Geometrical structure, molecular docking and potentiometric studies of Schiff base ligand

Article abstract of DOI:10.1016/j.molliq.2015.10.011

Schiff base ligand of 4-(((2-hydroxynaphthalen-1-yl)methylene)amino)-1,5-dimethyl-2-phenyl-1,2-dihydro-3H-pyrazol-3-one (HL) was synthesized and characterized by IR spectroscopy. The molecular structure of the ligand is optimized theoretically and the qua

Full text of DOI:10.1016/j.molliq.2015.10.011

Journal of Molecular Liquids 212 (2015) 576–584
Contents lists available at ScienceDirect
Journal of Molecular Liquids
journal homepage: www.elsevier.com/locate/molliq
Geometrical structure, molecular docking and potentiometric studies of
Schiff base ligand
⁎
A.A. El-Bindary , A.F. Shoair, A.Z. El-Sonbati, M.A. Diab, E.E. Abdo
Chemistry Department, Faculty of Science, Damietta University, Damietta 34517, Egypt
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 13 July 2015
Received in revised form 28 September 2015
Accepted 5 October 2015
Available online xxxx
Schiff base ligand of 4-(((2-hydroxynaphthalen-1-yl)methylene)amino)-1,5-dimethyl-2-phenyl-1,2-dihydro-
3H-pyrazol-3-one (HL) was synthesized and characterized by IR spectroscopy. The molecular structure of the li-
gand is optimized theoretically and the quantum chemical parameters are calculated. Molecular docking was
used to predict the binding of the ligand with the receptor of prostate cancer 2q7k-hormone and 3hb5-
oxidoreductase receptor of breast cancer. The proton–ligand dissociation constant of HL and its metal stability
constants with Mn2+, Co2+, Ni2+ and Cu2+ have been determined potentiometrically. The potentiometric stud-
ies were carried out in 0.1 M KCl and 20% (by volume) DMF–water mixture. At constant temperature the stability
constants of the formed complexes increase in the order of Cu2+ N Ni2+ N Co2+ N Mn2+. The effect of temperature
was studied at 298, 308 and 318 K and the corresponding thermodynamic parameters (ΔG, ΔH and ΔS) were
derived and discussed. The dissociation process is non-spontaneous, endothermic and entropically unfavorable.
The formation of the metal complexes has been found to be spontaneous, endothermic and entropically
favorable.
Keywords:
Schiff base
Molecular structure
Molecular docking
Potentiometry
© 2015 Elsevier B.V. All rights reserved.
1. Introduction
proton transfer between the hydroxyl oxygen and the imine nitrogen. It
is well known that the proton transfer can occur in ground and/or excit-
Schiff bases form an interesting class of chelating ligands that has
enjoyed popular use in the coordination chemistry of transition and
inner transition metals which show various industrial, biological and
catalytic applications. Various studies have shown that, the azomethine
group (NC_N–) in Schiff base metal complexes has considerable bio-
logical significance and found to be responsible for biological activity
such as fungicidal and insecticidal [1]. Structural analyses reveal that
hydrazone Schiff base ligands have strong coordination ability, a possi-
bility of keto enol tautomerism and multi-coordination modes [2]. The
hydrazones and their metal complexes have many important applica-
tions in analytical chemistry and pharmacology [3]. The excited state
intramolecular proton transfer (ESIPT) reactions have attracted consid-
erable attention due to their wide range of applications in technology.
These reactions are used in the development of laser dyes, optical
memories and switches, in the control and measurement of radiation
intensity. In this respect, the photochromic compounds have been in-
vestigated for many years [4].
ed state [7–9]. Therefore tautomerization equilibrium exists between
enol-imine form (N…H–O) and keto-amine form (N–H…O) occurring
through intramolecular proton transfer for 2-hydroxy Schiff base li-
gands [10,11]. This proton transfer causes a change in the p-electron
configuration. However the Schiff bases prepared from 2-hydroxy-1-
naphthaldehyde form both type of hydrogen bonds [12,13]. Many Schiff
bases derived from 2-hydroxynaphthaldehyde have been studied
by NMR spectroscopy and X-ray analysis in the solid state [14–17].
