Synthesis and enzyme inhibitory activities of some new pyrazole-based heterocyclic compounds

Article abstract of DOI:10.1007/s00044-011-9804-0

Three tridentate N,N-bis(3,5-dimethylpyrazol- 1-ylmethyl)-1-hydroxy-2- aminoethane (2), N,N-bis(3,5-dimethylpyrazol- 1-ylmethyl)-cyclohexylamine (3) and 2-[bis (1,5-dimethyl-1H-pyrazol-3-ylmethyl)amino]ethan-1-ol (4) are synthesized and spectroscopically characterized togetherwith 1-hydroxymethyl-3,5-dimethylpyrazole (1). These have been tested in inhibitory activities against various hyperactive enzymes like urease, β- glucuronidase, phosphodiesterase, α-chymotrypsin, acetylcholinesterase and butyrylcholinesterase. Compounds 1, 2 and 3 were found to be selective inhibitors of urease. Compound 4 was found to be selective inhibitor of butyrylcholinesterase. The nature of the junction between pyrazoles cycles determined the activities of these tripods. While the tripods are inactive towards urease or glucuronidase, they turn to be selective towards butyrylcholinesterase.

Full text of DOI:10.1007/s00044-011-9804-0

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res (2012) 21:2772–2778
DOI 10.1007/s00044-011-9804-0
ORIGINAL RESEARCH
Synthesis and enzyme inhibitory activities of some new
pyrazole-based heterocyclic compounds
•
•
•
•
Tariq Harit Fouad Malek Brahim El Bali Ajmal Khan Kourosh Dalvandi
•
•
•
•
•
Bishnu P. Marasini Shagufta Noreen Rizwana Malik Sadia Khan
M. Iqbal Choudhary
Received: 11 August 2011 / Accepted: 6 October 2011 / Published online: 21 October 2011
Ó Springer Science+Business Media, LLC 2011
Abstract Three tridentate N,N-bis(3,5-dimethylpyrazol-
1-ylmethyl)-1-hydroxy-2-aminoethane (2), N,N-bis(3,5-dime-
thylpyrazol-1-ylmethyl)-cyclohexylamine (3) and 2-[bis
(1,5-dimethyl-1H-pyrazol-3-ylmethyl)amino]ethan-1-ol (4)are
synthesized and spectroscopically characterized together with
1-hydroxymethyl-3,5-dimethylpyrazole (1). These have been
tested in inhibitory activities against various hyperactive
enzymes like urease, b-glucuronidase, phosphodiesterase,
a-chymotrypsin, acetylcholinesterase and butyrylcholinest-
erase. Compounds 1, 2 and 3 were found to be selective
inhibitors of urease. Compound 4 was found to be selective
inhibitor of butyrylcholinesterase. The nature of the junction
between pyrazoles cycles determined the activities of
these tripods. While the tripods are inactive towards urease
or glucuronidase, they turn to be selective towards
butyrylcholinesterase.
Keywords Pyrazole Á Tripod Á Microwave Á
Enzyme inhibition Á Acetylcholinesterase Á
a-Chymotrypsin Á b-Glucuronidase Á
Butyrylcholinesterase Á Phosphodiesterase Á Urease
Introduction
Polypyrazolic ligands have diverse applications in phar-
macology (Park et al., 2005; Tewari and Mishra, 2001;
Finn et al., 2003; Yahyi et al., 2010), biology (Radi et al.,
2010; Janus et al., 1999; Pimerova and Voronina, 2001;
Michon et al., 1995; Bailey et al., 1985), and catalysis
(Sorrell et al., 1984; Boussalah et al., 2009) and electronics
(Marzin et al., 1987; Steel and Constable, 1990). They are
also used in extraction, complexation and the transport of
some alkaline and transition metals (Tarrago et al. 1988;
Malek et al., 2002, 2005a, b; Radi et al., 2006; Malek and
Radi, 2009).
