New N,N,N',N'-tetradentate pyrazoly agents: Synthesis and evaluation of their antifungal and antibacterial activities

Article abstract of DOI:10.2174/1573406411666150519111800

A new library of N,N,N',N'-tetradentate pyrazoly compounds containing a pyrazole moiety was synthesized by the condensation of (3,5-dimethyl-1H-pyrazol-1-yl)methanol 2a or (1H-pyrazol-1-yl)methanol 2b with a series of primary diamines in refluxed acetonitrile for 6h. The antifungal activity against the budding yeast Saccharomyces cerevisiae, as well as the antibacterial activity against Escherichia coli of these new tetradentate ligands were studied. We found that these tetradentate ligands act specifically as antifungal agents and lack antibacterial activity. Their biological activities depend on the nature of the structure of the compounds.

Full text of DOI:10.2174/1573406411666150519111800

Send Orders for Reprints to reprints@benthamscience.ae
Medicinal Chemistry, 2016, 12, 83-89
83
New N,N,N’,N’-tetradentate Pyrazoly Agents: Synthesis and Evaluation of
theirꢀAntifungal and Antibacterial Activities
1
,*
2
3
3
1
Farid Abrigach , Btissam Bouchal , Olivier Riant , Yohan Macé , Abdelilah Takfaoui ,
1
4
2,*
1,4
Smaail Radi , Abdelouahad Oussaid , Mohammed Bellaoui and Rachid Touzani
1
Laboratory of Applied Chemistry & Environment (LCAE-URAC18), COSTE,
Faculty of Science, University Mohammed the First, Oujda, Morocco;
2
Medical Biology Unit, Faculty of Medicine and Pharmacy of Oujda, Univer-
3
sity Mohammed the First, Oujda, Morocco; Institute of Condensed Matter
and Nanosciences (IMCN). Molecules, Solids and Reactivity (MOST). Catho-
lic University of Louvain, Place Louis Pasteur, 1348 Louvain-la-Neuve, Bel-
4
gium; Faculté Pluridisciplinaire de Nador BP300, Selouane 62702 Nador,
Morocco
Abstract: A new library of N,N,N’,N’-tetradentate pyrazoly compounds containing a pyrazole moiety was synthesized by
the condensation of (3,5-dimethyl-1H-pyrazol-1-yl)methanol 2a or (1H-pyrazol-1-yl)methanol 2b with a series of primary
diamines in refluxed acetonitrile for 6h. The antifungal activity against the budding yeast Saccharomyces cerevisiae, as
well as the antibacterial activity against Escherichia coli of these new tetradentate ligands were studied. We found that
these tetradentate ligands act specifically as antifungal agents and lack antibacterial activity. Their biological activities de-
pend on the nature of the structure of the compounds.
Keywords: Tetradentate pyrazole, synthesis, donor-groups, antibacterial, antifungal.
1
. INTRODUCTION
In this paper we report the synthesis of some new
N,N,N’,N’-tetradentate pyrazole as well as their antifungal
and antibacterial biological activities.
The growing interest in finding new bioactive compound
against diseases provides exciting prospects for the prepara-
tion of many functionalized heterocyclic rings such as pyra-
zole [1], triazole [2] and tetrazole [3]. This continuing inter-
est is evident from the large and the enormous research in
this section and from the potential applications in bioinor-
ganic and medicinal chemistry [4-7]. In fact, most of the new
drugs contain heterocyclic compounds [8]. In this paper,
specially newly prepared pyrazole compounds are reported.
Indeed, over the past few years, increasing attention has been
paid to pyrazole and their complexes in the pharmaceutical
and agro-chemical industries, and large advanced synthetic
methods have been designed recently due to the non-
existence of pyrazole derivatives in nature, probably, due to
the difficulty in the construction of N–N bond by living or-
ganisms [9]. Actually, the pyrazole system represents an
important heterocyclic template due to its long history and
various applications such as antiproliferative [10], antibacte-
rial [11], analgesics [12], antiparasitic [13], antiviral [14],
antiglycemic [15] or as anti-in ammatory agents [16].
2
2
. MATERIALS AND METHODS
.1. Procedure of Synthesis
The following products illustrated below were prepared
after a modification on the method of the synthesis reported
in the literature [19-26]. The compounds were obtained by a
simple condensation between (3,5-dimethyl-1H-pyrazol-1-
yl)methanol 2a or (1H-pyrazol-1-yl)methanol 2b and vari-
ous primary diamines (Scheme (1)).
2.2. Determination of the Antifungal Activity
The antifungal activity against the yeast (Saccharomyces
cerevisiae) strain BY4741 [27] has been determined using
liquid cell culture assay as described [18].
