Chemistry and antioxidant properties of titanium(IV) complexes

Article abstract of DOI:10.1007/s11243-015-9960-z

Abstract The synthesis of titanium(IV) complexes with biologically active hydrazide ligands has been carried out. The complexes were characterized by spectroscopic methods (IR, ¹H NMR and ¹³C NMR), elemental analysis and conductivity studies. These studies suggest bidentate coordination of the ligands through carbonyl oxygen and primary amine nitrogen, resulting in octahedral geometries. Hydrazides with pyridyl substituents displayed 1:2 metal-to-ligand ratio, and hydrazides with imino substituents exhibited 1:3 metal-to-ligand ratio resulting in an outer sphere complex. The remaining complexes displayed inner sphere coordination with 1:1 metal-to-ligand ratio. These complexes exhibit varying degrees of radical scavenging properties against DPPH, superoxide and nitric oxide free radicals. The free ligands showed inhibition against DPPH but were inactive against superoxide and nitric oxide free radicals. The structure-activity relationships of the complexes are discussed.

Full text of DOI:10.1007/s11243-015-9960-z

Transition Met Chem (2015) 40:665–671
DOI 10.1007/s11243-015-9960-z
Chemistry and antioxidant properties of titanium(IV) complexes
Zara Shaikh1 Uzma Ashiq1 Rifat Ara Jamal1 Mohammad Mahroof-Tahir2,3
•
•
•
•
Bushra Shamshad1 Sadaf Sultan1
•
Received: 15 May 2015 / Accepted: 23 June 2015 / Published online: 5 July 2015
Ó Springer International Publishing Switzerland 2015
Abstract The synthesis of titanium(IV) complexes with
biologically active hydrazide ligands has been carried out.
The complexes were characterized by spectroscopic
Introduction
Titanium complexes show a range of biological properties,
including promising activity toward a number of tumor cell
types [1–3] as well as anticancer, antifungal and antibac-
terial activities [4]. The antitumor activity of titanocene
dichloride has been established against various animal and
xenografted human tumors and found to be more efficient
than cisplatin [5]. Similarly, a number of biological
activities have been determined for hydrazides and their
complexes [6–10]. Hydrazides may behave as a bidentate
ligand to give a five-membered ring, using their carbonyl
oxygen and amino nitrogen as donor atoms to the metal
[11, 12], or may act as monodentate ligands using one of
these donor atoms [12].
1
methods (IR, H NMR and 13C NMR), elemental analysis
and conductivity studies. These studies suggest bidentate
coordination of the ligands through carbonyl oxygen and
primary amine nitrogen, resulting in octahedral geometries.
Hydrazides with pyridyl substituents displayed 1:2 metal-
to-ligand ratio, and hydrazides with imino substituents
exhibited 1:3 metal-to-ligand ratio resulting in an outer
sphere complex. The remaining complexes displayed inner
sphere coordination with 1:1 metal-to-ligand ratio. These
complexes exhibit varying degrees of radical scavenging
properties against DPPH, superoxide and nitric oxide free
radicals. The free ligands showed inhibition against DPPH
but were inactive against superoxide and nitric oxide free
radicals. The structure–activity relationships of the com-
plexes are discussed.
A number of reactive oxygen species (ROS) including
free radicals and non-radicals are generated by a variety of
metabolic processes [13]. Low levels of ROS are important
for protecting the host from microorganisms, but their
excessive production is associated with adverse effects on
the body. ROS attack biomolecules, leading to local injury,
oxygen dysfunction and diseases such as cancer, inflam-
mation, premature aging, Parkinson’s disease and neu-
rodegeneration [14]. The diffusion-limited reaction of
nitric oxide (NO) and superoxide (SO) is associated with
the production of the toxic oxidant peroxynitrite. Super-
oxide dismutases, a family of metalloenzymes, are known
for their crucial role in body defense mechanisms against
the unfavorable effects of oxygen free radicals. They cat-
Electronic supplementary material The online version of this
article (doi:10.1007/s11243-015-9960-z) contains supplementary
material, which is available to authorized users.
& Mohammad Mahroof-Tahir
mmahroof@stcloudstate.edu; mmahroof@qu.edu.qa
-
1
alyze the conversion of O2 to H2O2 and O2 at the diffu-
Department of Chemistry, University of Karachi,
Karachi 75270, Pakistan
sion limit [15]. The free radical scavenging properties of
metal complexes may also make them useful for the
treatment of these diseases.