T. Harit Á F. Malek
Laboratory of Organic Chemistry, Macromolecular and Naturals
Products, URAC 25, Faculty of Sciences, University Mohamed
I, P.O. Box 717, 60000 Oujda, Morocco
B. E. Bali (&)
Laboratory of Mineral Solid and Analytical Chemistry,
Faculty of Sciences, University Mohamed I, P.O. Box 717,
60000 Oujda, Morocco
e-mail: b.elbali@fso.ump.ma
A. Khan Á K. Dalvandi Á B. P. Marasini Á S. Noreen Á
R. Malik Á M. Iqbal Choudhary
A number of tripod pyrazolic ligands have been studied
in our laboratory (Malek et al., 2004, 2007; El Kodadi
et al., 2003, 2008; Attayibat et al., 2010; Tebbji et al.,
2005; Bouabdallah et al., 2007). These compounds were
synthesized creating N–C–N or C–N–C junctions
(Scheme 1). Their main feature is two sp2 and sp3
hybridized amine nitrogen atoms as donors. The three sites
of complexation form a pyramidal complexing metal.
Moreover, the nature of the lateral arm R can be modified
according to intended application. Nevertheless, these tri-
dentate compounds show a powerful complexing effect
HEJ Research Institute of Chemistry, Dr. Panjwani Centre for
Molecular Medicine and Drug Research, International Centre for
Chemical and Biological Sciences, University of Karachi,
Karachi 75270, Pakistan
S. Khan
Dr. Panjwani Centre for Molecular Medicine and Drug Research,
International Centre for Chemical and Biological Sciences,
University of Karachi, Karachi 75270, Pakistan
M. Iqbal Choudhary
Department of Chemistry, School of Sciences,
King Saudi University, Riyadh 11475, Saudi Arabia
123

Med Chem Res (2012) 21:2772–2778
2773
towards transition metals (Malek et al., 2004, 2007; El
Kodadi et al., 2003; Attayibat et al., 2010) and thus acquire
catalytic action (El Kodadi et al., 2008; Tebbji et al., 2005;
Bouabdallah et al., 2007).
encephalopathy, hepatic coma and urinary catheter encrus-
tation (Rama et al., 2010).
Acetylcholinesterase (AChE) (EC 3.1.1.7) is a key
component of cholinergic brain synapses and neuromus-
cular junctions. The major biological role of the enzyme is
the termination of impulse transmission by rapid hydrolysis
of the cationic neurotransmitter acetylcholine (Tougu,
2001). According to the cholinergic hypothesis, memory
impairments in patients with the senile dementia disease
are due to a selective and irreversible deficiency in the
cholinergic functions in brain (Perry, 1986). This serves as
a rationale for the use of AChE inhibitors for the symp-
tomatic treatment of Alzheimer’s disease (AD) in its early
stages. The role of butyrylcholinesterase (BChE) (EC
3.1.1.8) in normal ageing and brain diseases is still elusive.
It has been found that BChE is found in significantly higher
quantities in Alzheimer’s plaques than in plaques of normal
age related non-demented brains (Yu et al., 1999).
The inhibitors of AChE and BChE help to enhance the
efficiency of the remaining neurons (Trabace et al., 2000).
Due to the diverse functions of these enzymes, their inhi-
bition by potent and specific compounds could provide an
invaluable addition for treatment of infections.
Recently, we studied the anticancer effects of two tri-
dentate ligands against mastocytoma murine P815 cell line.
Results showed that these tripods possess good cytotoxic
activities against the cell line P815 (El Kodadi et al., 2007;
Bouabdallah et al., 2006). Moreover, pyrazole diaryl
derivatives, known as Celebrex, exhibit anti-inflammatory,
analgesic and antipyretic activities in animal models
ˆ
(Milletre-Berdardin et al., 1995). The mechanism of action
of Celebrex involves inhibition of the synthesis of prosta-
glandins through the inhibition of cyclooxygenase-2. It was
also reported that Celebrex does not prevent the action of
the isoenzyme cyclooxygenase-1. In the animal models of
tumour, the Celebrex reduced the impact and multiplicity
of tumours. Pyrazoles were also reported as potent inhibi-
tors of the Helicobacter pylori dihydroorotate dehydroge-
nase (Haque et al., 2002).
We hereby report the synthesis of 1-hydroxymethyl-3,
5-dimethylpyrazole (1), [N,N-bis(3,5-dimethylpyrazol-1-
ylmethyl)-1-hydroxy-2-aminoethane] (2) and [N,N-bis(3,5-
dimethylpyrazol-1-ylmethyl) cyclohexylamine (3), as well
as a molecule with a tripod C–N–C junction, 2-[bis(1,5-
dimethyl-1H-pyrazol-3-ylmethyl)amino]ethan-1-ol (4) and
their inhibitory activities against various hyperactive
enzymes such as urease, b-glucuronidase, phosphodiester-
ase, a-chymotrypsin, acetylcholinesterase and butyrylcho-
linesterase. Urease (urea amidohydrolase EC 3.5.1.5) is a
nickel containing metalloenzyme which catalyzes the
hydrolysis of urea to ammonia and carbon dioxide. It is an
enzyme responsible for the use of urea as a nitrogen source.