2
.3. Determination of the Antibacterial Activity
Disc diffusion assay has been used to evaluate the anti-
In previous work, we showed that some tridentate ligands
based on pyrazole and triazole have some biological activi-
ties [17-18]. Using functional genomics technologies in
yeast, we also showed that two tridentate ligands based on
pyrazole and triazole act as DNA damage agents [18].
bacterial activity of the newly synthesized molecules [28-
1]. In this assay, the Gram-negative bacterial strain E. coli
DH5ꢀ strain) has been used. The bacterial isolate was culti-
3
(
o
vated overnight in liquid Luria-Bertani medium (LB) at 37 C
8
under aeration. After that, a suspension containing 10
CFU/mL of bacteria cells was prepared and used to inoculate
Petri plates containing solid (LB) medium. The plates were
then allowed to dry for 15 minutes. Then, the paper discs
(6mm in diameter) which had previously been impregnated
*
Address correspondence to these authors at the Medical Biology Unit,
Faculty of Medicine and Pharmacy of Oujda, University Mohammed
the First, Oujda, Morocco; Tel: +212 670 314 410;
E-mails: bmbellaoui@gmail.com; abrigach.farid@live.fr
1
875-6638/16 $58.00+.00
© 2016 Bentham Science Publishers

8
4
Medicinal Chemistry, 2016, Vol. 12, No. 1
Abrigach et al.
R
R
R
R
R
R
R
R
N
N
N
N
R
N
N
N
N
CH O/EtOH
N
2
H N
2
NH2
N
N
N
R
1
2
. Reflux: 1h
. Stiring for 12h
HN
CH
CN
3
N
OH
Reflux: 6h
1
1
a: R= CH3
b: R= H
2a: R= CH3
2b: R= H
R
R
Comp.
R
Yield (%)
3
a
-CH3
-H
82.21
3
b
70.58
4
a
-CH3
-H
8
3.73
4
b
65.69
84.93
5
a
-CH3
6
a
82.85
55.28
-
CH3
7a
-CH3
-H
7
b
a
44.28
22.28
8
-CH3
-CH3
O
O
9a
28.03
60.73
9
b
-
H
Scheme 1. General pathway of synthesized pyrazolic compounds.
with the tested compounds were placed on the inoculated
agar plates. The compounds were then allowed to diffuse
into the medium by incubating the plates for one hour at
6a), doublet for 7a (7b, 8a and 9a) and a double of doublet
for the compound 5a. The difference in the multiplicity of
the N-CH -N signal is due to the space structure of each
2
molecule. Therefore, in the case of the singlet peak of the
compound 4a for example, the symmetry makes atoms
equivalent in the molecule, which means that all the proton
o
room temperature. These were then incubated at 37 C.
Twenty-four hours later, the antibacterial activity was evalu-
ated by measuring the inhibition zone diameters in millime-
tre. The measurements of inhibition zones were performed
three times for each drug including compound 15 as a posi-
tive control (PC) [32].
2
atoms of N-CH -N bond are in identical locations relative to
a plane of symmetry in the molecule, then these atoms are
equivalent and we see just one peak with an integration of 8
proton. The doublet peak for example 7a means that the
molecule is not symmetric relative to a plane or a center of
symmetry that means the two protons are not equivalent to
each other. Finally, the compound 5a shows two unequiva-
lent methylene groups with partially overlapping signals as a
consequence of the chiral carbon centre.
3
3
. RESULTS AND DISCUSSION
.1. Synthesis
2
From Fig. (1), we clearly show that the N-CH -N signal
of our compounds is different from a singlet for 4a (3a and

New N,N,N’,N’-tetradentate Pyrazoly Agents
Medicinal Chemistry, 2016, Vol. 12, No. 1 85
2
Fig (1). Multiplicity of the N-CH -N signal in the compounds 4a, 7a and 5a.
The methylene protons are diastereotopic in the chiral
ligand 5a (Fig. (1)) and their signals appear as AB systems
with a coupling constants of 13 Hz. Very sensitive probes for
changes in the environment are the methylene proton reso-
nances which agree with the reported literature [33-35].
slightly toxic, but compounds 3a, 4a and 6a showed moder-
ate antifungal activity. Interestingly, compound 5a displayed
strong antifungal activity. Overall, these results suggest that
the 3,5-dimethyl-1H-pyrazoly group of these tetradentate
ligands is not important for the antifungal activity of these
compounds. However, the central diamine group is critical
for bioactivity in yeast. In addition, compound 5a was more
potent than the other tetradentate ligands, indicating that the
central cyclohexane-1,2-diamine group of 5a is the most
active followed by propane-1,3-diamine of 4a, ethane-1,2-
diamine of 3a, Benzene-1,2-diamine of 6a, aniline of 9a and
then 9H-fluorene-2,7-diamine of 8a. Because compound 7a
showed no antifungal activity, the central naphthalene-1,5-
diamine group is inactive.