2
Department of Chemistry and Biochemistry, St. Cloud State
University, St. Cloud, MN 56304, USA
3
In spite of its interesting structural and biological
activities, little has been reported in this context for
Department of Chemistry and Earth Sciences, Qatar
University, Doha, Qatar
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Transition Met Chem (2015) 40:665–671
Radical scavenging activities
titanium. In this paper, we report the synthesis and chem-
istry of hydrazide complexes of Ti(IV). The DPPH,
superoxide and nitric oxide radical scavenging potentials of
these complexes are also presented.
Reported methods were used for measuring antioxidant
properties for the test compounds. The change in absor-
bance of DPPH was examined at 515 nm by the spec-
trophotometric method described by Lee [21]. Superoxide
scavenging activities of the compounds were determined
using the modified method described by Gaulejac et al.
[22]. Sodium nitroprusside in aqueous solution at physio-
logical pH spontaneously generates nitric oxide to produce
nitrite ion, which can be estimated using the Griess Illos-
voy reaction [23].
Experimental
Materials and methods
TiCl4 and chemicals for antioxidant activities were of
reagent grade, purchased from Merck or Sigma-Aldrich
and used without further purification. Organic solvents
were purified and dried before use by standard methods
[16]. Conductance was measured with a Hanna (HI-8633)
conductivity meter (Romania). Infrared spectra were
recorded on a Shimadzu 460 IR spectrometer in the range
of 4000–400 cm-1 using KBr disks. 1H NMR and 13C
NMR spectra were recorded in DMSO solvent at 600 MHz
on a Bruker AVANCE AV 600 spectrophotometer. Car-
bon, hydrogen and nitrogen analyses were performed on a
PerkinElmer 2400 series II CHN/S analyzer. Chloride
contents were determined volumetrically using AgNO3
[17]. Complexometric EDTA back-titration was performed
for the analysis of titanium contents in which sodium
potassium tartrate was used as a masking agent in the
presence of indicator xylenol orange (1 g in 100 g KNO3)
[18].
IC50 values were calculated by observing the results of
different concentrations of the test compounds at
1–1000 lM. The EZ-Fit Enzyme kinetics program was
used to calculate IC50 values of the compounds.
Results and discussion
Synthesis and physicochemical properties
Hydrazide ligands (1–7) were synthesized in reasonable
yields as depicted in Scheme 1. The synthesized hydrazide
ligands were characterized using spectroscopic and micro-
1
analytical techniques. Their HNMR spectra displayed the
appropriate splitting patterns for the benzene rings. The
parent peak of correct m/z ratio was observed in their mass
spectra. Elemental, physical and analytical data of com-
plexes (1c–7c) are summarized in Table 1. Based upon
these spectral data, the Ti(IV) complexes are tentatively
assigned octahedral geometries as depicted in Fig. 1. These
studies indicate that Ti(IV) complexes with ligands 1 and 2
exhibit 1:2 metal-to-ligand ratio, while ligands 3–6 show 1:1
ratio and ligand 7 displays 1:3 ratio, as detailed below.
All the complexes obtained were non-hygroscopic and
stable at room temperature, having light brown colors, and
soluble in polar organic solvents like DMSO and DMF.
Complexes 1c and 2c have the conductivity values 103 and
123 X-1 cm2 mol-1, respectively, indicating 1:2 electrolytic
ratio with two chloride ions outside the coordination sphere,
whereas complex 7c exhibits 1:4 electrolytic ratio with four
Synthesis of the hydrazide ligands
Hydrazides were synthesized by reported methods [6, 9,
10]. The appropriate hydrated hydrazine (2 mL, 40 mmol)
was added to a solution of the ester (1 mmol) in ethanol
(50 ml). The mixture was refluxed for 2–3 h to get a solid
product. This was filtered off, washed with hexane and
dried. The hydrazides were recrystallized from methanol.
Analytical data for all the free ligands have been reported
previously [19, 20].
Synthesis of the complexes
Cl- ions outside the sphere (KM = 213.0 X-1 cm2 mol-1
)
All the experimental manipulations were carried out under
dry nitrogen using Schlenk techniques to avoid the
hydrolysis of TiCl4. Complexes were synthesized by slow
addition of a solution of the hydrazide (10 mmol) in
methanol (10 ml) to an orange solution of TiCl4 (5 mmol)
in toluene (10 ml) with constant stirring at 0 °C. The
mixture was stirred for 4 h. The solid product so obtained
was filtered off, washed with a 1:1 mixture of toluene and
methanol and dried under vacuum. Elemental, physical and
analytical data are provided in Table 1.