In plants, urease also acts as defense protein in systemic
nitrogen transport pathways. Urease in organism is known
to be one of the major causes of pathologies induced by
H. pylori, thus allow them to survive at low pH of the
stomach and, therefore, play an important role in the path-
ogenesis of gastric and peptic ulcers. Urease is also directly
involved in the formation of kidney stones and contributes to
the pathogenesis of urolithiasis, pyelonephritis, and hepatic
Experimental
Techniques
The proton NMR spectra of the compounds (1–4) were
recorded in CDCl3 on a Bruker spectrometer (250 MHz), at
room temperature. Chemical shifts are reported in parts per
million (d) using internal TMS standard. The IR spectra
have been recorded, in film form, on a SHIMADZU FTIR
8400, between 4,000 and 600 cm-1 with a resolution of
4 cm-1. The number of scans was 20 for each sample.
Letters s, f, F and m indicate broadband, low, medium and
heavy, respectively. Mass spectra were measured on a
Platform II Micromass instrument (ESI?, CH3CN/H2O:
50/50). Elemental analyses were performed by Micro-
analysis Central Service (CNRS). Melting points were
determined on a Bu¨chi–Totolli capillary apparatus and are
uncorrected. Microwave-assisted synthesis were carried out
using a Prolabo Maxidigest MX 350 focused monomode
system (100% power = 300 W).
Me
Me
N
N
Me
Me
N
N
N
N
Me
Me
Reagents
N
R
R
N
The 3,5-dimethylpyrazole and 3-chloromethyl-1,5-dime-
thyl-1H-pyrazole were prepared according to the procedure
described in the literature (Dvoretzky and Richter, 1950;
Fifani et al., 1977). The 37% formaldehyde solution,
ethanolamine, cyclohexylamine, dichloromethane, ethyl
N
N
Me
Scheme 1 Structures and junctions of bipyrazolic tripods
Me
123

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Med Chem Res (2012) 21:2772–2778
alcohol and ethyl acetate were all high quality reagents
(Aldrich 99%).
1310 (m); 1260(m); 1190(m); 1095(F); 970(f); 890(f);
870(f); 776(m); 636 (m); m/z : 316 [M ? 1]? (FAB [ 0);
Anal. calc. for C18H29N5: C: 68.57; H: 9.20; N: 22.22%;
Found: C: 69.12; H: 8.82; N: 21.72%.
Synthesis of the 1-hydroxymethyl-3,
5-dimethylpyrazole (1)
Synthesis of 2-[bis(1,5-dimethyl-1H-pyrazol-3-ylmethyl)
amino]ethan-1-ol (4)
20 g (0.208 mol) of 3,5-dimethylpyrazole, in 20 ml of
ethyl alcohol and 25 ml of formaldehyde solution 35%
were introduced in a beaker. The mixture was maintained
under agitation at room temperature for 12 h. The con-
centrate solvent was thus reduced to half, after which ice
was added. Deposited precipitate was washed with water
and dried under pressure. Finally, a white solid was recu-
perated in 80% (21 g) yield with following characteristics:
To acetonitrile (150 ml) containing 3-chloromethyl-1,5-
dimethylpyrazole (2.96 g, 20.5 mmol) and sodium car-
bonate (8.64 g, 80 mmol) was added slowly (0.62 g,
10.2 mmol) with ethanolamine in 50 ml of acetonitrile.
The mixture was stirred under reflux for 5 h. The solid
material was filtered and the filtrate was concentrated under
reduced pressure. The residue was purified on alumina
using 97/3 CH2Cl2/MeOH as eluant to obtain an 80% yield
(2.26 g).
