Molecular properties prediction, synthesis, and diuretic activity of phenoxy acetic acid bearing pyrazolines

Article abstract of DOI:10.1007/s00044-012-0086-y

A new series of phenoxyacetic acid bearing pyrazoline derivatives 7a-k were synthesized and characterized by IR, ¹H-NMR, and mass spectral data. The investigated compounds were screened for their diuretic activity by standard Lipschitz method.

Full text of DOI:10.1007/s00044-012-0086-y

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res (2013) 22:916–926
DOI 10.1007/s00044-012-0086-y
ORIGINAL RESEARCH
Molecular properties prediction, synthesis, and diuretic activity
of phenoxy acetic acid bearing pyrazolines
•
Mohammed Afroz Bakht M. Shahar Yar
•
•
Anees A. Siddiqui M. M. Abdullah Hamadeh Tarazi
•
•
•
Moawiah M. Naffaa Ahmed M-Alafeefy
Received: 20 February 2012 / Accepted: 3 May 2012 / Published online: 22 May 2012
Ó Springer Science+Business Media, LLC 2012
Abstract A new series of phenoxyacetic acid bearing
pyrazoline derivatives 7a–k were synthesized and charac-
terized by IR, 1H-NMR, and mass spectral data. The inves-
tigated compounds were screened for their diuretic activity
by standard Lipschitz method. Furthermore, the series
under investigation were assessed for their drug-likeness by
suitable software programs. These compounds were found
to have promising results against a given set of diuretic
parameters, i.e., cumulative urine output, diuretic activity,
diuretic action, and Lipchitz values. Nevertheless, com-
pounds 7d, 7h, 7i, and 7k bearing electron withdrawing
group (Cl-) showed pronounced diuretic propensity than
the standard furosemide.
of diuretics as safe and effective therapy for hypertension
management (Earnst and Moser, 2009). As a monotherapy,
diuretics are as efficacious as drugs from each of the
other commonly used classes of antihypertensive drugs,
i.e., ACE inhibitors and calcium channel antagonists. On
the other hand, diuretics are probably more effective in
older patients than any other hypertensive treatment
groups. Therefore, they were recommended as a first-line
therapy in most of the major outcome studies concerning
treatment of hypertension in elderly. The effects of
diuretics on plasma concentrations of electrolytes and urate
have been well characterized. They are clearly dose
dependent and are minimized at doses currently recom-
mended in the management of hypertension (Joint National
Committee on Prevention, Detection, Evaluation, and
Treatment of High Blood Pressure, 1997). In contrast,
diuretics are inexpensive, effective, generally well toler-
ated at low doses and have clearly been shown to prevent
major cardiovascular events in a variety of hypertensive
patient groups. Thus, there exist an urgent clinical
requirement enabling clinicians to select the best diuretic
candidate avoiding many unpleasant side effects, i.e.,
hypokalemia, hyperuricemia, etc., associated with their use
as a monotherapy or as part of other antihypertensives.
Several phenoxy acetic acid derivatives as potential
diuretic agents were previously reported (Bicking et al.,
1976). On the other hand, pyrazoline derivatives were
found to have wide range of applications in many drug
classes, i.e., antimicrobial (Ozdemir et al., 2007), antiviral
(Shahar Yar et al., 2009), and anticancer (Mansour et al.,
2003), but their diuretic activity is not reported so far. The
structure similarity between ethacrynic acid, a class of loop
diuretic, and pyrazoline bearing phenoxyacetic acid, both
shared the same pharmacophoric features encouraged us
for the present study.
Keywords Drug-likeness Á Lipinski’s rule Á Pyrazoline Á
Phenoxy acetic acid Á Lipschitz method
Introduction
Diuretics are one of the most efficient therapies that long
been utilized for the treatment of cardiovascular ailments,
i.e., hypertension as described by the WHO–ISH guidelines
(Guidelines Subcommittee of the World Health Organiza-
tion–International Society of Hypertension, 1999). Earnest
and Moser in a recent report emphasized the applicability
M. A. Bakht (&) Á H. Tarazi Á M. M. Naffaa Á A. M-Alafeefy
Department of Pharmaceutical Chemistry, College of Pharmacy,
Salman Bin Abdul Aziz University, P.O. Box 173,
Al-Kharj 11942, Kingdom of Saudi Arabia
e-mail: m_afroz007@yahoo.com
M. A. Bakht Á M. Shahar Yar Á A. A. Siddiqui Á M. M. Abdullah
Department of Pharmaceutical Chemistry, Faculty of Pharmacy,
Hamdard University, P.O. Box 110062, New Delhi, India
123

Med Chem Res (2013) 22:916–926
917
H
O
R'
T
Scheme 1 Protocol of
synthesis
KOH / CH3OH
H
R
R'
HO
O
O
CHO
O
R
CH3
HO
O
R
CH
3
O
1
O
3-6
O
2
CH3
R''CONHNH 2
AcOH
R''
R'
N
O
N
R
7a-k
HO
O
O
Pyrazoline pattern
O
O
CH
3
R''
N
N
R'
R''
H
X
R'
N
O
N
R
HB
HA
7b, 7g
HO
R
O
HO
7a, 7c, 7d, 7e, 7f, 7h, 7i, 7j, 7k
O
O
O
O
H3C
O
CH
3
R = H, Cl, OCH3 , OH
R’ = H
R’’ = p- ClC6 H4 , p- OHC6 H4 , o- OHC6 H4 , p- OCH3 C6 H4, C6H5-CH2,
P- CH3 -C6 H4 – O -CH2 , C6 H5 - O- CH2
In the development of drugs intended for oral use, good
drug absorption and appropriate drug delivery are very
important (Hou and Xu, 2004). The failure of development
of about 30 % of orally available drugs was due to their
poor pharmacokinetic profile (De-Waterbeemd and Gif-
ford, 2003). The much publicized Lipinski ‘‘rule of 5’’ has
been widely adopted among the pharmaceutical industry. It
is used as a first step filter to perform virtual screening of
compound libraries, in an effort to exclude candidates with
poor physicochemical properties for oral bioavailability.