[24] as shown in Fig. 1. Formation of white precipitates upon
addition of AgNO3 to solutions of the complexes confirmed
outer sphere complexes. Molar conductivity values of 3c–6c
were found to be in the range of 17–21 X-1 cm2 mol-1
,
indicating non-electrolytic natures for these complexes [25].
Infrared spectroscopy
The infrared spectral data and assignments for the free
hydrazides (1–7) and their complexes (1c–7c) are
123

Transition Met Chem (2015) 40:665–671
667
Table 1 Physical and elemental data of complexes (1c–7c)
Compound
Molecular
mass (g)
Molecular formula
Elemental analysis: % cal (found)
KM (DMSO) ohm-1
cm2 mol-1
C
H
N
Ti
Cl
1c
2c
3c
4c
5c
6c
7c
463.95
463.95
325.82
343.83
451.88
360.38
643.19
C12H14N6O2Cl4Ti
31.1
3.0
18.1
(18.5)
18.1
(18.4)
8.6
10.3
30.6
(30.7)
30.6
(30.1)
–
103
123
18
(31.6)
31.1
(3.2)
3.0
(10.6)
10.3
C
12H14N6O2Cl4Ti
(30.9)
25.8
(3.1)
2.5
(10.4)
14.7
C7H8N2OCl4Ti
C7H7N2OFCl4Ti
C7H7N2OICl4Ti
C7H7N2OCl5Ti
(25.3)
24.5
(2.8)
2.1
(8.0)
8.1
(14.6)
13.9
–
–
–
17
(24.8)
18.6
(2.3)
1.5
(7.8)
6.2
(13.8)
10.6
21
(18.5)
23.3
(1.7)
1.9
(6.2)
7.8
(10.7)
13.3
20
(23.6)
39.2
(2.1)
4.2
(8.0)
19.6
(18.9)
(13.3)
7.4
C
21H27N9O3Cl4Ti
22.1
213
(40.0)
(4.5)
(7.8)
(21.4)
O
C
O
C
O
C
C2H5OH
N2H5OH
C2H5OH
SOCl2
R
OH
R
NHNH2
R
OC2H5
Scheme 1 Synthesis of hydrazide ligands (1–7). 1. R = 4-Pyridyl; 2. R = 3-Pyridyl; 3. R = C6H5; 4. R = 2-F-C6H4; 5. R = 4-I-C6H4; 6.
R = 4-Cl-C6H4; 7. R = NH-C6H5
summarized in Table 2. The hydrazide ligands have more
than one potential coordination site, and IR spectral data help
in determining the bonding modes of the ligands. The free
hydrazides all exhibit a sharp C=O stretching frequency at
1654 35 cm-1, which is in agreement with the earlier
reported values of 1670–1640 cm-1 [10, 19, 20]. The con-
siderable increase in C=O frequency upon complexation
(1670 35 cm-1) indicates coordination of the carbonyl
oxygen to the Ti(IV) center, resulting in a decrease in the
double bond character of C=O and an increase in C–N double
bond character. This is also supported by a negative shift in
C–N frequency in all the complexes except 7c [26]. In
complex 7c, there is no significant shift in the C=O peak
which is an indication that carbonyl oxygen takes no part in
coordination. The possibility of coordination through both
the pyridyl nitrogen and carbonyl oxygen is probably ruled
out by steric considerations [27].
A pair of fairly intense bands around 3207–3322 cm-1
is characteristic of the N–H stretching frequencies of the
hydrazinic group. Upon complexation with Ti(IV), this
band broadens (2927–3447 cm-1) and shows positive or
negative shift, suggesting involvement of the primary
nitrogen in coordination with Ti. This results in bidentate
coordination of the ligands via coordination through
primary amine nitrogen and carbonyl oxygen [26]. Bands
due to aromatic C=C stretching, NH2 bending and NH
stretching are also identified in the spectra of both the free
ligands and their complexes.