1
MP: 106–108°C (CH2Cl2); H-NMR: (d) : 2.15 (s, 3H,
CH3); 2.30 (s, 3H, CH3); 4.80 (s, 1H, OH); 5.45 (s, 2H,
CH2); 5.90 (s, 1H, Hpz). m/z : 127 [M ? 1]? (FAB [ 0);
Anal. Calc. for C6H10N2O: C: 57.14; H: 7.93; N: 22.22;
Found: C: 57.41; H: 7.68; N: 22.04;
1
MP: 64–66°C (CH2Cl2/EtOH); H NMR (d): 2.21 (s,
6H, CH3); 2.66 (t, 2H, J = 5,1 Hz, N–CH2); 3.55 (t, 2H,
J = 5,1 Hz, CH2OH); 3.65 (s, 4H, CH2–N); 3.70 (s, 6H,
N–CH3); 5.95 (s, 2H, Hpz); IR (cm-1): 3380 (l, –OH);
2980 (m, =CH); 1680(f, –C=C–); 1460 (f, –C=N–); 1400
(m); 1300(m); (F, –C–OH); 1140(f); 1070(f); 1040(f);
990(f); 800(m). m/z: 278 [M ? 1]? (FAB [ 0) Anal. Calc.
for C14H23N5O: C: 60.65, H: 8.30; N: 25.27; Found: C:
60.02; H: 7.98; N: 25.85.
Synthesis of [N,N-bis(3,5-dimethylpyrazol-1-ylmethyl)
-1-hydroxy-2-aminoethane] (2)
A
mixture of 1-hydroxymethyl-3,5-dimethylpyrazole
(3.78 g, 30 mmol) and ethanolamine (0.92 g, 15 mmol)
was introduced into a Pyrex tube, which was then placed in
a microwave reactor and irradiated with microwaves
(60 W) in the absence of solvent for 20 min. The reaction
mixture was extracted with dichloromethane and washed
with water to eliminate the residual ethanolamine. The
organic solution was dried under reduced pressure. The
resulting solid was crystallized from ethyl acetate to obtain
white crystals (3.8 g, 92%); MP: 81–83°C (ethyl acetate);
1H-NMR (d): 2.20 (s, 6H); 2.25 (s, 6H, CH3); 2.95 (t, 2H,
J = 5.4 Hz, N-CH2); 3.65 (t, 2H, J = 5.4 Hz, CH2OH);
4.95 (s, 4H, CH2–N), 5.80 (s, 2H, Hpz); IR (cm-1): 3259
(l, –OH); 2923 (m, =CH); 2858 (f, –CH); 1548 (f, C=C);
1457 (f, –C=N–); 1365 (m); 1333 (m); 1294(F); 1245(m);
1175 (F, –C–OH); 1135(f); 1070 (f); 797(m); 784(m);
736(m); m/z: 278 [M ? 1]? (FAB [ 0); Anal. Calc. for
C14H23N5O: C: 60.65, H: 8.30, N: 25.27; Found: C: 60.25,
H: 8.06, N: 25.07.
Urease inhibition assay
Reaction mixtures comprising one unit of urease enzyme
(Jack bean) solution, and 55 ll of buffers containing
100 mM urea were incubated with 5 ll of test compound
(0.5 mM concentration) at 30°C for 15 min in 96-well
plates. Urease activity was determined by measuring
ammonia production using the indophenol method. Briefly,
45 ll of phenol reagent and 70 ll of alkali reagent were
added to each well. The increasing absorbance at 630 nm
was measured after 50 min, using a microplate reader. All
reactions were performed in triplicate in a final volume of
200 ll. The results (change in absorbance per min) were
processed by using SoftMax Pro software (Khan et al.,
2010).
Synthesis of [N,N-bis(3,5-dimethylpyrazol-1-ylmethyl)
-cyclohexylamine (3)
Cholinesterase inhibition assay
AChE and BChE inhibiting activities were measured by the
spectrophotometric method by using acetylthiocholine
iodide and butyrylthiocholine chloride as substrates. The
reaction mixture contained 130 ll of (100 mM) sodium
phosphate buffer (pH 8.0), 20 ll of DTNB, 10 ll of tested
compound solution and 20 ll of AChE or BChE solution,
which were mixed and incubated for 15 min at 25°C. The
reaction was then initiated by the addition of 20 ll
In similar procedure, the title compound was obtained as
solid crystals, with a yield of 87% (4.1 g).