Thus, predictions of bioavailability-related properties, such
as solubility, lipophilicity are important before conducting
the actual synthesis to reduce enormous waste of expensive
chemicals. An in silico model for predicting oral bio-
availability is very important, both in the early stage of
drug discovery to select the most promising compounds for
further optimization and in the later stage to identify can-
didates for further clinical development (Hou et al., 2007).
In the present study, some new phenoxy acetic acid bearing
pyrazolines (Scheme 1, compound 7a–k were subjected to
molecular property prediction and drug-likeness by Mol-
inspiration (2008) and MolSoft (2007) softwares. Further-
more, lipophilicity and solubility parameters were assessed
by ALOGPS 2.1 program. Consequently, we synthesized
and screened the target compounds and their diuretic
activities were performed employing standard Lipschitz
method (Vogel 1997).
Drug-likeness and molecular properties
Computational sensitivity analysis and structural analysis
have been used to study the drug-likeness of the candidate
compounds. A good bioavailability can be achieved with an
appropriate balance between solubility and partitioning
properties. Thus, to achieve good orally available drugs, the
phenoxy acetic acid bearing pyrazoline series 7a–k were
subjected for the prediction of lipophilicity, solubility, and
123

918
Med Chem Res (2013) 22:916–926
Lipinski ‘‘rule of five’’ (Tetko and Tanchuk, 2002) along
with other properties to select the appropriate compounds to
be synthesized and in vivo diuretic activity assessment.
Lipophilicity of compounds 7h and 7k are exceeding
([5) to consider as an oral drug. Since logP is the
descriptor of lipophilicity for neutral compounds, it rep-
resents the most lipophilic state of a molecule. Compounds
under investigation 7a–k have a free carboxylic acid;
therefore, LogD (Distribution Co-efficient) prediction is to
be considered also. LogD was calculated using Spark
online calculator. Predicting LogD at a physiologically
relevant pH (instead of logP) reflects the true behavior of
ionizable compounds and accounts for the mixture of
species that may exist at any given pH; hence, it would be
expected to observe an increase in the number of com-
pounds that pass lipophilicity screening (logD B 5). In this
study, logD values of the studied compounds varied
between -0.31 and 2.21 as shown in Table 2 and Fig. 1.
Lipophilicity
The ALOGPS method is part of the ALOGPS 2.1 program
(Tetko et al., 2001b) was used to predict lipophilicity
(Tetko et al., 2001a) and aqueous solubility (Balakin et al.,
2006; Meylan and Howard, 1995) of the compounds. The
lipophilicity calculations within this program are based on
the associative neural networking approach and the effi-
cient partition algorithm. The LogKow (Kow-WIN) pro-
gram (Remko, 2009; www.syrres.com, 2008) estimates the
log octanol/water partition coefficient (logP) of organic
chemicals and drugs by an atom/fragment contribution
method developed at Syracuse Research Corporation
(Wang et al., 1997). The XLOGP2 is an atom-additive
method applying corrections (Wang et al., 2000; Zhao
et al., 2002). Computed partition coefficients for the
studied compounds by XLOGP2 method varied between
4.01–5.47 and 3.98–5.76 by KoWWIN method (Table 1).
Solubility
Drug solubility is an important factor that affects the
movement of a drug from the site of administration into the
blood. It is known that insufficient solubility of drug can
leads to poor absorption (Muegge, 2003). Investigation of
the rate-limiting steps of human oral absorption of 238
drugs (Muegge, 2003) showed that the absorption of a
drug is usually very low if the calculated solubility is
\0.0001 mg/l. According to that, the investigated com-
pounds 7a–k were found to fulfill the requirements of
solubility (ALOGPS) and could be considered as a candi-
date drug for oral absorption (Table 1).
Table 1 Calculated partition coefficients and solubilities of the
pyrazolines investigated
Compounds
ALOGPS (mg/l)
KoWWIN
XLOGP2
7a
7b
7c
7d
7e
7f
-4.74 (9.02)
-4.67 (9.50)
-4.93 (5.63)
-5.26 (2.69)
-5.33 (2.32)
-4.96 (5.37)
-4.87 (8.97)
-5.46 (1.65)
-5.26 (2.69)
-5.39 (1.95)
-5.42 (1.93)
3.98
4.87
4.74
4.56
5.30
3.99
4.26
5.76
4.56
5.02
5.10
4.12
4.43
4.62
4.71
4.95
4.01
4.22
5.47
4.71
4.84
5.15
Absorption, polar surface area (PSA), and ‘‘rule of
five’’ properties
7g
7h
7i
Molecular properties such as membrane permeability and
bioavailability is always associated with some basic
molecular descriptors such as logP (partition coefficient),
molecular weight (MW), or counts of hydrogen bond
7j
7k
Table 2 Calculated absorption (%ABS), PSA and Lipinski parameters of the pyrazolines investigated
Compounds
%ABS
PSA (A2)
NROTB
HBA
HBD
LogP
LogD (At pH 7.4)
Formula wt
7a
7b
7c
7d
7e
7f
74.94
77.71
77.77
83.72
80.83
78.01
71.82
83.72
80.90
83.78
80.90
98.73
90.72
90.54
73.28
81.67
89.85
107.78
73.28
81.46
73.12
81.46
9
7
8
7
7
6
7
8
8
6
7
6
7
2
2
2
1
1
1
3
1
1
1
1
3.30
3.01
3.50
4.59
4.02
3.41
3.65
4.36
4.05
4.38
4.51
1.38
0.49
1.14
1.95
1.86
1.56
-0.31
1.89
1.71
1.69
2.21
490
446
481
498
495
490
540
479
494
479
509
7
7
8
10
9
7g
7h
7i
9
9
7j
8
7k
9
123

Med Chem Res (2013) 22:916–926
919
Fig. 1 The showing compounds of minimum (7g) and maximum (7k) computed. LogD at pH 7.4 using Spark online calculator
acceptors and donors in a molecule (Ertl et al., 2000).