1H NMR spectroscopy
1H NMR spectral data of the free hydrazides and their
complexes in DMSO are summarized in Table 3. The free
ligands all displayed a singlet assigned to the NH group in
the range of 9.49–10.07 ppm. This peak does not show any
significant shift upon complexation, indicating non-coor-
dination of this group. The free ligands also exhibit a
singlet at about 4.47–4.61 ppm attributed to the NH2 pro-
tons, which shifts to 10.37–13.54 ppm in the spectra of the
complexes. This indicates bonding of the hydrazinic NH2
to the metal center, supporting the IR results. Earlier
studies with divalent cations of Pt, Zn, Hg and Cd also
supported this conclusion [28]. The imino (NH) group
which is directly attached to the aromatic ring displayed a
singlet at 7.32 ppm for ligand 7. Upon complexation (7c),
this peak shifts to 9.69 ppm, indicating coordination of this
group to the metal. Hence, this ligand forms a five-mem-
bered chelate ring with Ti by using its hydrazinic and imino
123

668
Transition Met Chem (2015) 40:665–671
Fig. 1 Structures of the Ti(IV)
complexes
H2
N
Cl
Ti
Cl
R
R
O
O
Cl
Cl
C
C
HN
. Cl2
Ti
Cl
NH
NH
C
N
O
N
Cl
H2
H2
R
3c-6c
1c, 2c
O
R
C
HN
H2N
N
H2
N
NH
C
. Cl4
Ti
N
R
O
N
NH2
C
O
R
N
H
7c
Table 2 IR spectral data of
hydrazide ligands 1–7 and their
complexes 1c–7c
Compound
-NH2
C=O
NH bending
C–N
Others t
1
3304, 3113
3447, 3163
3322, 3207
3174, 3061
3230, 3198
3190, 2931
3288, 3207
3190, 3169
3295, 3188
3205, 2927
3309, 3217
3232, 2958
3260, 3303
3285, 2984
1668
1688
1672
1696
1661
1671
1615
1641
1630
1672
1661
1686
1687
1689
1633
1607
1595
1628
1616
1640
1568
1617
1583
1587
1557
1597
1593
1615
1335
1313
1338
1309
1348
1306
1343
1324
1328
1306
1345
1311
1303
1319
1136, 995, 845, 675, 436
1219, 996, 846, 755, 674
1121, 953, 708, 631, 525
1c
2
2c
3
1201, 1106, 1014, 840, 730, 647
1119, 989, 882, 803, 685, 516, 412
1004, 826, 842, 724, 558
3c
4
993, 744, 653, 508
4c
5
862, 815, 781, 754, 698, 658, 575
1169, 1057, 1005, 963, 845
1306, 1277, 1170, 1143, 1003
1095, 999, 839, 729, 674, 533
1278, 1094, 846, 746, 681, 528
1225, 1145, 925, 753, 696, 643, 509
1245, 981, 752, 691, 633, 502
5c
6
6c
7
7c
N as donor atoms. The aromatic protons show their signals
at 6.88–8.94 ppm for the free hydrazides; these peaks are
shifted to 6.98–9.46 ppm in the spectra of the complexes.
numbers of carbon signals were observed in the spectra of
both the free ligands and complexes. The free ligands gave a
singlet in the range of 163.23–157.33 ppm which is char-
acteristic of a C=O carbon atom [29]. Upon complexation,
the position of this signal shifted upfield or downfield in 1c–
6c [30, 31], indicating coordination of the C=O oxygen to the
metal center, in agreement with the IR assignments. The
position of the C=O peak for ligand 7 remains unchanged
13C NMR spectroscopy
13C NMR spectral data for the free hydrazides and their
complexes are summarized in Table 3. The expected
123

Transition Met Chem (2015) 40:665–671
669
Table 3 NMR data for the
hydrazide ligands (1–7) and
their complexes (1c–7c)
Compound
1H NMR (d ppm)
13C NMR (d ppm)
NH2
NH
Aromatic protons
C=O
Aromatic carbons
1
4.61
10.07
11.23
9.93
7.71–8.68
8.10–8.94
7.45–8.95
7.73–9.46
7.40–7.81
7.62–7.91
7.23–7.56
7.27–7.61
7.75–7.83
7.66–7.94
7.45–7.83
7.60–7.94
6.88–7.49
6.98–7.44
163.86
159.10
164.26
158.36
163.09
165.32
163.23
157.3
120.95–150.16
122.87–147.53
123.37–151.67
126.57–152.75
120.65–151.20
129.24–137.48
115.88–132.21
115.99–132.61
128.87–137.14
129.45–137.61
128.35–135.80
128.81–137.54
118.08–139.92
118.33–138.68
1c
2
13.54
4.54
2c
3
13.53
4.47
10.02
9.74
3c
4
11.03
4.51
10.93
9.49
4c
5
10.40
4.47
10.13
9.81
165.09
160.35
164.72
161.56
157.33
157.25
5c
6
10.37
4.49
11.65
9.84
6c
7
12.36
4.30
11.59
8.57, 7.32
9.09, 9.69
7c
10.10
even after complexation, confirming the non-coordination of
this group. The signals for the aromatic carbons were
observed in the range of 115.88–151.67 ppm in the spectra of
the free hydrazides (1–7) and were shifted by 1–2 ppm for
the complexes (1c–7c).