MP: 95–97°C (ethyl acetate); 1H NMR (d): 1.10–1.80 (m,
10H, CH2 cyclohexyl); 2.10 (s, 6H, CH3); 2.25 (s, 6H, CH3);
2.60 (s, 1H, N–CH cyclohexyl); 4.80 (s, 4H, –CH2–N); 5.75
(s, 2H, Hpz); IR (cm-1): 3125 (m, =CH); 2928(f, –CH);
2875(f, –CH); 1650 (m, –C=C–); 1556 (f); 1464 (f, –C=N–);
123

Med Chem Res (2012) 21:2772–2778
2775
acetylthiocholine or butyrylthiocholine, respectively. The
hydrolysis of acetylthiocholine and butyrylthiocholine
were monitored at a wavelength of 412 nm (15 min).
Absolute ethanol, which becomes 5% in the reaction
mixture, was used as solvent for test compounds and the
standard inhibitor. All the reactions were performed in
triplicate in 96-well microplate using SpectraMax Plus 384
(Ellman et al., 1961).
the procedure described in the literature (Dvoretzky and
Richter, 1950).
Compound 2 was obtained by reacting the precursor 1
with commercially available ethanolamine in the ratio 2:1.
The mixture was placed for 20 min in a microwave reactor
and irradiated with microwaves (60 W) in the absence of
any solvent; it yielded the product (2) in excellent yield
(92%). Compound 3 was prepared in a 75% yield through a
similar procedure by reacting cyclohexylamine with the
synthon (1).
a-Chymotrypsin inhibition assay
The route that we used to prepare the target ligand (4) is
shown in Scheme 3. The process involves tree steps of the
precursor 3-chloromethyl-1,5-dimethylpyrazole (Fifani
et al., 1977) that possesses a good leaving group. Scheme 3
summarizes the preparation process of the title compound.
Compound 4 was obtained in a 80% yield by reacting the
chloro derivative with 2-aminoethanol in a ratio of 2:1
under reflux condition using sodium carbonate as base. The
Enzyme and substrate both are prepared in Tris–HCl buffer
pH 7.6. Chymotrypsin 12 U/ml, was preincubated with test
compounds, which was prepared in final concentration of
7% DMSO, for 25 min at 30°C. The 0.4 mM substrate,
N-succinyl-phenylalanine-p-nitroanilide, was added to start
the enzyme reaction. The absorbance of released p-nitro-
aniline was continuously monitored at 410 nm using a
microplate reader, SpectraMax M2 (Molecular Device,
CA, USA) until a significant colour change was observed
(Cannell et al., 1988).
1
compounds 2–4 were characterized by H NMR, FTIR,
elemental analyses and mass spectrometry.
Assay for b-glucuronidase
Enzyme inhibitory activities
b-Glucuronidase inhibitory activity was evaluated in 0.1 M
acetate buffer pH 8.8. The buffer, various concentrations of
test compounds and enzyme were incubated at 37°C for
30 min. Then, the 96-well plates were read on SpectraMax
plus 384 (Molecular Devices, CA, USA) at 405 nm after
the addition of 0.4 mM p-nitrophenyl-b-D-glucuronide
(Riaz et al., 2003).
Enzyme inhibition is active area of research in drugs
development. Here, we have synthesized two series of
pyrazoles tripods 2–4, which differ only from the junction
between pyrazoles. To check their potential, we subjected
these derivatives to various hyperactive enzymes inhibition
assays against urease, b-glucuronidase, phosphodiesterase,
a-chymotrypsin, acetylcholinesterase and butyrylcholin-
esterase. Both these series showed significant activity
against urease and butyrylcholinesterase enzymes.
Phosphodiesterase inhibition assay
Compound 1 is a pyrazole found to be a selective
inhibitor of urease. After its dimerization, the urease
activity enhanced by twofold. The tripod 2 was also found
to be selective for the inhibitor of urease, while the tripod 3
is found to be a weak inhibitor of b-glucuronidase. This
activity is probably due to the cyclohexyl arm held by the
lateral chain, which may have hydrophobic interaction with
the active site. Its inhibition of urease is ten times higher
than its activity against b-glucuronidase. The nature of the
lateral arm has no influence on the activity of these tripods
towards the urease, but it can inhibit other enzymes.
The tripod 4, differing from the tripod 2 by the nature of
the junction linking the two pyrazoles, acts selectively
towards butyrylcholinesterase. It is however inactive
towards the urease and other enzymes. It probably interacts
with the active site of the butyrylcholinesterase. Results of
the assay are presented in Table 1. The inhibition activities
of these tripods depend on the nature of the junction
between the pyrazoles.