Lipinski et al. (1997) used these molecular properties in
formulating his ‘‘rule of five.’’ The rule states that most
molecules with good membrane permeability have
logP B 5, molecular weight B 500, number of hydrogen
bond acceptors B 10, and number of hydrogen bond
donor’s B 5. This rule is widely used as a filter for drug-
like properties. Table 2 contains calculated percentage of
absorption (%ABS), molecular PSA, and Lipinski param-
eters of the investigated compounds of the series (7a–k).
Magnitude of absorption is expressed by the %ABS.
Absorption percent was calculated by the expression:
%ABS = 109–0.345 PSA (Wang et al., 2000). PSA was
determined by the fragment-based method of Ertl and
coworkers (www.molinspiration.com, 2008; Wani et al.,
2011). A poor permeation or absorption is more likely to
occur when there are more than 5 H-bond donors, 10 H-
bond acceptors. The hydrogen-bonding capacity has also
been identified as an important parameter for describing
drug permeability (Ertl et al., 2000). The series 7a–k was
found to have an acceptable range of hydrogen bond
donors and acceptors as shown in Table 2.
Compounds 7d, 7h, and 7i were found to have maximum
percentage absorption as shown in Table 2.
Results and discussion
Chemistry
The titled compounds 7a–k was prepared by Claisen–
Schmidt condensation. The structures were elucidated by
1
IR, H-NMR, and mass spectroscopy. All the spectral data
1
were in agreement with the assumed structures. H-NMR
spectra of compounds 3–6 exhibited two doublets with
coupling constant within J = 12.6–13.0 Hz conforming
the trans coupling. In general, IR spectrum of 7k exhibited
absorption bands due to stretching vibrations of C=N, C–N,
and C=O groups at 1560, 1381, and 1694 cm-1, respec-
tively. The 1H-NMR spectra of compounds showed double
doublet as a usual pyrazoline (7k) pattern at d 6.3 (HX,
J = 6.6, 6.6 Hz), d 3.8 (HB, J = 11.7, 11.7 Hz), and d 2.9
(HA, J = 6.3, 6.6 Hz) for all compounds of the series. 7b
and 7g showed a characteristic doublet and triplet for C-3
methylene and C-4 protons at d 3.6 and 4.8 ppm.
Number of rotatable bonds is a determinant factor for
molecular flexibility and in turn conformational changes of
molecules and ultimately for the binding of receptors to
elicit pharmacological response. It is bare that for passing
oral bioavailability criteria, number of rotatable bond
should be B10 (Jeffery et al., 1989). The compounds in this
series 7a–k in general possess high number of rotatable
bonds (7–10); therefore, they exhibit large conformational
flexibility as shown in Table 2.
Diuretic activity
The synthesized compounds 7a–k were screened for their
in vivo diuretic screening by standard Lipschitz method
(Jeffery et al., 1989) on albino rats at a oral dose of 0.02
g/kg body weight using furosemide as a reference drug. All
the data are presented in Tables 3, 4, 5, and 6. At the end of
5 h, compounds 7d, 7h, 7i, and 7k showed a significant
increase in cumulative urine output 7.28 0.030
(P \ 0.0001), i.e., increased by 247 % in respect to control
as in compound 7i, 7f, 7g, and 7j compounds lie between
control (98.40 %) and standard furosemide (194.54 %) as
Molecular PSA is a very useful parameter for the pre-
diction of drug transport properties. PSA is a sum of sur-
faces of polar atoms (usually oxygen, nitrogen, and
attached hydrogen) in a molecule. Larger the PSA of a
molecule, lesser will be the percentage absorption.
123

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Med Chem Res (2013) 22:916–926
Table 3 Diuretic activity of pyrazoline investigated (0–5 h)
S. no
Treatment
Dose (mg/Kg
body wt)
Total urinary
output (ml)
Normal saline
intake (ml)
Urinary
excretion (%)
Diuresis
Diuretic
action
Diuretic
activity
Lipschitz
value
1
7a
20
20
20
20
20
20
20
20
20
20
20
–
1.81 0.074***
1.16 0.033
2.88 0.007
2.34 0.004
2.84 0.006
2.67 0.005
2.85 0.007
2.84 0.004
2.74 0.007
2.61 0.005
2.94 0.005
2.84 0.004
2.86 0.007
2.50 0.036
2.73 0.021
2.75 0.003
62.84
49.57
0.6
0.5
0.9
2.2
0.4
1.8
1.5
2.2
2.5
1.5
2.0
1.0
1.90
1.97
0.30
0.25
0.45
1.11
0.20
0.91
0.76
1.11
1.26
0.76
1.01
0.50
0.96
1.0
0.35
0.22
0.48
1.18
0.23
1.0
2
7b
3
7c
2.50 0.036*
89.28
4
7d
6.06 0.033***
1.21 0.047***
5.13 0.021***
4.11 0.030***
5.83 0.049***
7.28 0.030***
4.45 0.125***
5.65 0.125***
2.46 0.125*
226.96
42.45
5
7e
6
7f
180.63
150.00
223.37
247.61
156.69
197.55
98.40
7
7g
0.80
1.13
1.41
0.86
0.47
0.48
1.0
8
7h
9
7i
10
11
12
13
14
7j
7k
CONT
UREA
1000
20
5.13 0.033***
5.35 0.042***
187.91
194.54
FRUSEMIDE
1.04
Each value represents the mean S.E.M. (n = 6)
CONT control
*** P \ 0.0001 (Dunnett’s multiple comparison test)
Table 4 Diuretic activity of pyrazoline investigated (5–18 h)
S. no
Treatment
Dose (mg/Kg
body wt)
Total urinary
output (ml)
Normal saline
intake (ml)
Urinary
excretion (%)
Diuresis
Diuretic
action
Diuretic
activity
Lipschitz
value
1
7a
20
20
20
20
20
20
20
20
20
20
20
–
0.33 0.033***
0.20 0.036***
5.21 0.047***
7.43 0.061***
0.23 0.042***
5.41 0.047***
7.65 0.067***
12.18 0.047***
10.17 0.042***
6.23 0.033***
8.15 0.042***
1.26 0.049***
6.30 0.036***
6.81 0.087***
2.88 0.007
2.34 0.004
2.84 0.006
2.67 0.005
2.85 0.007
2.84 0.004
2.74 0.007
2.61 0.005
2.94 0.005
2.84 0.004
2.86 0.007
2.50 0.036
2.73 0.021
2.75 0.003
11.45
8.54
0.22
0.16
3.66
5.56
0.16
3.8
0.04
0.03
0.74
1.12
0.03
0.76
1.12
1.88
1.39
0.88
1.14
0.20
0.93
1.0
0.05
0.03
0.82
1.17
0.03
0.85
1.21
1.93
1.61
0.98
1.29
0.2
2
7b
3
7c
183.45
278.
