic ring whereas the compounds 3l and 3m having
methyl substitution in the aromatic ring have shown lowest yield
(28% and 35%). It has also been observed that compounds substi-
tuted in the meta position of phenyl ring have shown greater yield
Both analytical and spectral data of all the synthesized com-
pounds were in full agreement with the proposed structures. The
1H NMR spectrum of 1 showed two broad singlets at d 4.30 and d
4.33 corresponding to the protons due to –CH2 at position 2 and
3, respectively. A singlet at d 9.79 could be assigned to the aldehy-
dic protons at position-6. The formation of compounds 2a–o is ob-
served in 1H NMR by the disappearance of the aldehydic proton
signal and the appearance of a signal of the olefinic proton at about
7.54–7.95 ppm. The 1H NMR spectrum of compounds 2a–o also
showed doublets at d 4.20 due to methylenic protons of dioxane
ring system. The IR spectra of the compounds 3a–o revealed
absorption bands in the regions 1523–1590 cmÀ1 corresponding
to C@N stretching bands because of ring closure. In addition, the
absorption bands at 1420–1480 cmÀ1 were attributed to the
(N–N) stretch vibrations, which also confirm the formation of the
desired pyrazoline ring in all the compounds. The 1H NMR spec-
trum of 3a–o showed peaks due to the protons at positions 2
and 3 of benzodioxane as broad singlets (unresolved doublet) at
d 4.12–4.38. The compounds also exhibited the presence of two
magnetically nonequivalent protons of a methylene group (HA/HB)
at d 3.00–3.40 and d 3.72–3.80, respectively, coupled with each
other and in turn with the vicinal methine proton at d 5.14–5.24.
The phenyl protons were observed at the expected chemical shifts
and integral values. The mass spectrum gave molecular ion peak
corresponding to the molecular formula of the compounds.
The CCl4-induced hepatotoxicity is mediated by primary and
secondary bond formation of reactive species to critical cellular
molecules such as DNA, lipid, proteins or carbohydrates. It is well
established that hepatotoxicity by CCl4 is due to enzymatic activa-
Table 1
Chemical structures, melting point and percentage yield of the synthesized pyrazoline
derivatives
O
R
Á
O
tion to release CCl3 radical in free state, which in turn disrupts the
structure and function of lipid and protein macromolecules in the
membrane of the cell organelles. Elevated levels of serum enzymes
are indicative of cellular leakage and loss of functional integrity of
the cell membrane due to toxicity produced by CCl4. Significant
rise in serum enzymatic concentration viz. SGOT and SGPT could
be taken as an index of liver damage. It generally induces deposi-
tion of fat in liver and plays a significant role in inducing triacyl
glycerol accumulation, depletion of GSH, increase lipid oxidation,
membrane damage, and depression of protein synthesis and loss
of enzyme activity. Being cytoplasmic in location, the damage mar-
ker enzymes SGOT, SGPT are released in serum. It has been shown
that protective agents exert their action against CCl4 mediated lipid
peroxidation, either through decreased production of free radical
derivatives or due to the anti-oxidant activity of the protective
agent itself.