3
.2. Antifungal Activity of Tetradentate Based on (3,5-
dimethyl-1H-pyrazol-1-yl)methanol and (1H-pyrazol-1-
yl)methanol Compounds
We first evaluated seven new tetradentate based on (3,5-
dimethyl-1H-pyrazol-1-yl)methanol for their antifungal ac-
tivity against budding yeast (Saccharomyces cerevisiae)
cells. Using liquid cell culture assay, yeast cells were grown
in the presence of 500 ꢀM of each compound and assayed
for growth inhibition (Fig. 2A,2B). Compound 7a did not
inhibit yeast growth, however compounds 8a and 9a were
We next assessed four tetradentate compounds based on
(1H-pyrazol-1-yl)methanol for toxicity against budding yeast

8
6
Medicinal Chemistry, 2016, Vol. 12, No. 1
Abrigach et al.
A
B
8
7
6
5
4
3
2
1
0
No drug
3
a
a
4
5a
6a
7a
8
a
a
9
0
2
4
6
8
10 12 14 16 18 20 22 24
Time (hours)
Fig (2). Antifungal activity of tetradentate ligands based on (3,5-dimethyl-1H-pyrazol-1-yl)methanol. A. Structures of the tetradentate
ligands analyzed. B. Yeast cells were cultured in the presence of 500 ꢀM of the compounds shown in 2A. Optical density was measured
every 2 hours to follow cell growth.
A
B
8
7
6
5
4
3
2
1
0
No drug
3
b
b
4
7b
9b
0
2
4
6
8
10 12 14 16 18 20 22 24
Time (hours)
Fig (3). Antifungal activity of tetradentate ligands based on (1H-pyrazol-1-yl) methanol. A. Structures of the tetradentate ligands analyzed.
B. Yeast cells were cultured in the presence of 500 ꢀM of the compounds shown in 3A. Optical density was measured every 2 hours to fol-
low cell growth.
cells. Cells were grown in the presence of 500 ꢀM of each
compound and assayed for growth inhibition in liquid culture
and 9b were much more toxic to yeast cells than 3a, 4a, 7a
and 9a, respectively.
(
Fig. 3A, 3B). Compounds 7b showed weak antifungal activ-
3
.3. Antibacterial Activity of Tetradentate Based on (3,5-
ity, whereas compounds 3b, 4b and 9b displayed strong bio-
activity. Interestingly, these results suggest that tetradentate
ligands based on (1H-pyrazol-1-yl)methanol are much more
bioactive than tetradentate ligands based on (3,5-dimethyl-
dimethyl-1H-pyrazol-1-yl)methanol and (1H-pyrazol-1-
yl)methanol Compounds
It has been previously shown that tridentate ligands have
1
H-pyrazol-1-yl)methanol. As a matter of fact, 3b, 4b, 7b
antibacterial activity against E. coli [17]. Therefore, it is

New N,N,N’,N’-tetradentate Pyrazoly Agents
Medicinal Chemistry, 2016, Vol. 12, No. 1 87
7a
4a
3a
8a
PC
PC
3b
9b
6a
9a
4b
7b
5a
Fig (4). Antibacterial activity of tetradentate based on (3,5-dimethyl-1H-pyrazol-1-yl)methanol and (1H-pyrazol-1-yl)methanol compounds.
E. coli cells were first spread on petri plates containing solid LB medium. Then, the paper discs (6mm in diameter) which had previously
o
been impregnated with the tested compounds were placed on the inoculated agar plates. These were then incubated at 37 C. Twenty-four
hours later, the antibacterial activity was assessed by measuring the diameter of the growth-inhibition zone in millimetre. The tested com-
pounds including the positive control (PC) are indicated.
likely that these tetradentate ligands have antibacterial activ-
ity against E. coli. To test this hypothesis, we evaluated these
compounds for their antibacterial activity against E. coli as
described in materials and methods. Interestingly, all the
tetradentate compounds tested 3a, 3b, 4a, 4b, 5a, 6a, 7a, 7b,
Melting points were obtained using the capillary tube
method with an Electrothermal 9100 apparatus. Proton and
carbon nuclear magnetic resonance spectra were recorded on
1
a Bruker 300 instrument (operating at 300.13 MHz for H,
1
3
75.47 MHz for C) spectrometer. Chemical shifts are re-
ported in parts per million (ppm). The band positions on In-
frared Spectra (IR) are reported in reciprocal centimeters
8
a, 9a and 9b showed no antibacterial activity when they
were used at 500 ꢀM (Fig. 4); Data not shown). Thus, to-
gether with the antifungal activity analysis, these results
suggest that these tetradentate ligands act specifically as anti-
fungal agents and lack antibacterial activity. Indeed, specific
inhibitory compounds are extremely valuable because they
are leading compounds for designing new drugs. Further
investigation is required to determine the biological activity
of these compounds against more fungal and bacterial
strains, and to better understand their mode of action.