The UV–vis spectra of some 2-hydroxyl Schiff bases have been investi-
gated in polar and non-polar solvent [18–20]. The absorption band at
N400 nm belongs to keto-amine form of the Schiff base. The results
showed that the enol-imine form is dominant in non-polar solvent
while the keto-amine form is dominant in polar solvent for such
Schiff bases. Recently, the UV–vis spectroscopic study for quantitative
analysis of undefined mixtures of the substituted Schiff bases of 2-
hydroxynaphthaldehydes is based on the chemometric approach [19].
Schiff bases can be incorporated into crown ether structures to form
interesting cation binding ligands. In such structures the cation can
occupy the crown cavity depending on the donor atom and cation
character or form the Schiff base complex through the imine group.
Some crown ether-containing ortho hydroxylated Schiff bases have
been synthesized and their complexation properties with transition
metal cations have been investigated [21]. However, the crown ether
moieties carrying only oxygen and nitrogen donor atoms exist in
these compounds.
The ortho hydroxylated Schiff bases have interesting properties such
as photochromism and thermochromism in the solid state and in solu-
tion [5,6]. Such compounds can show reversible color changes photo-
induced (photochromism) or thermo-induced (thermochromism).
Both properties are directly related to the occurrence of intramolecular
⁎
Corresponding author.
E-mail address: abindary@yahoo.com (A.A. El-Bindary).
http://dx.doi.org/10.1016/j.molliq.2015.10.011
0167-7322/© 2015 Elsevier B.V. All rights reserved.

A.A. El-Bindary et al. / Journal of Molecular Liquids 212 (2015) 576–584
577
2.2. Measurements
All the compounds and solvents used were purchased from Aldrich
and Sigma and used as received without further purification. The
IR spectra were recorded as KBr disks using a Perkin-Elmer 1340
spectrophotometer.
The calculations of geometry optimization were performed using
Perkin Elmer ChemBio 3D software by HF method with 3-21G basis
set [26,27]. Geometry optimization option was employed to obtain the
most stable structure.
In the study simulates the actual docking process in which the
ligand–protein pair-wise interaction energies are calculated using
Docking Server [28]. The MMFF94 force field was for used energy min-
imization of ligand molecule using Docking Server. Gasteiger partial
charges were added to the ligand atoms. Non-polar hydrogen atoms
were merged, and rotatable bonds were defined. Docking calculations
were carried out on 2q7k-hormone and 3hb5-oxidoreductase protein
model. Essential hydrogen atoms, Kollman united atom type charges,
and solvation parameters were added with the aid of AutoDock tools
[29]. Affinity (grid) maps of 20 × 20 × 20 Å grid points and 0.375 Å
spacing were generated using the Autogrid program [30]. AutoDock pa-
rameter set- and distance-dependent dielectric functions were used in
the calculation of the Van der Waals and the electrostatic terms,
respectively.
The pH measurements were carried out using VWR Scientific Instru-
ments Model 8000 pH-meter accurate to 0.01 units. The pH-meter
readings in the non-aqueous medium were corrected [31]. The elec-
trode system was calibrated according to the method of Irving et al.
[32]. Titrations were performed in a double walled glass cell at ionic
strength of 0.1 M KCl. Potentiometric measurements were carried out
at different temperature. The temperature was controlled to within
0.05 K by circulating thermostated water (Neslab 2 RTE 220) through
the outer jacket of the vessel.
Fig. 1. Structure of Schiff base ligand (HL).
In continuation of our previous work [22–24], the present work is
centered on the synthesis and characterization of Schiff base derived
from the condensation of 2-hydroxy-1-naphthaldehyde with 4-
aminoantipyrine. The geometrical structure of Schiff base ligand (HL)
by HF method with 3-21G basis set was studied. Molecular docking
was used to predict the binding of the ligand with the receptor of pros-
tate cancer 2q7k-hormone and 3hb5-oxidoreductase receptor of breast
cancer. Furthermore, we report herein the dissociation constant of the
Schiff base ligand (HL) and the stability constants of its complexes
with Mn2+, Co2+, Ni2+ and Cu2+ at different temperatures. Further-
more, the corresponding thermodynamic functions are evaluated and
discussed.
2. Materials and methods
2.1. Preparation of the ligand
Schiff base ligand 4-(((2-hydroxynaphthalen-1-yl)methylene)
amino)-1,5-dimethyl-2-phenyl-1,2-dihydro-3H-pyrazol-3-one (HL)
(Fig. 1) was prepared according to the previous procedure [25]. An
ethanolic solution of 4-aminoantipyrine (0.1 mmol) was added slowly
to the solution of 2-hydeoxy-1-naphthaldehyde (0.1 mmol) in ethanol
with constant stirring. The mixture was refluxed for 4 h in a water
bath. After concentration of the solution, the precipitate was separated,
filtered, washed with ethanol and dried in vacuum desiccator over an-
hydrous CaCl2.