4
7d
5
7e
8.07
6
7f
190.49
279.19
466.66
345.91
219.36
284.96
50.4
7
7g
5.58
9.32
6.92
4.38
5.68
1.0
8
7h
9
7i
10
11
12
13
14
7j
7k
CONT
UREA
1000
20
230.76
247.63
4.6
1.0
FRUSEMIDE
4.94
1.08
Each value represents the mean S.E.M. (n = 6)
CONT control
*** P \ 0.0001 (Dunnett’s multiple comparison test)
shown in Table 3. At the end of 18 h, the cumulative urine
output of most compounds was drastically increased in
comparison to the standard. Compounds 7h, 7i, and 7k
showed an increase in urine output which is almost double
to their first 5 h of study as revealed in Tables 3 and 4.
Among these, 7h and 7i were highly significant 12.18
0.047 and 10.17 0.042, respectively, i.e., increased by
466.66 % for 7h and 345.91 % for compound 7i. Diuretic
action of 7d, 7h, 7i,and 7k were found to be 2.2, 2.2, 2.5,
and 2.0, respectively, in comparison to 1.90 for urea and
123

Med Chem Res (2013) 22:916–926
921
Table 5 Effects on electrolyte excretion of Pyrazoline investigated (0–5 h)
S. no
Treatment
Dose (mg/kg
body wt)
Electrolyte concentration (mEq L-1
)
Na?
K?
Cl-
Na?/K?
Na?/Cl-
1
7a
20
20
20
20
20
20
20
20
20
20
20
–
0.45 0.005***
0.35 0.004***
0.87 0.004***
2.82 0.003***
0.76 0.004***
1.92 0.003***
1.92 0.003***
1.56 0.003***
3.26 0.004***
1.26 0.004***
2.61 0.006***
0.90 0.003***
1.91 0.004***
2.44 0.004***
0.25 0.008***
0.16 0.012***
0.45 0.009
0.24 0.004***
0.16 0.006***
0.46 0.008
1.8
2.1
1.9
1.8
2.1
3.5
3.4
1.9
1.8
1.7
1.9
1.9
2.0
1.9
1.8
2.1
1.8
1.4
2.1
2.0
2.9
2.0
1.9
1.8
1.9
1.9
2.0
1.9
2
7b
3
7c
4
7d
1.55 0.010***
0.36 0.007***
0.54 0.01***
0.55 0.01***
0.81 0.004***
1.74 0.008***
0.74 0.007***
1.32 0.007***
0.46 0.006***
0.94 0.009***
1.27 0.005***
1.94 0.010***
0.36 0.010***
0.96 0.004***
0.66 0.008***
0.76 0.004***
1.66 0.006***
0.67 0.004***
1.36 0.007***
0.46 0.005***
0.95 0.009***
1.24 0.004***
5
7e
6
7f
7
7g
8
7h
9
7i
10
11
12
13
14
7j
7k
CONT
UREA
1000
20
FRUSEMIDE
Each value represents the mean S.E.M. (n = 6)
CONT control
*** P \ 0.0001 (Dunnett’s multiple comparison test)
Table 6 Effects on electrolyte excretion of Pyrazoline investigated (5–18 h)
S. no
Treatment
Dose (mg/kg
body wt)
Electrolyte concentration (mEq L-1
)
Na?
K?
Cl-
Na?/K?
Na?/Cl-
1
7a
20
20
20
20
20
20
20
20
20
20
20
–
0.12 0.003
0.16 0.004
1.95 0.007
3.26 0.004
0.11 0.005
2.62 0.006
3.66 0.007
4.31 0.034
3.82 0.004
2.86 0.008
3.13 0.004
0.65 0.006
2.82 0.004
3.11 0.005
0.19 0.120
0.07 0.004
0.06 0.004
0.95 0.007
1.77 0.004
0.06 0.007
1.38 0.017
1.69 0.012
2.69 0.012
1.77 0.006
1.96 0.006
1.68 0.016
0.38 0.011
1.94 0.009
1.83 0.007
0.63
1.33
3.48
1.85
1.83
1.94
1.72
1.62
1.94
1.73
1.67
2.95
1.00
1.00
1.71
2.66
2.05
1.84
1.83
1.89
2.16
1.60
2.15
1.45
1.86
1.71
1.45
1.69
2
7b
0.12 0.008
0.56 0.005
1.76 0.006
0.068 0.003
1.35 0.007
2.12 0.007
2.66 0.004
1.96 0.005
1.65 0.006
1.87 0.004
0.22 0.004
2.82 0.004
3.11 0.005
3
7c
4
7d
5
7e
6
7f
7
7g
8
7h
9
7i
10
11
12
13
14
7j
7k
CONT
UREA
1000
20
FRUSEMIDE
1.97 for furosemide, respectively, as revealed in Table 3.
Diuretic action at the end of 18 h was found to increase by
three- to fourfold (shown in Table 4). Diuretic activity for
most of the compounds did not show much increase in
diuretic potential except 7h, 7i, and 7k (Tables 3, 4).
Lipschitz values showed that compounds 7d, 7h, 7i, and 7k
were more potent than urea for entire duration of study.