-
1
(cm ) on a Shimadzu infrared spectrophotometer using the
KBr disc technique. Mass spectra (MS) were obtained by
using electrospray ionization (ESI) technique. All analysis
has been done in the Catholic University of Louvain plat-
form, Belgium and in University of Rennes 1 France.
5.2. General Experimental Protocol
A solution of primary diamine (one equiv.) in acetonitrile
(
20 mL), was slowly added to a solution of 2a or 2b (four
equiv.) in 60 mL of acetonitrile. The reaction mixture was
stirred under refluxed for 6h then dried over MgSO . The
4
. CONCLUSION
New series of N,N,N’,N’-tetradentate pyrazole with N-C-
4
solvent was removed under reduced pressure. The solid was
dried using a Schlenk line.
N junction were synthesized using the condensation between
a pyrazole moiety and a primary diamine. Their structures
were characterized by H, C NMR, Infrared and mass spec-
troscopy. The nature of the multiplicity of the N-CH -N sig-
1
13
5
.3. Spectral Data
2
nal was also discussed. We found that some tetradentate
compounds have strong antifungal activity and that the cen-
tral diamine group is critical for bioactivity in yeast. As mat-
ter of fact, the central cyclohexane-1,2-diamine group of 5a
is the most active. In addition we found that tetradentate
ligands bearing pyrazol-1-yl methyl moiety are much more
active than those bearing (3,5-dimethyl-pyrazol-1-yl)methyl
moiety. Further investigation is required to better understand
the mode of action of this class of compounds.
For abbreviations we took: pz = pyrazole; bz = benzene;
cyh1 = CH of cyclohexane; cyh2 = CH
2
of cyclohexane; cyp
=
cyclopentadiene; naph = naphthalene.
The compounds 3a-b and 6a are already described in the
literature, but the method of their synthesis is different from
the reported one [24].
1
1
3
3
5
.3.1.
N ,N ,N ,N -tetrakis((3,5-dimethyl-1H-pyrazol-1-
yl)methyl)propane-1,3-diamine 4a
White solid, yield = 86.73%. MP: 64-66 °C. IR (ꢁ
5
5
. EXPERIMENTAL
.1. General
-
1
(
(
cm )): 3200 - 2864 (CH); 1556 (C=N); 1458(C=C); 1303
1
C-N aromatic); 1145 (C-N aliphatic). H NMR (300 MHz,
CDCl
3
, ꢂppm): 5.78 (s, 4H, pz), 4.74 (s, 8H, N-CH
t, 4H, N-CH -CH of amine, J = 6 Hz), 2.24 (s, 3H, CH
.19 (s, 3H, CH ), 1.71 – 1.64 (m, 2H, N-CH -CH
, ꢂppm): 147.31
2
-N), 2.68
),
of
3
,5-dimethyl-1H-pyrazole 1a, 1H-pyrazole 1b, formalde-
(
2
2
2
3
hyde and used solvent were commercially available, were of
sufficient purity, and were used without further treatment.
3
2
2
1
3
amine). C NMR (75 MHz, CDCl
3

8
8
Medicinal Chemistry, 2016, Vol. 12, No. 1
Abrigach et al.
(
3)
(5)
(3)
(5)
(
(
1
C
pz),139.70(C pz),105.57(pz),70.45(N-CH
2
-N),49.17
DMSO, ꢁppm): 143.08 (C pz), 138.44 (C pz), 105.20
(pz), 57.69(N-CH -N),36.37(cyp),13.31(CH ), 10.71(CH ).
MS [M ] (m/z): calculated 628,38, found 675,13
N-CH
3.43(CH ), 11.08 (CH
2
-CH
2
of amine), 22.43 (N-CH
).
2
-CH
2
of amine),
2
3
3
+
3
3
+
(
[M +2Na+1]).
1
1
3
3
5
.3.2.