2.3. Potentiometric studies
A ligand solution (0.001 M) was prepared by dissolving an ac-
curately weighted amount of the solid in DMF. Metal ion solutions
(0.0001 M) were prepared from metal chlorides in bidistilled water
Fig. 2. Molecular structure with atomic numbering for Schiff base ligand (HL).

578
A.A. El-Bindary et al. / Journal of Molecular Liquids 212 (2015) 576–584
and standardized with EDTA [33]. Solutions of 0.001 M HCl and 1 M KCl
were also prepared in bidistilled water. A carbonate-free NaOH solution
in 20% (by volume) DMF–water mixture was used as titrant and stan-
dardized against oxalic acid.
3. Results and discussion
3.1. Characterization of the Schiff base ligand (HL)
The apparatus, general conditions and methods of calculation were
the same as in previous work [22–24]. The following mixtures (i)–(iii)
were prepared and titrated potentiometrically at 298 K against standard
0.02 M NaOH in a 20% (by volume) DMF–water mixture:
The IR spectrum of the Schiff base ligand (HL) is characterized by a
very strong carbonyl stretching peak at 1648 cm−1 of pyrazole ring
[34]. A sharp peak appearing around 1594 cm−1 is assigned to
ν(C_N) azomethine group, which is characteristic of Schiff bases
[35–38]. The region between 1500–900 cm−1 is due C–N stretching
out-of-plane C–H bending vibrations. The IR spectrum of the ligand
show a weak broad band at 3440 cm−1 which are assigned to enolic –
OH group. The weakness and broadness of these peaks are mainly due
to intra-molecular hydrogen bonding between the enolic –OH group
with azomethine nitrogen atom of pyrazolone ring [39].
i) 5 cm3 0.001 M HCl + 5 cm3 1 M KCl + 10 cm3 DMF.
ii) 5 cm3 0.001 M HCl + 5 cm3 1 M KCl + 5 cm3 DMF + 5 cm3
0.00 l M ligand.
iii) 5 cm3 0.001 M HCl + 5 cm3 l M KCl + 5 cm3 DMF + 5 cm3
0.001 M ligand + 10 cm3 0.0001 M metal chloride.
For each mixture, the volume was made up to 50 cm3 with bidistilled
water before the titration. These titrations were repeated for the tem-
peratures of 308 and 318 K. All titrations have been carried out between
pH 4–10 and under nitrogen atmosphere.
3.2. Geometrical structure
The optimized structure of Schiff base ligand (HL) is given in Fig. 2.
The bond lengths and bond angles for ligand (HL) are listed in Table 1.
Table 1
The selected geometric parameters for Schiff base ligand (HL).
Bond lengths (Å)
Bond angles (°)
Bond angles (°)
C(27)–H(46)
C(26)–H(45)
C(25)–H(44)
C(24)–H(43)
C(22)–H(42)
O(21)–H(41)
C(18)–H(40)
C(17)–H(39)
C(14)–H(38)
C(13)–H(37)
C(12)–H(36)
C(11)–H(35)
C(10)–H(34)
C(9)–H(33)
C(9)–H(32)
C(9)–H(31)
C(8)–H(30)
C(8)–H(29)
C(8)–H(28)
C(18)–C(17)
C(15)–C(17)
C(16)–C(15)
C(27)–C(15)
C(26)–C(27)
C(25)–C(26)
C(24)–C(25)
C(16)–C(24)
C(20)–C(16)
C(19)–C(20)