NH
N
S. No
Compd
R
Mol. Formula
Mp (°C)
Yield
(%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
3p
H
C
17H16N2O2
17H16N2O3
17H16N2O3
17H15N2O4
17H15ClN2O2
17H15ClN2O2
17H15FN2O2
17H15BrN2O2
18H18N2O3
19H20N2O4
18H18N2O2
18H18N2O2
18H18N2O2
17H15N3O4
19H21N3O2
115–117
124–125
119–122
140–42
110–12
165–67
98–100
102–04
134–36
154–56
175–77
97–99
54
52
49
63
58
43
36
33
37
45
47
28
35
45
52
2-Hydroxy
4-Hydroxy
2,4-Dihydroxy
2-Chloro
4-Chloro
4-Fluoro
4-Bromo
4-Methoxy
3,4-Dimethoxy
2-Methyl
3-Methyl
4-Methyl
4-Nitro
C
C
C
C
C
C
C
C
C
C
C
C
C
C
138–140
149–151
180–182
Some of the synthesized compounds were evaluated for antihe-
patotoxic activity against CCl4-induced hepatic damage in rats. The
N,N-Dimethylamino

H. Khalilullah et al. / Bioorg. Med. Chem. Lett. 21 (2011) 7251–7254
7253
Table 2
Effect of selected pyrazoline derivatives on serum enzymatic activity in CCl4-induced liver damage in rats
Groups n = 5
Treatment
Dose
SGOT (IU/L)
SGPT (IU/L)
ALP KA units
Total protein (g/dl)
I
II
Normal control
Toxic control
Silymarin (standard drug)
Compd 3a
Compd 3d
Compd 3f
—
34.82 0.697
74.52 0.695⁄⁄
56.19 0.808⁄⁄
62.85 1.654⁄⁄
58.57 1.457
63.42 1.471⁄⁄
58.85 1.948⁄⁄
64.85 1.726⁄⁄
45.60 1.18
85.27 2.05
42.08 3.57
66.157 2.886⁄⁄
48.62 3.385⁄⁄
53.14 0.172⁄
58.22 1.097⁄⁄
46.06 0.495
49.48 0.254⁄⁄
55.74 0.595
6.46 0.53
3.54 0.67⁄⁄
4.2 0.84
1.5 ml/kg (p.o.)
10 mg/kg (p.o.)
10 mg/kg (p.o.)
10 mg/kg (p.o.)
10 mg/kg (p.o.)
10 mg/kg (p.o.)
10 mg/kg (p.o.)
III
IV
V
VI
VII
VIII
61.29 1.78⁄⁄
65.00 1.458⁄⁄⁄
62.09 0.700⁄⁄
65.81 1.463
64.95 1.105⁄⁄
64.13 0.828⁄
4.04 0.10⁄⁄
3.82 0.438⁄
3.91 0.63⁄⁄⁄
3.82 0.15
3.98 0.43⁄⁄
Compd 3j
Compd 3l
SGOT, serum glutamate Oxaloacetate transaminase; SGPT, serum glutamate pyruvate transaminase; ALP, alkaline phosphatase; TP, total protein; p.o., per oral.
⁄⁄⁄P <0.0001; ⁄⁄P <0.01; ⁄P <0.05 vs CCl4; P >0.05 ns.
Values are mean SEM (n = 5). ANOVA followed by Dunnett test was performed.
Table 3
Histopathological changes in liver of Wistar rats
Groups n = 5
Treatment
Microscopic observations
I
Normal control
Normal liver architecture, no degeneration, necrosis, or inflammation
II
III
Toxic control
Silymarin (standard drug)
Prominent centrilobular necrosis enlarged central vein, significant periportal inflammation reflecting liver damage
Hepatocytes with uniformly staining cytoplasm, mild dilatation of sinusoidal spaces, central vein
was clearly visible, good recovery with the absence of necrosis
IV
V
VI
VII
VIII
Compd 3a
Compd 3d
Compd 3f
Compd 3j
Compd 3l
Moderate sinusoidal dilatation around the central vein, fine vascular change is also seen in scattered hepatocytes
Moderate dilatation of sinusoids, normal parenchyma
Sinusoidal dilatation around the central vein, fine vascular changes in scattered hepatocytes
Mild dilatation of sinusoids in centrizonal area, liver parenchyma is otherwise normal
Little dilatation of sinusoids and central vein appeared clear
degree of hepatoprotection of the synthesized compounds 3a, 3d,
3f, 3j and 3l (10 mg/kg, p.o., respectively) was determined by mea-
suring the various biochemical parameters such as serum gluta-
mate oxaloacetate transaminase (GOT),15 glutamate pyruvate
transaminase (GPT),15 alkaline phosphatase (ALP),16 and total pro-
tein.17 The extent of CCl4-induced liver injury and hepatoprotective
effect of the synthesized compounds was also analyzed through
histopathological observation.18
showed hepatocytes swelling and necrosis in CCl4-treated rats in
comparison with normal control rats. Administration of synthe-
sized compounds exhibited a significant protection of hepatocytes
injury and showed normalization of the tissues as neither fatty
accumulation nor necrosis was observed. The central vein ap-
peared clearly indicating a potent antihepatotoxic activity.