N ,N ,N ,N -tetrakis((1H-pyrazol-1-yl)methyl)pro-
pane-1,3-diamine 4b
5.3.7. 4,4'-oxybis(N,N-bis((3,5-dimethyl-1H-pyrazol-1-
yl)methyl)aniline) 9a
-
1
Transparent oil, yield = 65.69 % .IR (ꢀ (cm )): 3200 -
2
1
7
4
858 (CH); 1514 (C=N); 1440 (C=C); 1280 (C-N aromatic);
Beige solid, yield = 28.23%. MP: 78-80°C. IR (ꢀ
1
-1
143 (C-N aliphatic). H NMR (300 MHz, CDCl
3
) ꢁ (ppm):
(cm )): 2954- 2920 (CH); 1556 (C=N); 1456(C=C); 1317
(5)
(3)
1
.49 – 7 .36 (m, 8H, pz /pz ), 6.19 (t, 4H, pz, J = 3 Hz),
.85 (d, 8H, N-CH -N, J = 3 Hz), 2.50 (t, 4H, N-CH -CH of
-CH of amine).
(C-N aromatic); 1232 (C-O); 1161 (C-N aliphatic). H NMR
2
2
2
(300 MHz, DMSO, ꢁppm): 7.08 – 6 .40 (m, 8H, bz), 5.78 (s,
amine, J = 3 Hz),1.57 – 1.51 (m, 2H, N-CH
2
2
4H, pz), 5.22 (d, 8H, N-CH -N, J = 7.4 Hz), 2.23 (s, 12H,
2
1
3
(3)
13
C NMR (75 MHz, CDCl
3
, ꢁppm): 139.59 (C pz), 129.57
C pz), 105.91(pz), 67.69(N-CH -N), 48.85 (N-CH -CH of
-CH of amine). MS [M ] (m/z): calcu-
lated 394,48, found 420,12 ([M + Na+3]).
CH
ꢁppm): 145.93(C
3 3
70.35(N-CH -N),13.33(CH ), 10.52(CH ). MS [M ] (m/z):
+
3
), 2.08 (s, 12H, CH ). C NMR (75 MHz, DMSO,
3
(5)
(3) (5)
(
2
2
2
pz), 138.68 (C pz), 105.31(pz),
+
+
amine), 22.96 (N-CH
2
2
2
+
calculated 632.37, found 655.35 ([M +Na]).
1
1
2
2
5
.3.3.
(1S,2S)-N ,N ,N ,N -tetrakis((3,5-dimethyl-1H-
5.3.8. 4,4'-oxybis(N,N-bis((1H-pyrazol-1-yl)methyl)aniline)
9b
pyrazol-1-yl)methyl)cyclohexane-1,2-diamine 5a
-
1
Yellow solid, yield = 84.93 %. MP: 120-122°C. IR (ꢀ
Beige solid, yield = 60.73%. MP: 68-70°C. IR (ꢀ (cm )):
-
1
(
1
cm )): 3100- -2860 (CH); 1556 (C=N); 1460(C=C);
3310- 2816 (CH); 1504 (C=N); 1400(C=C); 1273 (C-N aro-
matic); 1215 (C-O); 1165 (C-N aliphatic). H NMR (300
1
1
303(C-N aromatic); 1195 (C-N aliphatic). H NMR (300
MHz, CDCl , ꢁppm): 5.77 (s, 4H, pz), 4.72 (dd, 8H, N-CH
N, J = 13Hz), 2.38 – 2.30 (m, 2H, cyh1), 2.22 (s, 12H, CH
3
2
-
MHz, CDCl
bz, J = 3 Hz), 7.04(d, 4H, pz , J = 9Hz ), 6.88(d, 4H, pz , J
= 6Hz ), 6.27 (t, 4H, pz, J = 3 Hz), 5.39 (s , 8H, N-CH -N).
, ꢁppm): 140.40 (C pz), 129.52
3
, ꢁppm): 7.57(d, 4H, bz, J = 3 Hz), 7.45(d, 4H,
(5) (3)
3
),
), 1.90 – 1.14 (m, 8H, cyh2). C NMR (75
1
3
2
.17 (s, 12H, CH
3
2
(3)
(5)
13
(3)
MHz, CDCl
3
,
ꢁppm): 147.33(C
05.70(pz), 71.90(N-CH -N), 66.13(cyh1), 28.87(cyh2),
.14(cyh2), 13.48(CH ), 11.11(CH
pz), 139.47(C pz),
C NMR (75 MHz, CDCl
3
(5)
+
1
4
2
(C pz),106.22(pz), 66.94 (N-CH -N). MS [M ] (m/z): cal-
2
+
+
3
3
). MS [M ] (m/z): calcu-
culated 520,29, found 523,01 ([M +3]).
+
lated 546.77, found 586.9 ([M +K+1]).
1
1
5
5
CONFLICT OF INTEREST
5
.3.4.