On the basis of the IR, NMR and elemental data dis-
cussed above, the geometry of these Ti complexes is ten-
tatively assigned as octahedral. All the ligands are
bidentate, coordinating through their primary amine nitro-
gen and carbonyl oxygen, except 7c in which coordination
is through the imino N atom instead of carbonyl O atom.
Radical scavenging activities
DPPH radical scavenging activity
Fig. 2 DPPH radical scavenging of the free hydrazides, their Ti
complexes and TiCl4 solution
The antioxidant potential of the free hydrazides, their
titanium complexes, and titanium tetrachloride solution
was determined using DPPH. All tested compounds
showed varying degrees of scavenging potential. Their IC50
values against DPPH are presented in Fig. 2. Butyl
hydroxyanisole (BHA) and propyl gallate (PG) were used
as standards.
antioxidant. It is visually observed by a change in color
from purple to yellow [34].
The results reveal that the nature and position of sub-
stituent on the benzene ring of the hydrazide have con-
siderable effect on the activity of these compounds against
DPPH. The IC50 value exhibited by unsubstituted ligand 3
was 133.3 lM, while substitution of iodo (39 lM) and
chloro (87 lM) groups at the para position of the benzene
ring of hydrazide increased activity, and substitution of
fluoro at the ortho (650 lM) position decreased the activ-
ity, indicating that electronic and steric factors both play an
important role in their radical scavenging potential. Ligand
4 with an ortho-fluoro substituent exhibits lowest radical
scavenging potential, indicating that electron withdrawing
substituents have a negative effect on their antioxidant
potential. It is interesting to note that free ligand 7 exhibits
DPPH is a stable free radical that can accept an electron
or hydrogen radical to become a diamagnetic molecule
[32]. The hydrogen-donating ability of antioxidants is
responsible for the reduction of DPPH radical to DPPHH
[32, 33]. In hydrazides and their metal complexes, a- or b-
hydrazinic nitrogen could be the site for removal of
hydrogen radical required for the reduction of DPPH.
DPPHÁ þ AH ! DPPHH þ AÁ
The reduced form of DPPH can be assayed by the
decrease in absorbance at 517 nm induced by an
123

670
Transition Met Chem (2015) 40:665–671
the highest IC50 value; however, after complexation with
the metal center, it shows the lowest IC50 value. This may
be attributed to the coordination with two N atoms instead
of one N and one O as exhibited by the other compounds.
Based upon these results, it is concluded that the electronic
properties of the ligands play a crucial role in their
antioxidant potential, since Ti(IV) is an electron-deficient
system and cannot itself facilitate the reduction of DPPH.
The Ti(IV) salt solution showed very weak radical scav-
enging activity (IC50 = 407 lM) against DPPH. It is
hypothesized that a- or b-hydrazinic nitrogen is responsible
for the reduction of DPPH.
200
100
0
Compound
Superoxide radical scavenging activity
Fig. 3 Superoxide radical scavenging of TiCl4 and its complexes
with hydrazide ligands. All free ligands are inactive
-
SOD catalyzes the dismutation of superoxide radical (O2
)
to molecular oxygen and hydrogen peroxide by redox reac-
tions involving electron–proton coupling [35]. The free
hydrazide ligands and their complexes were investigated for
their scavenging potential against superoxide using a non-
enzymatic radical generating system. In this system, reduc-
tion of PM? (phenazine methosulphate) to PMH is carried
out by NADH with the generation of OÁ2-which in turn
reduces NBT (nitroblue tetrazolium) to formazan dye. Any
antioxidant present in the system scavenges the superoxide
and hinders the formation of formazan, which is measured by
the decrease in absorbance at 560 nm. Propyl gallate (PG)
and butyl hydroxyanisole were used as standard superoxide
radical scavengers. IC50 values for all of the compounds are
shown in Fig. 3. The free hydrazide ligands are inactive
against O2-, whereas their Ti complexes give IC50 values in
the range of 17–243 lM. Four of the Ti complexes (1c, 2c,
6c, and 7c) showed better or similar scavenging of super-
oxide compared to the standard PG (IC50 = 106 lM).