Snake venom phosphodiesterase activity was performed in
33 mM Tris–HCl buffer with 30 mM Mg-acetate buffer
pH 8.8. The buffer, various concentrations of test com-
pounds, and enzyme (0.742 mU/well) were incubated at
37°C for 30 min. The plates were read on a multi-
plate reader, SpectraMax plus 384 (Molecular Devices,
CA, USA) at 410 nm after the addition of 0.33 mM bis-
(p-nitropheny1) phosphate (Mamillapalli et al., 1998).
Results and discussion
The basic precursor for the synthesis of N,N-bis(3,
5-dimethylpyrazol-1-ylmethyl)-1-hydroxy-2-aminoethane(2)
and N,N-bis(3,5-dimethylpyrazol-1-ylmethyl)-cyclohexyl-
amine (3) is 1-hydroxymethyl-3,5-dimethylpyrazole (1).
The later was obtained by condensation of a formaldehyde
solution on 3,5-dimethylpyrazole (Scheme 2) according to
123

2776
Med Chem Res (2012) 21:2772–2778
Scheme 2 Process for
preparing tridentate compounds
2 and 3
Me
O
O
EtOH
,
H2N NH2
H2O
N
+
Me
N
H
HCOH / EtOH
Me
N
Me
N
Me
N
R
NH
2
R
N
Me
N
N
Me
HO
N
Me
2
R = CH CH OH
2
2
3
R =
Me
Me
Me
N
N
Me
N
-
+
H N-CH CH OH
t
1)
1/2
2
2
BuO K / MeI
LiAlH4
2
N
H
CO2Et
CH2Cl
N
CH CH OH
2
2
Me
N
N
Na CO
2
2)
3)
3
N
Me
SOCl2
N
Me
4
Scheme 3 Preparation steps of compound 4
Table 1 Enzymes inhibitory activities of compounds 1–4
Compound IC50 SEM (lM)
code
a-Chymotrypsin Phosphodiesterase Urease
Acetylcholinesterase Butyrylcholinesterase b-Glucuronidase
1
NA
NA
94.3 0.47 NA
44.66 0.03 NA
43.46 0.02 NA
NA
NA
2
NA
NA
NA
NA
3
NA
NA
NA
456.6 1.36
NA
4
NA
NA
NA
NA
68 0.0025
Galanthamine
0.17 0.01
Standard
Chymostatin
5.7 0.13
EDTA
74 1.25
Thiourea
21 0.011
Galanthamine
0.5 0.01
D-Saccharic acid 1,4-lactone
48.4 1.25
NA not active, % of inhibition is less than 50% at 500 lM; SEM standard error of mean
123

Med Chem Res (2012) 21:2772–2778
2777
Ellman GLKD, Andres V, Featherstone RM (1961) A new and rapid
colorimetric determination of acetylcholinesterase activity. Bio-
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Fifani J, Ramdani A, Tarrago G (1977) 1,6,11,16-tetraazaporphyri-
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Conclusions
Three tripods were synthesized from the substrate
1-hydroxymethyl-3,5-dimethylpyrazole. This concerns N,
N-bis(3,5-dimethylpyrazol-1-ylmethyl)-1-hydroxy-2-amino-
ethane, N,N-bis(3,5-dimethylpyrazol-1-ylmethyl)-cyclohex-
ylamine and 2-[bis(1,5-dimethyl-1H-pyrazol-3-ylmethyl)
amino]ethan-1-ol. Their structures were characterized by 1H
NMR, FTIR, elemental analyses and mass spectrometry.
Compounds 1, 2 and 3 were found to be selective inhibitors of
urease, while compound 4 is of butyrylcholinesterase. The
nature of the junction between pyrazoles cycles seems to
determine the activities of these tripods. While the tripods are
inactive towards urease or glucuronidase, they turn to be
selective towards butyrylcholinesterase.
Khan I, Ali S, Hameed S, Rama NH, Hussain MT, Wadood A, Uddin
R, Ul-Haq Z, Khan A, Ali S, Choudhary MI (2010) Synthesis,
antioxidant activities and urease inhibition of some new 1,2,4-
triazole and 1,3,4-thiadiazole derivatives. Eur J Med Chem 45:
5200–5207
Acknowledgements The authors would like to thank the CNRST
(Morocco), URAC 25, for financial support.
Malek F, Radi S (2009) Transport abilities of new synthesised
membrane materials incorporating tetrapyrazolic tripods. J Appl
Polym Sci 111:57–62
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