N ,N ,N ,N -tetrakis((3,5-dimethyl-1H-pyrazol-1-
yl)methyl)naphthalene-1,5-diamine 7a
The authors confirm that this article content has no con-
flict of interest.
Purple solid, yield= 55.28 %. MP: 196-198 °C. IR (ꢀ
-
1
(
cm )): 3336- -2941 (CH); 1589 (C=N); 1438(C=C);
1
ACKNOWLEDGEMENTS
1
384(C-N aromatic); 1161 (C-N aliphatic). H NMR (300
MHz, DMSO, ꢁppm): 7.48 – 7.02 (m, 6H, naph), 5.76 (s,
H, pz), 5.45 (d, 8H, N-CH -N, J = 6.1 Hz), 2.31 (s, 12H,
The authors would like to thank the CUD of Belgium for
its generous support. Mohammed Bellaoui is grateful to Prof.
Abderrahim Azzouzi for supporting the setting up of the
Medical Biology Unit at the Faculty of Medicine and Phar-
macy of Oujda.
4
2
1
3
CH
ppm): 142.23 (C
7.83(N-CH -N), 13.34(CH
calculated 590.36, found 613.34 ([M +Na]).
3
), 2.08 (s, 12H, CH ). C NMR (75MHz, DMSO,
3
(3) (5)
ꢁ
5
pz),
138.79 (C pz),105.10(pz),
+
2
3 3
), 10.81(CH ). MS [M ] (m/z):
+
1
1
5
5
REFERENCES
5
.3.5. N ,N ,N ,N -tetrakis((1H-pyrazol-1-yl)methyl)napht-
halene-1,5-diamine 7b
[
1]
Bol, J. E.; Driessen, W. L.; Reedijk, J. Synthesis and crystal struc-
ture of a dinuclear copper(II) complex with a novel tetrapyrazolyl
macrocycle. J. Chem. Soc., Chem. Commun., 1995, (13), 1365.
Fernández-Lázaro, F.; Mendoza, J. D.; Mó, O.; Rodríguez-
Morgade, S.; Torres, T.; Yáñez, M.; Elguero, J. Phthalocyanine
analogues. Part 1. Synthesis, spectroscopy, and theoretical study of
8,18-dihydrodibenzo[b,l]-5,7,8,10,15,17,18,20-octa-azaporphyrin
and MNDO calculations on its related Huckel heteroannulene. J.
Chem. Soc., Perkin Trans. 2, 1989, (7), 797.
Perez, M. A.; Bermejo, J. M. Synthesis of multidentate 1,3,4-
oxadiazole-, imine-, and phenol-containing macrocycles. J. Org.
Chem., 1993, 58(9), 2628-2630.
Trofimenko, S. Coordination chemistry of pyrazole-derived
ligands. Chem. Rev., 1972, 72(5), 497-509.
Trofimenko, S. The Coordination Chemistry of Pyrazole-Derived
Ligands. In Prog. Inorg. Chem., Lippard, S. J., Ed. John Wiley &
Sons, Inc.: Hoboken, NJ, USA, 1986; Vol. 34, pp. 115-210.
Gupta, T.; Dhar, S.; Nethaji, M.; Chakravarty, A. R. Bis(dipyrido-
phenazine)copper(II) complex as major groove directing synthetic
hydrolase. Dalton Trans., 2004, (12), 1896-1900.
Purple solid, yield = 44.28%. MP: 194-196°C. IR (ꢀ
cm )): 3444- -2903 (CH); 1593 (C=N); 1435(C=C);
-
1
(
[
2]
1
1
396(C-N aromatic); 1145 (C-N aliphatic). H NMR (300
(5) (3)
MHz, DMSO, ꢁppm): 7.80 –7 .17 (m, 14H, pz /pz /naph),
6
.22 (t, 4H, pz, J = 3 Hz), 5.62 (d, 8H, N-CH -N, J=6.8 Hz).
2
1
3
(3)
C NMR (75MHz, DMSO, ꢁppm): 142.29 (C pz), 138.66
(5)
+
(
C pz), 105.85(pz), 60(N-CH -N). MS [M ] (m/z): calcu-
2
+
[3]
lated 478.23, found 501.22 ([M +Na]).
2
2
7
7
5
.3.6.