In summary, the study has shown that some of the synthesized
compounds possess significant antihepatotoxic activity. They are
simple, low molecular weight compounds and could be prepared
easily. On the other hand, silybin is a complex molecule of high
molecular weight and thus cannot be prepared easily. Furthermore
the compounds are expected to be easily metabolizable, in com-
parison to silybin being simple and of low molecular weight.
Declaration of interest: The authors are thankful for University
Grant Commission, New Delhi, for providing financial assistance
in the form of research project. The authors report no declarations
of interest.
Details of antihepatotoxic activity of the synthesized pyrazole
derivatives 3a, 3d, 3f, 3j and 3l have been summarized in Table 2.
As shown in Table 2, the activities of the liver enzymes SGOT, SGPT,
ALP were markedly increased and TP were decreased in CCl4-trea-
ted rats in comparison with normal values. Administration of
silymarin (standard drug) and synthesized compounds at the dose
levels 10 mg/kg body weight, prevented CCl4-induced elevation of
SGOT, SGPT, ALP and also prevented decrease in total protein.
Silymarin (10 mg/kg) had significantly decreased the level of SGOT,
SGPT, and ALP and increased that in total protein. The activities of
the liver enzymes such as SGOT and SGPT were elevated on admin-
istration of CCl4 to 74.52 and 85.27 IU/L in comparison to normal
values of 34.82 and 45.60 IU/L, respectively. The level of alkaline
phosphatase was also elevated on administration of CCl4 to 66.15
KA units as compared to normal values of 42.08 KA units. The
administration of compound under investigation significantly
reduced the elevated enzyme level to values in the range of
58.57–64.85 IU/L for SGOT, 62.09–65.81 IU/L for SGPT and 46.06–
58.22 KA units for ALKP which were found to be comparable to
the reduced enzyme level with the standard drug silymarin
(56.19 and 61.29 IU/L for SGOT and SGPT, respectively). The toxi-
cant CCl4 reduced the level of total protein (3.54 g/dl) in compari-
son to normal values (6.46 g/dl). The administration of the test
compound elevated the reduced level of total protein to values in
the range of 3.82–4.04 g/dl. The histopathological studies also
showed significant recovery of hepatocytes of the liver in the stan-
dard drug and compound-treated animals which has again corre-
lated with the biochemical parameters. The results of the liver
histopathological studies have been presented in Table 3 which
Acknowledgements
The authors are thankful to the Head, Department of Pharma-
ceutical Chemistry, Faculty of Pharmacy, Jamia Hamdard, New Del-
hi, India for providing necessary research facilities. Finally we
thank Mrs. Showkat Ahmad Shah, In charge, Animal House facility,
Jamia Hamdard, New Delhi for providing experimental animals for
carrying out the antihepatotoxic activity.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.bmcl.2011.10.056.
References and notes
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3. Latha, U.; Rajesh, M. G.; Latha, M. S. Indian Drugs 1999, 36, 470.

7254
H. Khalilullah et al. / Bioorg. Med. Chem. Lett. 21 (2011) 7251–7254
4. Mitra, S. K.; Seshadri, S. J.; Venkataranganna, M. V.; Gopumadhavan, S.; Udupa,
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at room temperature. After completion of the reaction, the reaction mixture
was poured onto crushed ice; the resulting solid was filtered, washed with
water, dried and crystallized from ethanol. Compound 2a: mp 82–84 °C; 82%
yield : 1H NMR (300 MHz, DMSO-d6): d 4.20 (4H, unresolved doublet , 2 Â CH2),
7.36–7.55 (5H, m, Ring A), 7.26 (1H, s, ArH-5), 7.10 (1H, d, ArH-7), 6.91 (1H, d,
J = 9.0 Hz, ArH-8), 7.57 (1H, d, J = 18.9 Hz, H-a), 7.68 (1H, d, J = 15.6 Hz, H-b);
FTIR (KBr) cmÀ1: 3052 (@C-H, aromatic), 1647 (C@O), 1590 (C@C str.); HRMS
(m/z): 266.2911; [M]+ Anal. Calcd for C, 76.68; H, 5.30; O, 18.02. Found: C,
76.63; H, 5.25; O, 18.06.