C(18)–C(19)
C(7)–C(14)
C(13)–C(14)
C(12)–C(13)
C(11)–C(12)
C(10)–C(11)
C(7)–C(10)
N(3)–C(2)
1.104
1.103
1.104
1.099
1.09
H(37)–C(13)–C(14)
H(37)–C(13)–C(12)
C(14)–C(13)–C(12)
H(36)–C(12)–C(13)
H(36)–C(12)–C(11)
C(13)–C(12)–C(11)
H(35)–C(11)–C(12)
H(35)–C(11)–C(10)
C(12)–C(11)–C(10)
H(38)–C(14)–C(7)
H(38)–C(14)–C(13)
C(7)–C(14)–C(13)
H(34)–C(10)–C(11)
H(34)–C(10)–C(7)
C(11)–C(10)–C(7)
H(30)–C(8)–H(29)
H(30)–C(8)–H(28)
H(30)–C(8)–N(3)
H(29)–C(8)–H(28)
H(29)–C(8)–N(3)
H(28)–C(8)–N(3)
C(14)–C(7)–C(10)
C(14)–C(7)–N(4)
120.169
119.783
120.044
120.491
120.518
118.99
C(20)–C(19)–C(18)
C(20)–C(19)–O(21)
C(18)–C(19)–O(21)
C(15)–C(16)–C(24)
C(15)–C(16)–C(20)
C(24)–C(16)–C(20)
C(16)–C(20)–C(19)
C(16)–C(20)–C(22)
C(19)–C(20)–C(22)
H(42)–C(22)–N(23)
H(42)–C(22)–C(20)
N(23)–C(22)–C(20)
C(1)–N(23)–C(22)
C(1)–C(5)–N(4)
118.769
126.037
115.187
115.132
120.217
124.651
119.346
121.281
119.373
113.455
121.079
125.454
131.352
111.093
123.024
125.744
107.971
103.753
112.395
110.294
110.827
111.344
114.409
115.901
129.133
104.075
128.703
127.049
106.932
135.358
117.706
0.967
1.104
1.104
1.103
1.103
1.103
1.103
1.101
1.112
1.113
1.112
1.113
1.114
1.112
1.335
1.341
1.354
1.347
1.338
1.337
1.342
1.353
1.363
1.36
119.573
120.111
120.314
120.887
116.816
122.266
116.055
121.952
121.961
109.053
103.771
112.568
109.375
110.706
111.122
116.414
119.602
123.965
102.355
130.25
123.336
120.903
120.707
118.389
119.413
120.476
120.111
116.69
118.513
119.305
122.182
121.386
117.701
120.913
118.565
121.917
119.518
113.024
123.716
123.26
C(1)–C(5)–O(6)
N(4)–C(5)–O(6)
H(33)–C(9)–H(32)
H(33)–C(9)–H(31)
H(33)–C(9)–C(2)
H(32)–C(9)–H(31)
H(32)–C(9)–C(2)
H(31)–C(9)–C(2)
C(2)–N(3)–N(4)
C(2)–N(3)–C(8)
N(4)–N(3)–C(8)
N(3)–C(2)–C(1)
N(3)–C(2)–C(9)
C(10)–C(7)–N(4)
C(5)–N(4)–N(3)
C(5)–N(4)–C(7)
N(3)–N(4)–C(7)
H(45)–C(26)–C(27)
H(45)–C(26)–C(25)
C(27)–C(26)–C(25)
H(44)–C(25)–C(26)
H(44)–C(25)–C(24)
C(26)–C(25)–C(24)
H(41)–O(21)–C(19)
H(40)–C(18)–C(17)
H(40)–C(18)–C(19)
C(17)–C(18)–C(19)
H(46)–C(27)–C(15)
H(46)–C(27)–C(26)
C(15)–C(27)–C(26)
H(39)–C(17)–C(18)
H(39)–C(17)–C(15)
C(18)–C(17)–C(15)
H(43)–C(24)–C(25)
H(43)–C(24)–C(16)
C(25)–C(24)–C(16)
C(17)–C(15)–C(16)
C(17)–C(15)–C(27)
C(16)–C(15)–C(27)
C(1)–C(2)–C(9)
C(2)–C(1)–C(5)
C(2)–C(1)–N(23)
C(5)–C(1)–N(23)
1.343
1.349
1.342
1.34
1.34
1.343
1.349
1.277
1.345
1.364
1.273
1.363
1.263
1.26
1.355
1.369
1.508
1.485
1.279
1.216
C(1)–C(2)
C(5)–C(1)
N(4)–C(5)
N(3)–N(4)
C(1)–N(23)
C(22)–N(23)
C(20)–C(22)
C(19)–O(21)
C(2)–C(9)
N(3)–C(8)
N(4)–C(7)
C(5)–O(6)
119.967
117.84
122.194

A.A. El-Bindary et al. / Journal of Molecular Liquids 212 (2015) 576–584
579
Fig. 3. The Highest Occupied Molecular Orbital (HOMO) and the Lowest Unoccupied Molecular Orbital (LUMO) of Schiff base ligand (HL).