N ,N ,N ,N -tetrakis((3,5-dimethyl-1H-pyrazol-1-
[
4]
5]
yl)methyl)-9H-fluorene-2,7-diamine 8a
[
Brown solid, yield = 22.28%. MP: 216-218 °C. IR (ꢀ
-
1
(
cm )): 3298- -2811 (CH); 1616 (C=N); 1485(C=C);
1
1
265(C-N aromatic); 1164 (C-N aliphatic). H NMR (300
MHz, DMSO, ꢁppm): 7.36 – 6.63 (m, 6H, bz), 5.76 (s, 4H,
pz), 5.30 (d, 8H, N-CH -N, J = 6.7 Hz), 3.63 (s, 2H, cyp),
.28 (s, 12H, CH ), 2.08 (s, 12H, CH
[
6]
2
1
3
2
3
3
). C NMR (75MHz,
[7]
Zeglis, B. M.; Pierre, V. C.; Barton, J. K. Metallo-intercalators and
metallo-insertors. Chem. Commun., 2007, (44), 4565-4579.

New N,N,N’,N’-tetradentate Pyrazoly Agents
Medicinal Chemistry, 2016, Vol. 12, No. 1 89
[
[
[
8]
Saini, M. S.; Kumar, A.; Dwivedi, J.; Singh, R. A review : Biologi-
cal significances of heterocyclic compounds. Int. J. Pharma Sci.
Res., 2013, 4 (3), 66-77.
Aggarwal, R.; Kumar, V.; Kumar, R.; Singh, S. P. Approaches
towards the synthesis of 5-aminopyrazoles. Beilstein J. Org.
Chem., 2011, 7, 179-97.
El-Gamal, M. I.; Oh, C.-H. Design and synthesis of 3-(3-Chloro-4-
substituted phenyl)-4-(pyridin-4-yl)-1Hpyrazole- 1-carboxamide
derivatives and their antiproliferative activity against melanoma
cell line. Bull. Korean Chem. Soc., 2011, 32(3), 821-828.
Jungheim, L. N. Bicyclic pyrazolidinone antibacterial agents. Syn-
thesis of side chain analogues of carbapenems PS-5 and thienamy-
cin. Tetrahedron Lett., 1989, 30(15), 1889-1892.
Menozzi, G.; Mosti, L.; Fossa, P.; Mattioli, F.; Ghia, M. ꢀ-
Dialkylaminoalkyl ethers of phenyl-(5-substituted 1-phenyl-1H-
pyrazol-4-yl)methanols with analgesic and anti-inflammatory activ-
ity. J. Heterocycl. Chem., 1997, 34(3), 963-968.
tion, with theoretical study. Res. Chem. Intermed., 2015, 41(6), 3319-
3334..
Harit, T.; Cherfi, M.; Isaad, J.; Riahi, A.; Malek, F. New generation
of functionalized bipyrazolic tripods: synthesis and study of their
coordination properties towards metal cations. Tetrahedron, 2012,
68(21), 4037-4041.
Driessen, W. L. Synthesis of some new pyrazole-containing chelat-
ing agents. Recl. Trav. Chim. Pays-Bas, 1982, 101(12), 441-443.
Kim, S.; Kim, D.; Lee, H.-J.; Lee, H. Synthesis, structural features,
and methyl methacrylate polymerisation of binuclear zinc(II) com-
plexes with tetradentate pyrazolyl ligands. J. Mol. Struct., 2014,
1063, 70-76.
Sheu, S.-C.; Tien, M.-J.; Cheng, M.-C.; Ho, T.-I.; Peng, S.-M.; Lin,
Y.-C. Synthesis, properties and molecular structures of iron(III),
cobalt(II), nickel(II), copper(II), copper(I) and zinc(II) complexes
with N,N-bis(pyrazol-1-ylmethyl)benzylamine. J. Chem. Soc.,
Dalton Trans., 1995, (21), 3503.
Baker Brachmann, C.; Davies, A.; Cost, G. J.; Caputo, E.; Li, J.;
Hieter, P.; Boeke, J. D. Designer deletion strains derived from Sac-
charomyces cerevisiae S288C: A useful set of strains and plasmids
for PCR-mediated gene disruption and other applications. Yeast,
1998, 14(2), 115-132.
SFM (2008), Société Française de Microbiologie, Recommanda-
tions du Comité de l’Antibiogramme de la Société Française de
Microbiologie. Janvier 2008; p. 49.
National Committee for Clinical Laboratory Standards, Perform-
ance Standards for Antimicrobial Disk Susceptibility Tests - Sixth
Edition; Approved Standard. NCCLS Document M2-A6, Vol. 17,
No. 1, NCCLS, 940 West Valley Road, Suite 1400, Wayne, PA.
January 1997.
Adesokan, A. A.; Akanji, M. A.; Yakubu, M. T. Antibacterial
potentials of aqueous extract of Enantia chlorantha stem bark. Afr.