There are with values nearly equal to urea (when Lipschitz
value more than one that means positive value).
Compounds 7a–k were also tested for saluretic and
kaliuretic effects in albino rat model. During the first 5 h,
the compounds 7d, 7i, and 7k showed a significant increase
in sodium excretion (P \ 0.001), i.e., 2.82 0.003, 3.26
0.004, and 2.61 0.006, which are almost similar or more
123

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Med Chem Res (2013) 22:916–926
than furosemide. Also, 7d, 7i, and 7k showed significant
kaliuretic property (P \ 0.0001), i.e., 1.55 0.01, 1.74
0.08, and 1.32 0.007, which are to some extent similar to
furosemide (1.27 0.005). With regards to Na?/K? ratio,
it was observed that 7j is stronger kaliuretic (1.7). Table 4
showed that compound 7f and 7g were potassium sparing
3.5, 3.4, respectively, while the other ratio comes between
1.8 and 2.1, i.e., it had more kaliuretic than sparing effect.
At the end of 18th h, most of the compounds showed
kaliuretic outcome. Their saluretic property was found to
decrease except compound 7c the Na?/K? ratio of which
was 3.48, and was maximum during the entire experiments
as shown in Table 6. Chloride excretion has also increased
in similar fashion to sodium. In the next 5–18 h, chloride
excretion was not so much high.
Perkin-Elmer 1720 FT-IR spectrometer (KBr Pellets). The
1H-NMR spectra were recorded on a Bruker AC 300 MHz,
spectrometer using TMS as internal standard in DMSO-d6.
The FAB mass spectra were recorded on a JEOLSX 102/
DA-6000 Mass Spectrometer. The elemental analysis was
done using Perkin Elmer analyzer and results were within
0.4 % of the theoretical values.
General procedure for the synthesis of chalcones (3–6)
A mixture of 2-(4-formyl-2-methoxyphenoxy) acetic acid 1
(0.01 mol, 2.10 g) and appropriate acetophenone
2
(0.01 mol) is reacted as per Claisen–Schmidt condensation,
in absolute methanol were stirred at room temperature in
the presence of base (alcoholic solution of potassium
hydroxide 30 %; 5 ml) for 30 min. The reaction mixture
was allowed to stand overnight and then poured into ice-
cold water followed by neutralization with HCl. The sep-
arated solid product was filtered, dried, and crystallized
from ethanol. The purity of the chalcone was checked by
column chromatography, viz: toluene: ethyl acetate: formic
acid (5:4:1) and petroleum ether: toluene: acetic acid
(5:4:1) and elemental analysis using Perkin Elmer analyzer.
Conclusion
The present series 7a–k of phenoxyacetic acid pyrazoline
were subjected to prediction of molecular properties and
drug-likeness by different softwares to find the most suit-
able molecules for the synthesis and in-vivo diuretic
screening. Compounds 7a–k were found suitable to act as
an oral bioavailable drugs. The SAR has revealed that for
the best activity, chloro group should be present at position
‘R’ as in compounds 7d, 7h, 7i, and 7k. Cumulative urine
output, saluretic, kaliuretic, and potassium sparing prop-
erties were generally increased at the end of 18 h as
compared to initial 5 h of study. The outcome of this
experiment indicates that most of the compounds behave as
longer acting diuretics even better than std. furosemide. It
is conceivable that further derivatization of these signifi-
cant compounds will be of great interest with the hope to
get more selective diuretic agents.
{2-Methoxy-4-[(1E)-3-oxo-3-phenylprop-1-en-1-yl]
phenoxy} acetic acid (3)
IR: (KBr) cm-1: 3174 (COOH), 1688–1682 (2C=O), 1560
1
(C=C). H-NMR (DMSO-d6) ppm: 3.7 (3H, s, OCH3); 4.5
(2H, s, OCH2); 6.6 (1H, d, HT, J = 12.9 Hz); 6.8 (1H, d,
HR, J = 12.6 Hz); 7.2–8.3 (m, Ar–H); 10.1 (1H, s,
COOH). Mass spectra of the compound exhibited molec-
ular ion peak at m/z 312 (M?); other important fragments
were observed at 313 (M? ? 1), 314 (M? ? 2), 253, 207,
281 and 270. Anal. Calcd. for C18H16O5: C, 62.22; H, 5.16;
O, 25.61 %. Found: C, 62.24; H, 5.17; O, 25.63 %. Melting
Point (8C): 110–112. Color, white cream. Yield (%), 81. Rf,
0.32.
Experimental procedures
Chemistry
{4-[(1E)-3-(4-Chlorophenyl)-3-oxoprop-1-en-1-yl]-2-
methoxyphenoxy} acetic acid (4)
All the chemicals used were laboratory grade and pur-
chased from E. Merck (Germany) and S.D. Fine Chemicals
(India). Melting points were determined by open tube
capillary method and are uncorrected using EZ-Melt
automated melting point apparatus. Thin layer chroma-
tography (TLC) plates (silica gel G) were used to confirm
the purity of commercial reagents used, compounds syn-
thesized, and to monitor the reactions as well. Two dif-
ferent solvent systems; toluene: ethyl acetate: formic acid
(5:4:1) and petroleum ether: toluene: acetic acid (5:4:1),
were used to run the TLC. The spots were located under
iodine vapors/UV light. The IR spectra were obtained on a
IR: (KBr) cm-1: 3177 (COOH), 1689–1680 (2C=O), 1577
1
(C=C). H-NMR (DMSO-d6) ppm: 3.6 (3H, s, OCH3); 4.5
(2H, s, OCH2); 6.8 (1H, d, HT, J = 12.7 Hz); 7.1 (1H, d,
HR, J = 12.7 Hz); 7.8–8.3 (m, Ar–H); 10.3 (1H, s,
COOH). Mass spectra of the compound exhibited molec-
ular ion peak at m/z 346 (M?); other important fragments
were observed at 347 (M? ? 1), 348 (M? ? 2), 206, 287
and 315. Anal. Calcd. for C18H15ClO5: C, 62.35; H, 4.36;
O, 23.07 %. Found: C, 62.34; H, 4.35; O, 23.06 %. Melting
Point (8C): 98–101. Color, white. Yield (%), 85. Rf, 0.37.