The C(22)–N(23) bond with length 1.26 Å for ligand (HL) is a normal
imine bond.
other cancer. The American Cancer Society (ACS) estimated 1 man in
6 will be diagnosed with prostate cancer during his life time. A
little over 1.8 million men in the United States are survivors of prostate
cancer [42].
Breast cancer is one of the most recurring worldwide diagnosed and
deadliest cancers next to lung cancer with a high number of mortality
rates among females [43]. At global level, it accounted for more than
1.6 million new cases in 2010. The incidence or prevalence rate of the
breast cancer in India is expected to be more than 90,000 in the coming
years and over 50,000 women die each year.
Molecular docking is a key tool in computer drug design [44]. The
focus of molecular docking is to simulate the molecular recognition pro-
cess. Molecular docking aims to achieve an optimized conformation for
both the protein and drug with relative orientation between them such
that the free energy of the overall system is minimized.
In this context, we used molecular docking between ligand (HL) and
prostate cancer mutant 2q7k-hormone and breast cancer (3hb5). The
results showed a possible arrangement between ligand (HL) and recep-
tor (2q7k, 3hb5). The docking study showed a favorable interaction be-
tween ligand (HL) and the receptor (2q7k, 3hb5) and the calculated
energy is listed in Table 3, and Figs. 4(A, B) and 5(A1, B1) for receptor
2q7k and 3hb5, respectively. According to the results obtained in this
study, HB plot curve indicates that, the Schiff base ligand (HL) binds to
the two proteins with hydrogen bond interactions and decomposed in-
teraction energies in kCal/mol exist between the of Schiff base ligand
(HL) with 2q7k and 3hb5 receptors as shown in Fig. 6. The calculated
efficiency is favorable where ki values estimated by AutoDock were
compared with experimental ki values, when available, and the Gibbs
free energy is negative. Also, based on this data, we can propose that
interaction between the 2q7k and 3hb5 receptors and the Schiff base li-
gand (HL) is possible. 2D plot curves of docking with Schiff base ligand
(HL) are shown in Fig. 7. This interaction could activate apoptosis in
cancer cells energy of interactions with Schiff base ligand (HL). Binding
energies are most widely used as a mode of measuring binding affinity
of a ligand. Thus, decrease in binding energy due to mutation will in-
crease the binding affinity of the azo dye ligand towards the receptor.
The characteristic feature of Schiff base ligand was represented in
the presence of several active sites available for hydrogen bonding.
This feature gives them the ability to be good binding inhibitors to the
protein and will help to produce augmented inhibitory compounds.
The HOMO and LUMO are shown in Fig. 3. The HOMO–LUMO energy
gap, ΔE, which is an important stability index, is applied to develop the-
oretical models for explaining the structure and conformation barriers
in many molecular systems [40,41]. The value of ΔE for Schiff base li-
gand (HL) was found to be 3.23 eV. The calculated quantum chemical
parameters are given in Table 2. Additional parameters such as ΔE, ab-
solute electronegativities, χ, chemical potentials, Pi, absolute hardness,
η, absolute softness, σ, global electrophilicity, ω, global softness, S, and
additional electronic charge, ΔNmax, have been calculated according to
the following equations [30,40]:
ΔE ¼ ELUMO−EHOMO
ð1Þ
ð2Þ
−ðEHOMO þ ELUMO
Þ
χ ¼
2
ELUMO−EHOMO
η ¼
ð3Þ
2
1
σ ¼
η
ð4Þ
ð5Þ
ð6Þ
Pi ¼ −χ
1
S ¼
2η
Pi2
ω ¼
ð7Þ
ð8Þ
2η
Pi
η
ΔNmax ¼ −
:
3.3. Molecular docking
Cancer can be described as the uncontrolled growth of abnormal
cells. Prostate cancer is the most common non-skin malignancy in
men. Except for lung cancer, it is responsible for more deaths than any
Table 2
The calculated quantum chemical parameters for Schiff base ligand (HL).
E
HOMO (eV)
ELUMO (eV)
ΔE (eV)
χ (eV)
η (eV)
σ (eV)−1
Pi (eV)
S (eV)−1
0.3097
ω (eV)
ΔNmax
−6.569
−3.34
3.23
4.955
1.6145
0.6194
−4.955
7.6021
3.0688

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A.A. El-Bindary et al. / Journal of Molecular Liquids 212 (2015) 576–584
Table 3
Energy values obtained in docking calculations of Schiff base ligand (HL) with receptor prostate cancer mutant 2q7k and breast cancer mutant 3hb5.