6. Ahmed, B.; Khan, S. A.; Alam, T. Pharmazie 2003, 58, 173.
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12. Synthesis of 2,3-dihydro-1,4-benzodioxane-6-carbaldehyde (1): Anhydrous
potassium carbonate (21 g) was added in portions to a stirred solution of
27.6 g of 3,4-dihydroxy benzaldehyde in 100 ml of dry acetone followed by the
dropwise addition of 4.3 ml of ethylene dibromide. Another 21 g of potassium
carbonate and 4.3 ml of ethylene dibromide were added similarly and this was
repeated twice more using a total of 84 g of potassium carbonate and 17.2 g of
ethylene dibromide. Stirring and refluxing was continued for another 25 h. The
reaction mixture was then filtered by sintered glass funnel and the solid
residue was washed several times with acetone. The combined filtrate was
concentrated to about 25 ml and the residue was poured onto crushed ice, a
solid was separated which was filtered, dried and crystallized with methanol
to give a low melting solid; mp 35–37 °C; 67% yield; 1H NMR (300 MHz, DMSO-
d6): d 4.30 (2H, d, J = 8.7 Hz, CH2-2), 4.33 (2H, d, J = 8.7, CH2-3), 7.03 (1H, d,
J = 8.4 Hz, ArH-8), 7.36 (1H, d, J = 2.5 Hz, ArH-5), 7.43 (1H, dd, J = 8.4, 2.5 Hz,
ArH-7), 9.79 (1H, s, Ar-CHO).
14. General method for the synthesis of 5-(2,3-dihydro-1,4-benzodioxane-6-yl)-3-
phenyl-4,5-dihydro-1H-pyrazole (3a–o): To a solution of chalcone (2a–o) in
absolute ethanol, hydrazine hydrate (99%) and a few drops of glacial acetic acid
was added. The reaction mixture was heated under reflux for 10–15 h in
presence of molecular sieves and then cooled and poured onto crushed ice. The
solid thus obtained was filtered and recrystallized from ethanol. Compound 3a:
1H NMR (300 MHz, DMSO-d6): d 4.30 (4H, br s, 2 Â OCH2), 3.15 (1H, dd,
JAB = 17.2 Hz,
JBC = 10.8 Hz,CH2-4HB), 5.2 (1H, dd, JAB = 17.2 , JAC = 2.5 and JBC = 10.8 Hz, CH-
HC), 5.7 (1H, s, NH-pyrazoline), 6.92 -7.18 (m, 5H, Ar-ring A), 7.31 (1H, d,
JAC = 2.5 Hz,
CH2-4HA),
3.45
(1H,
dd,
JAB = 17.2 Hz,
4
J = 2.5 Hz, ArH-5), 7.22 (1H, dd, J = 8.4, 2.5 Hz, ArH-7), 7.14 (1H , s Ar H-8); FTIR
(KBr) cmÀ1: 3052 (@C–H, aromatic), 3300 (pyrazoline NH), 1653 (C@C), 1590
(ring C@N), 1480 (ring N-N); HRMS (m/z): 280.3210 [M]+; Anal. Calcd for:
C
17H16N2O2: C, 72.84; H, 5.75; N, 9.99; O, 11.42. Found: C, 72.89; H, 5.78; N,
10.02; O, 11.41.
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13. General method for the synthesis of 3-(2,3-dihydro-1,4-benzodioxane-6-yl)-1-
substituted-phenylprop-2-en-1-one (2a–o): 25% solution of potassium
hydroxide in aqueous ethanol (5 ml) was added dropwise to a mixture of
substituted acetophenone (0.01 mol) and aldehyde
1 (0.01 mol) in 25 ml
ethanol at 0–5 °C with stirring. The stirring was further continued for 10–12 h