123

Med Chem Res (2013) 22:916–926
923
{2-Methoxy-4-[(1E)-3-(4-methoxyphenyl)-3-oxoprop-
1-en-1-yl] phenoxy} acetic acid (5)
spectra of the compound exhibited molecular ion peak at
m/z 490 (M?); other important fragments were observed at
491 (M? ? 1), 492 (M? ? 2), 327, 475 and 383. Anal.
Calcd. for C27H26N2O7: C, 66.11; H, 5.34; N, 5.75 %.
Found: C, 66.13; H, 5.35; N, 5.77 %. Melting Point (8C):
110–112. Color, white. Yield (%), 85. Rf, 0.72.
IR: (KBr) cm-1: 3188 (COOH), 1686–1682 (2C=O), 1540
(C=C). 1H-NMR (DMSO-d6) ppm: 3.8 (6H, s, 2 9 OCH3);
4.5 (2H, s, OCH2); 7.0 (1H, d, HT, J = 12.7 Hz); 7.1 (1H,
d, HR, J = 12.7 Hz); 7.2–8.3 (m, Ar–H); 10.5 (1H, s,
COOH). Mass spectra of the compound exhibited molec-
ular ion peak at m/z 342 (M?); other important fragments
were observed at 343 (M? ? 1), 344 (M? ? 2), 207, 311
and 283. Anal. Calcd. for C19H18O6: C, 66.66; H, 5.30; O,
28.04 %. Found: C, 66.62; H, 5.32; O, 28.06 %. Melting
Point (8C): 105–107. Color, milky white. Yield (%), 87. Rf,
0.41.
2-{4-[1-(2-Hydroxybenzoyl)-3-phenyl-4,5-dihydro-1H-
5-pyrazolyl]-2-methoxyphenoxy} acetic acid (7b)
IR: (KBr) cm-1: 3146 (COOH), 1694–1689 (C=O), 1583
(C=N), 1378 (C–N). 1H-NMR (DMSO-d6) ppm: 3.3 (3H, s,
OCH3); 3.6 (2H, d, CH2); 4.6 (2H, s, OCH2); 4.8 (1H, t,
CH); 6.8–8.0 (m, Ar–H); 9.4 (1H, s, OH); 10.5 (1H, s,
COOH). Mass spectra of the compound exhibited molec-
ular ion peak at m/z 446 (M?); other important fragments
were observed at 447 (M? ? 1), 448 (M? ? 2), 325, 387,
404 and 429. Anal. Calcd. for C25H22N2O6: C, 67.26; H,
4.97; N, 6.27 %. Found: C, 67.29; H, 4.94; N, 6.28 %.
Melting Point (8C): 265–270. Color, white. Yield (%), 70.
Rf, 0.82.
{4-[(1E)-3-(4-Hydroxyphenyl)-3-oxoprop-1-en-1-yl]-
2-methoxyphenoxy} acetic acid (6)
IR: (KBr) cm-1: 3092 (COOH), 1688–1682 (2C=O), 1539
1
(C=C). H-NMR (DMSO-d6) ppm: 3.8 (3H, s, OCH3); 4.5
(2H, s, OCH2); 6.9 (1H, d, HT, J = 13 Hz); 7.0 (1H, d, HR,
J = 13 Hz); 7.2–7.8 (m, Ar–H); 9.1(1H, s, OH); 9.8 (1H, s,
COOH). Mass spectra of the compound exhibited molec-
ular ion peak at m/z 328 (M?); other important fragments
were observed at 329 (M? ? 1), 330 (M? ? 2), 269, 286,
206 and 297. Anal. Calcd. for C18H16O6: C, 65.85; H, 4.91;
O, 29.24 %. Found: C, 65.84; H, 4.95; O, 29.26 %. Melting
Point (8C): 113–115. Color, white. Yield (%), 82. Rf, 0.42.
2-{4-[1-(4-Chlorobenzoyl)-3-(4-hydroxyphenyl)-4,
5-dihydro-1H-5-pyrazolyl]-2-methoxy phenoxy}
acetic acid (7c)
IR: (KBr) cm-1: 3166 (COOH), 1686–1682 (2C=O), 1560
1
(C=N), 1385 (C–N). H-NMR (DMSO-d6) ppm: 3.1 ((1H,
dd, HA, J = 5.7, 5.7 Hz); 3.7 (3H, s, OCH3); 3.8 (1H, dd,
HB, J = 9.3, 9.3 Hz); 4.5 (2H, s, OCH2); 6.3 (1H, dd, Hx,
J = 6.3, 6.0 Hz); 6.4–7.7 (m, Ar–H); 9.2 (1H, s, OH); 10.1
(1H, s, COOH). Mass spectra of the compound exhibited
molecular ion peak at m/z 481 (M?); other important
fragments were observed at 482 (M? ? 1), 484 (M? ? 2),
341, 422, 459 and 450. Anal. Calcd. for C25H21ClN2O6: C,
62.44; H, 4.40; N, 5.83 %. Found: C, 62.42; H, 4.44; N,
5.82 %. Melting Point (8C): 208–110. Color, white cream.
Yield (%), 86. Rf, 0.76.
General procedure for synthesis of pyrazoline
derivatives (7a–k)
An equimolar quantity of each compound 3–6 and appro-
priate aryl acid hydrazide was dissolved in 15 ml of glacial
acetic acid. The solution was refluxed for 12 h and after
completion of reaction excess of solvent was removed
under reduced pressure and the reaction mixture was
poured onto crushed ice (20 g). The product 7a–k so
obtained was filtered, washed with water, and purified by
column chromatography, viz: toluene: ethyl acetate: formic
acid (5:4:1) and petroleum ether: toluene: acetic acid
(5:4:1) and elemental analysis using Perkin Elmer analyzer.