Receptor
Free energy of binding
(kCal/mol)
Inhibition constant (ki)
(μM)
vdW + bond + desolve energy
(kCal/mol)
Electrostatic energy
(kCal/mol)
Total intercooled energy
(kCal/mol)
Interact
surface
2q7k
3hb5
−2.3
−7.3
20.75
4.43
−3.75
−8.85
+0.04
−0.06
−3.71
−8.91
631.524
960.186
The results confirmed also that, the Schiff base ligand derived from 4-
aminoantipyrine is an efficient inhibitor of prostate cancer mutant
2q7k-hormone and 3hb5-oxidoreductase breast cancer.
aminoantipyrine Schiff base has one ionizable proton (the enolized hy-
drogen ion of the phenolic –OH group, pKH). Different computational
methods were applied to evaluate the dissociation constant [45].
Three replicate titrations were performed; the average values obtained
are listed in Table 4. The completely protonated form of ligand (HL) has
one dissociable proton, that dissociates in the measurable pH range. The
deprotonation of the o-hydroxy group in the Schiff base ligand most
probably results in the formation of stable intramolecular H-bonding
with the nitrogen atom of the C_N group. Such an interaction decreases
the dissociation process of 4-aminoantipyrine Schiff base, i.e. increases
the pKH value [46,47].
The formation curves for the metal complexes were obtained
by plotting the average number of ligands attached per metal ion
(nA) vs. the free ligand exponent (pL), according to Irving and Rossotti
[48]. The average number of the reagent molecules attached per metal
ion, n, and free ligand exponent, pL, can be calculated using Eqs. (10)
and (11):
3.4. Potentiometric studies
The interaction of a metal with an electron donor atom of a Schiff
base ligand (HL) is usually followed by the release of H+. Alkaline po-
tentiometric titrations are based on the detection of the protons re-
leased upon complexation. The main advantage of this technique,
compared to other methods is that from the titration curves it is possible
to follow complexation continuously as a function of pH and to detect
exactly at which pH complexation takes place. Furthermore, it is possi-
ble to calculate the dissociation constant and the stability constants
from the potentiometric titration curves. The average number of the
protons associated with ligand (HL) at different pH values, nA, was cal-
culated from the titration curves of the acid in the absence and presence
of ligand (HL) by applying the following equation:
ꢀ
ꢁ
ðV3−V2Þ No þ Eo
ꢀ
ꢁ
ꢀ
ꢁ
ðV1−V2Þ No þ Eo
n ¼
ð10Þ
Vo−V2 :nA:TCo
M
ꢀ
ꢁ
nA ¼ Y ꢀ
ð9Þ
Vo−V1 TCoL
and
where Y is the number of available protons in ligand (HL) (Y = 1) and
V1 and V2 are the volumes of alkali required to reach the same pH on the
titration curve of hydrochloric acid and reagent, respectively, V° is the
initial volume (50 cm3) of the mixture, TC°L is the total concentration
of the reagent, N° is the normality of sodium hydroxide solution and
E° is the initial concentration of the free acid. Thus, the formation curves
(nA vs. pH) for the proton–ligand systems were constructed and found
to extend between 0 and 1 in the nA scale. This means that 4-
!
n
n¼J
X
1
βnH
ꢂ
ꢃ
Hþ
Vo þ V3
n¼o
pL ¼ log10
:
ð11Þ
TCoL −n:TCoM
Vo
where TC°M is the total concentration of the metal ion present in the so-
lution, βHn is the overall proton-reagent stability constant. V1, V2 and V3
Fig. 4. The Schiff base ligand (HL) (green in (A) and blue in (B)) in interaction with receptor prostate cancer mutant 2q7k. (For interpretation of the references to color in this figure legend,
the reader is referred to the web version of this article).

A.A. El-Bindary et al. / Journal of Molecular Liquids 212 (2015) 576–584
581
Fig. 5. The Schiff base ligand (HL) (green in (A1) and blue in (B1)) in interaction with receptor breast cancer mutant 3hb5. (For interpretation of the references to color in this figure legend,
the reader is referred to the web version of this article.)
are the volumes of alkali required to reach the same pH on the titration
curves of hydrochloric acid, organic ligand and complex, respectively.