J. Biotechnol., 2007, 6 (22), 2502-2505.
[23]
9]
10]
[24]
[25]
[
11]
12]
[26]
[27]
[
[
13]
Garg, H. G.; Singhal, A.; Mathur, J. M. L. Synthesis and biological
activity of 1,5-diphenyl-4-arylazopyrazoles and 5,5-dimethylcyclo-
hexane-1,2,3-trione bishydrazones. J. Pharm. Sci., 1973, 62(3),
4
94-496.
[
14]
15]
Comber, R. N.; Gray, R. J.; Secrist Iii, J. A. Acyclic analogues of
pyrazofurin: syntheses and antiviral evaluation. Carbohydr. Res.,
[28]
[29]
1
992, 216(0), 441-452.
[
Bauer, V. J.; Dalalian, H. P.; Fanshawe, W. J.; Safir, S. R.; Tocus,
E. C.; Boshart, C. R. 4-[3(5)-Pyrazolyl]pyridinium salts. A new
class of hypoglycemic agents. J. Med. Chem., 1968, 11(5), 981-
9
84.
[
16]
17]
Bekhit, A. A.; Ashour, H. M. A.; Guemei, A. A. Novel Pyrazole
Derivatives as Potential Promising Anti-inflammatory Antimicro-
bial Agents. Arch. Pharm., 2005, 338(4), 167-174.
Al Bay, H.; Quaddouri, B.; Guaadaoui, A.; Touzani, R.; Benchat,
N.-E.; Hamal, A.; Taleb, M.; Bellaoui, M.; Kadiri, S. Synthesis and
biological activity of new triazole compounds. Lett. Drug Des. Dis-
cov., 2010, 7(1), 41-45.
Bendaha, H.; Yu, L.; Touzani, R.; Souane, R.; Giaever, G.; Nislow,
C.; Boone, C.; El Kadiri, S.; Brown, G. W.; Bellaoui, M. New
azole antifungal agents with novel modes of action: synthesis and
biological studies of new tridentate ligands based on pyrazole and
triazole. Eur. J. Med. Chem., 2011, 46(9), 4117-24.
Dvoretzky, I.; Richter, G. H. Formaldehyde condensation in the
pyrazole series. J. Org. Chem., 1950, 15(6), 1285-1288.
Touzani, R.; Ramdani, A.; Ben-Hadda, T.; El Kadiri, S.; Maury,
O.; Bozec, H. L.; Dixneuf, P. H. Efficient synthesis of new nitrogen
donor containing tripods under microwave irradiation and without
solvent. Synth. Commun., 2001, 31 (9), 1315-1321.
[30]
[31]
[32]
[
Ayari, B.; Riahi, L.; Ziadi, S.; Chograni, H.; Mliki, A. Evaluation
of antioxidant and antimicrobial activities of tunisian ajuga iva l.
essential oils. Revue F. S. B, 2013, XI.
Yu, L.; Lopez, A.; Anaflous, A.; El Bali, B.; Hamal, A.; Ericson,
E.; Heisler, L. E.; McQuibban, A.; Giaever, G.; Nislow, C.; Boone,
C.; Brown, G. W.; Bellaoui, M. Chemical-genetic profiling of imi-
dazo[1,2-a]pyridines and -pyrimidines reveals target pathways con-
served between yeast and human cells. PLoS Genetics, 2008, 4(11),
e1000284.
Niklas, N.; Hampel, F.; Alsfasser, R. Dipicolylglycyl-phenyl-
alanine zinc(II): a metallopeptide with a built-in conformational
switch and its homochiral helical coordination polymer. Chem.
Commun., 2003, (13), 1586.
[
18]
[
19]
20]
[
[33]
[
21]
22]
Touzani, R.; Garbacia, S.; Lavastre, O.; Yadav, V. K.; Carboni, B.
Efficient solution phase combinatorial access to a library of pyra-
zole- and triazole-containing compounds. J. Comb. Chem., 2003,
[34]
[35]
Niklas, N.; Walter, O.; Alsfasser, R. Chiral Quadridentate Ligands
Derived from Amino Acids and Some Zinc Complexes Thereof.
Eur. J. Inorg. Chem., 2000, 2000(8), 1723-1731.
Boussalah, N.; Touzani, R.; Bouabdallah, I.; Kadiri, S. E.; Ghalem,
S. Synthesis, structure and catalytic properties of tripodal amino-
acid derivatized pyrazole-based ligands. J. Mol. Catal. A: Chem.,
2009, 306(1–2), 113-117.
5
(4), 375-8.
[
Khoutoul, M.; Abrigach, F.; Zarrouk, A.; Benchat, N.-E.; Lam-
sayah, M.; Touzani, R. New nitrogen-donor pyrazole ligands for
2+
excellent liquid–liquid extraction of Fe ions from aqueous solu-
Received: November 23, 2014
Revised: April 25, 2015
Accepted: May 18, 2015