2-{4-[1-(4-Chlorobenzoyl)-3-(4-chlorophenyl)-4,
5-dihydro-1H-5-pyrazolyl]-2-methoxy phenoxy}
acetic acid (7d)
IR: (KBr) cm-1: 3163 (COOH), 1689–1682 (2C=O), 1557
2-(2-Methoxy-4-{3-(4-hydroxyphenyl)-1-[2-(4-
methylphenoxy)acetyl]-4,5dihydro-1H-5-
pyrazolyl}phenoxy) acetic acid (7a)
1
(C=N), 1378 (C–N). H-NMR (DMSO-d6) ppm: 3.2 (1H,
dd, HA, J = 5.7, 5.7 Hz); 3.5 (3H, s, OCH3); 3.8 (1H, dd,
HB, J = 10.5, 10.5 Hz); 4.3 (2H, s, OCH2); 6.2 (1H, dd,
Hx, J = 5.7, 5.7 Hz); 6.5–7.7 (m, Ar–H); 10.0 (1H, s,
COOH). Mass spectra of the compound exhibited molec-
ular ion peak at m/z 499 (M?); other important fragments
were observed at 500 (M? ? 1), 501 (M? ? 2), 359, 462,
440 and 468. Anal. Calcd. for C25H20Cl2N2O5: C, 60.13; H,
4.04; N, 5.61 %. Found: C, 60.16; H, 4.06; N, 5.63 %.
IR: (KBr) cm-1: 3242 (COOH), 1695–1688 (2C=O), 1514
(C=N), 1379 (C–N). 1H-NMR (DMSO-d6) ppm: 2.2 (3H, s,
CH3); 3.2 (1H, dd, HA, J = 5.4, 5.4 Hz); 3.6 (3H, s,
OCH3); 3.8 (1H, dd, HB, J = 10.5, 10.5 Hz); 4.5–4.4 (4H,
s, 2 9 OCH2); 6.3 (1H, dd, Hx, J = 5.7, 5.7 Hz); 6.7–8.6
(m, Ar–H); 9.5 (1H, s, OH); 10.4 (1H, s, COOH). Mass
123

924
Med Chem Res (2013) 22:916–926
2-{4-[1-(4-Methylbenzoyl)-3-(4-chlorophenyl)-4,5-
dihydro-1H-5-pyrazolyl]-2-methoxy phenoxy}
acetic acid (7h)
Melting Point (8C): 200–202. Color, white. Yield (%), 72.
Rf, 0.79.
2-{4-[1-(4-Chlorobenzoyl)-3-(4-methoxyphenyl)-4,5-
dihydro-1H-5-pyrazolyl]-2-methoxyphenoxy}
acetic acid (7e)
IR: (KBr) cm-1: 3222 (COOH), 1689–1682 (2C=O), 1560
(C=N), 1374 (C–N). 1H-NMR (DMSO-d6) ppm: 2.3 (3H, s,
CH3); 3.2 (1H, dd, HA, J = 6.0, 6.3 Hz); 3.6 (3H, s, OCH3);
3.9 (1H, dd, HB, J = 12.0, 12.3 Hz); 4.2 (2H, s, OCH2); 6.2
(1H,dd, Hx, J = 6.3, 6.0 Hz);6.8–8.0(m, Ar–H);10.2(1H, s,
COOH). Mass spectra of the compound exhibited molecular
ion peak at m/z 479 (M?); other important fragments were
observed at 480 (M? ? 1), 482 (M? ? 2), 360, 464, 420 and
437. Anal. Calcd. for C26H23ClN2O5: C, 65.20; H, 4.84; N,
5.85 %. Found: C, 65.24; H, 4.88; N, 5.87 %. Melting Point
(8C): 178–180. Color, white. Yield (%), 82. Rf, 0.79.
IR: (KBr) cm-1: 3232 (COOH), 1687–1680 (2C=O), 1567
1
(C=N), 1361 (C–N). H-NMR (DMSO-d6) ppm: 3.2 (1H,
dd, HA, J = 6.3, 6.3 Hz); 3.6–3.7 (6H, s, 2 9 OCH3); 3.9
(1H, dd, HB, J = 12.0, 12.3 Hz); 4.5 (2H, s, OCH2); 6.3
(1H, dd, Hx, J = 6.3, 6.0 Hz); 6.8–7.7 (m, Ar–H); 10.2
(1H, s, COOH). Mass spectra of the compound exhibited
molecular ion peak at m/z 495 (M?); other important
fragments were observed at 496 (M? ? 1), 497 (M? ? 2),
355, 436, 464 and 453. Anal. Calcd. for C26H23ClN2O6: C,
63.10; H, 4.68; N, 5.66 %. Found: C, 63.13; H, 4.69; N,
5.69 %. Melting Point (8C), 200–202. Color, white. Yield
(%), 82. Rf, 0.81.
2-{2-Methoxy-4-[3-(4-chlorophenyl)-1-(2-
phenoxyacetyl)-4,5-dihydro-1H-5-pyrazolyl] phenoxy}
acetic acid (7i)
IR: (KBr) cm-1: 3158 (COOH), 1692–1685 (2C=O), 1598
(C=N), 1375 (C–N). 1H-NMR (DMSO-d6) ppm: 3.2 (1H, dd,
HA, J = 6.0, 6.3 Hz); 3.6 (3H, s, OCH3); 3.9 (1H, dd, HB,
J = 10.5, 10.5 Hz); 4.1–4.2 (4H, s, 2 9 OCH2); 6.2 (1H,
dd, Hx, J = 6.3, 6.3 Hz); 7.0–8.1 (m, Ar–H); 10.7 (1H, s,
COOH). Mass spectra of the compound exhibited molecular
ion peak at m/z 495 (M?); other important fragments were
observed at 496 (M? ? 1), 497 (M? ? 2), 388, 436 and
453. Anal. Calcd. for C26H23ClN2O6: C, 63.10; H, 4.68; N,
5.66 %. Found: C, 63.13; H, 4.69; N, 5.69 %. Melting Point
(8C): 144–146. Color, white. Yield (%), 88. Rf, 0.81.