These curves were analyzed and the successive metal–ligand stability
constants were determined using different computational methods
[49,50]. The values of the stability constants (log K1 and log K2) are
given in Table 5. The following general remarks can be pointed out:
(ii) The metal ion solution used in the present study was very dilute
(2 × 10−5 M), hence there was no possibility of formation of poly
nuclear complexes [52,53].
(iii) The metal titration curves were displaced to the right-hand side
of the ligand titration curves along the volume axis, indicating
proton release upon complex formation of the metal ion. The
large decrease in pH for the metal titration curves relative to li-
gand titration curves points to the formation of strong metal
complexes [54,55].
(i) The maximum value of n was ~2 indicating the formation of 1:1
and 1:2 (metal:ligand) complexes only [1,51].
Fig. 6. HB plot of interaction between Schiff base ligand (HL) with receptor: a) prostate cancer mutant 2q7k and b) breast cancer mutant 3hb5.

582
A.A. El-Bindary et al. / Journal of Molecular Liquids 212 (2015) 576–584
Fig. 7. 2D plot of interaction between Schiff base ligand (HL) with receptor: a) prostate cancer mutant 2q7k and b) breast cancer mutant 3hb5.
(iv) At constant temperature, the stability of the chelates increases in
graphical representation of Van't Hoff (Eqs. (12) and (13)):
the order of Cu2+ N Ni2+ N Co2+ N Mn2+ [56–58]. This order
largely reflects that the stability of Cu2+ complexes is consider-
ably larger than those of other metals of the 3d series. Under
the influence of both the polarizing ability of the metal ion and
the ligand field [59] Cu2+ will receive some extra stabilization
due to tetragonal distortion of octahedral symmetry in its com-
plexes. The greater stability of Cu2+ complexes is produced by
the well known Jahn–Teller effect [60].
ΔG ¼ −2:303RTlog K ¼ ΔH−TΔS
ð12Þ
ð13Þ
or
ꢄ
ꢅꢄ ꢅ
−ΔH
2:303R
1
T
ΔS
log K ¼
þ
2:303R
where R gas constant = 8.314 J · mol−1 · K−1, K is the dissociation con-
stant for the ligand stability and T is the temperature (K).
From the ΔG and ΔH values, one can deduce the entropy ΔS using
the well known relationships Eq. (12) and Eq. (14):
Stepwise dissociation constants for the ligand (HL) and the stepwise
stability constants of their complexes with Mn2+, Co2+, Ni2+ and Cu2+
have been calculated at 298, 308 and 318 K. The corresponding thermo-
dynamic parameters (ΔG, ΔH and ΔS) were evaluated.
ΔS ¼ ðΔH−ΔGÞ=T:
ð14Þ
The dissociation constants (pKH) for HL, as well as the stability con-
stants of its complexes with Mn2+, Co2+, Ni2+ and Cu2+ have been
evaluated at 298, 308, 318 K and are given in Tables 4 and 5, respective-
ly. The enthalpy (ΔH) for the dissociation and complexation process
was calculated from the slope of the plot pKH or log K vs. 1/T using the
The thermodynamic parameters of the dissociation process of HL are
recorded in Table 4. From these results the following can be made:
(i) The pKH values decrease with increasing temperature, i.e. the
acidity of ligand increases [1].
Table 5
Table 4
Stepwise stability constants for ML and ML2 complexes of HL in 20% (by volume) DMF–
water mixture in the presence of 0.1 M KCl at different temperatures.
Thermodynamic functions for the dissociation of Schiff base ligand (HL) in 20%
(by volume) DMF–water mixture in the presence of 0.1 M KCl at different temperatures.
Mn+
298 K
log K1
308 K
log K1
318 K
log K1
Temperature Dissociation
(K)
Free energy
Enthalpy
change
Entropy change
(J mol−1 K−1
constant pKH charge
)
log K2
log K2
log K2
(kJ mol−1) ΔG (kJ mol−1) ΔH −ΔS
Mn2+
Co2+
Ni2+
Cu2+
5.08
5.25
5.33
5.45
4.15
4.32
4.41
4.54
5.17
5.35
5.44
5.56
4.24
4.42
4.50
4.65
5.28
5.45
5.54
5.67
4.35
4.53
4.59
4.75
298
308
318
9.32
9.13
8.95
53.18
53.84
54.49
33.57
33.57
33.57
65.82
65.83
65.82

A.A. El-Bindary et al. / Journal of Molecular Liquids 212 (2015) 576–584
583
(ii) Positive values of ΔH indicate that dissociation is accompanied
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