Complex 7c exhibits the lowest IC50 value of 17 lM. It is
interesting to note that the same complex also displayed the
highest antioxidation potential against DPPH. The presence
of the imino group in this complex may be responsible for its
potent antioxidant behavior because of its electron-donating
potential to the metal center. Complex 2c also shows a
notable scavenging activity with an IC50 value of 40 lM.
This observation supports our conclusion that electron-do-
nating substituents help in scavenging free radicals, due to
the pyridyl group with N at the para position [21].
facilitated due to a change in oxidation state of Ti(IV)
mediated by superoxide; however, complexation of metal
ions is crucial for their medicinal value because of their
potential to enter the cell.
Nitric oxide scavenging activity
The nitric oxide scavenging abilities of the free hydrazides
and their complexes were investigated by using the SNP
(sodium nitroprusside)–SNA (sulphanilic acid)–NBT sys-
tem. In this system, NO derived from sodium nitroprusside
produces nitrite ion. On reacting with SNA, the nitrite ion
forms a p-diazonium salt. This salt reacts with NED to give
an azo dye, a pink-colored complex with an absorbance at
540 nm. Antioxidants inhibit formation of the azo dye,
resulting in a decrease in absorbance at the same wave-
length. The IC50 values of the compounds are shown in
Fig. 4.
The lowest scavenging potential was exhibited by
complex 4c which has a fluoro substituent with hydrazide.
This compound also showed the lowest DPPH radical
scavenging potential. As described above, it may be due to
the high electronegativity of the fluoro group which may
hinder the removal of hydrogen from the a- or b-hydrazinic
nitrogen. The precursor titanium tetrachloride was also
found to be a potent scavenger of superoxide and displayed
the lowest IC50 value of 14 lM. The reaction may be
Fig. 4 Nitric oxide radical scavenging of TiCl4 and the hydrazide
complexes
123

Transition Met Chem (2015) 40:665–671
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The free hydrazides were all inactive against NO,
whereas their corresponding complexes exhibit promising
antioxidant potentials. TiCl4 solution was found to possess
poor scavenging ability against NO. Four of the complexes
(1c, 2c, 6c, and 7c) showed inhibitory values lower than the
standard ascorbic acid (AA). The chloro- and iodo-substi-
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(4c). Complexes 1 and 2 possess pyridyl rings with nitro-
gen at the meta and para position, respectively; they were
observed to be good antioxidants, but complex 2c exhibited
a
lower IC50 value of 177 lM compared to 1c
(IC50 = 283 lM). Both complexes have similar steric
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Titanium(IV) complexes with substituted hydrazide ligands
were synthesized and characterized by chemical and
physical measurements. The complexes have octahedral
geometries in which the hydrazide ligands are coordinated
by the primary amine nitrogen and carbonyl oxygen donor
atoms for complexes 1c–6c, while the imino nitrogen is
coordinated in complex 7c. These complexes were more
potent antioxidants against DPPH than their respective free
ligands. The free hydrazide ligands are inactive against
superoxide and nitric oxide, whereas their complexes
showed promising scavenging potential. The electronic and
steric properties of the ligands affect the antioxidative
behavior of their complexes. For nitric oxide, scavenging
ability seems to be dependent upon electronic effects.
Complex 2c exhibited the lowest IC50 values for DPPH and
superoxide and is therefore worthy of further research.
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Acknowledgments Authors are thankful to the Higher Education
Commission of Pakistan for financial support (‘The National
Research Grants Program for Universities,’ Grant No. 1862/R&D/10).
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Compliance with Ethical Standards
29. Kucukguzel SG, Mazi A, Sahin F, Ozturk S, Stables J (2003) Eur
J Med Chem 38:1005–1013
Conflict of interest No potential conflict of interest was reported by
the author(s).
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31. Despaigne AAR, Da Silva JG, Do Carmo ACM, Sives F, Piro
OE, Castellano EE, Beraldo H (2009) Polyhedron 28:3797–3803
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