2-{2-Methoxy-4-[3-(4-methoxyphenyl)-1-(2-
phenoxyacetyl)-4,5-dihydro-1H-5-
pyrazolyl]phenoxy}aceticacid (7f)
IR: (KBr) cm-1: 3162 (COOH), 1692–1685 (2C=O), 1567
1
(C=N), 1374 (C–N). H-NMR (DMSO-d6) ppm: 3.3 (1H,
dd, HA, J = 5.7, 5.7 Hz); 3.6–3.7 (6H, s, 2 9 OCH3); 3.8
(1H, dd, HB, J = 11.1, 11.1 Hz); 4.3–4.5 (4H, s,
2 9 OCH2); 6.3 (1H, dd, Hx, J = 6.6, 6.6 Hz); 6.7–8.1 (m,
Ar–H); 10.3 (1H, s, COOH). Mass spectra of the compound
exhibited molecular ion peak at m/z 490 (M?); other
important fragments were observed at 491 (M? ? 1), 492
(M? ? 2), 397, 431, 448, 459 and 475. Anal. Calcd. for
C27H26N2O7: C, 66.11; H, 5.34; N, 5.71 %. Found: C,
66.13; H, 5.36; N, 5.73 %. Melting Point (8C): 158–160.
Color, Milky white. Yield (%), 89. Rf, 0.80.
2-{2-Methoxy-4-[3-(4-chlorophenyl)-1-(2-phenylacetyl)-
4,5-dihydro-1H-5-pyrazolyl] phenoxy} acetic acid (7j)
IR: (KBr) cm-1: 3201 (COOH), 1688–1682 (2C=O), 1561
(C=N), 1347 (C–N). 1H-NMR (DMSO-d6) ppm: 3.2 (1H, dd,
HA, J = 6.3, 6.6 Hz); 3.6 (3H, s, OCH3); 3.9 (1H, dd, HB,
J = 10.5, 10.5 Hz); 4.1 (2H, s, OCH2); 4.2 (2H, s, CH2); 6.3
(1H, dd, Hx, J = 6.6, 6.6 Hz); 7.7–8.1 (m, Ar–H); 10.2 (1H,
s, COOH). Mass spectra of the compound exhibited molec-
ular ion peak at m/z 479 (M?); other important fragments
were observed at 480 (M? ? 1), 482 (M? ? 2), 388, 437
and 420. Anal. Calcd. for C26H23ClN2O5: C, 65.20; H, 4.84;
N, 5.85 %. Found: C, 65.22; H, 4.83; N, 5.84 %. Melting
Point (8C): 170–172. Color, white. Yield (%), 85. Rf, 0.85.
2-{4-[3-(2,4-Dihydroxyphenyl)-1-(2-phenoxyacetyl)-4,
5-dihydro-1H-5-pyrazolyl]-2-methoxyphenoxy}
acetic acid (7g)
IR: (KBr) cm-1: 3180 (COOH), 1692–1685 (2C=O), 1550
(C=N), 1342 (C–N). 1H-NMR (DMSO-d6) ppm: 2.5 (2H, d,
CH2); 3.5 (3H, s, OCH3); 3.9–4.1 (4H, s, 2 9 OCH2); 4.6
(1H, t, CH); 6.6–8.0 (m, Ar–H); 8.7–9.2 (2H, s, 2 9 OH);
10.3 (1H, s, COOH). Mass spectra of the compound
exhibited molecular ion peak at m/z 492 (M?); other
important fragments were observed at 493 (M? ? 1), 494
(M? ? 2), 385, 399 and 433. Anal.Calcd.for C26H24N2O8:
C, 63.41; H, 4.91; N, 5.69 %. Found: C, 63.40; H, 4.91; N,
5.70 %. Melting Point (8C):100–102. Color, light gray.
Yield (%),78. Rf, 0.77.
2-(2-Methoxy-4-{3-(4-chlorophenyl)-1-[2-(4-
methylphenoxy)acetyl]-4,5-dihydro-1H-5-
pyrazolyl}phenoxy) acetic acid (7k)
IR: (KBr) cm-1: 3237 (COOH), 1694–1686 (2C=O), 1560
(C=N), 1381 (C–N). 1H-NMR (DMSO-d6) ppm: 2.3 (3H, s,
123

Med Chem Res (2013) 22:916–926
925
Statistical analysis
CH3); 2.9 (1H, dd, HA, J = 6.3, 6.6 Hz); 3.7 (3H, s,
OCH3); 3.8 (1H, dd, HB, J = 11.7, 11.7 Hz); 4.2–4.3 (4H,
s, 2 9 OCH2); 6.3 (1H, dd, Hx, J = 6.6, 6.6 Hz); 6.8–8.1
(m, Ar–H); 9.9 (1H, s, COOH). Mass spectra of the com-
pound exhibited molecular ion peak at m/z 509 (M?); other
important fragments were observed at 510 (M? ? 1), 511
(M? ? 2), 388, 402, 494 and 450. Anal. Calcd. for
C27H25ClN2O6: C, 63.72; H, 4.95; N, 5.50 %. Found: C,
63.74; H, 4.95; N, 5.53 %. Melting Point (8C): 150–152.
Color, milky white. Yield (%), 87. Rf, 0.81.
All the statistical calculations were performed by means of
pad prism software by one-way ANOVA followed by
Dunnett’s multiple comparison test (***P \ 0.0001). Each
value represents the mean S.E.M. (n = 6).
Acknowledgments The authors wish to express the gratitude to the
staff of Jamia Hamdard for providing necessary facility to carry out
research work and central animal house facility to provide animal for
carryout diuretic activity.
In vivo diuretic activity
References
The method of Lipschitz was employed for the assessment
of diuretic activity. The experimental protocols have been
approved by the CPCSEA, Jamia Hamdard (Form No 421).
Albino rats, 5-week old, were obtained from Central Ani-
mal House Facility, Jamia Hamdard, New Delhi-110062.
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