Molecular docking, theoretical calculations and potentiometric studies of some azo phenols

Article abstract of DOI:10.1016/j.molliq.2015.06.070

Abstract The ligands 5-amino-2-(phenyldiazenyl)phenol and its derivatives (HL_n) were synthesized from the coupling of 3-aminophenol with aniline and its p-derivatives and characterized by different spectroscopic techniques. The molecular and el

Full text of DOI:10.1016/j.molliq.2015.06.070

Journal of Molecular Liquids 211 (2015) 256–267
Contents lists available at ScienceDirect
Journal of Molecular Liquids
journal homepage: www.elsevier.com/locate/molliq
Molecular docking, theoretical calculations and potentiometric studies of
some azo phenols
a,
b
a,1
A.A. El-Bindary ⁎, M.A. Hussein , R.A. El-Boz
a
Chemistry Department, Faculty of Science, University of Damietta, Damietta 34517, Egypt
Chemistry Department, Faculty of Science, University of Port Said, Egypt
b
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 6 June 2015
Received in revised form 27 June 2015
Accepted 30 June 2015
Available online xxxx
The ligands 5-amino-2-(phenyldiazenyl)phenol and its derivatives (HL ) were synthesized from the coupling of
n
3-aminophenol with aniline and its p-derivatives and characterized by different spectroscopic techniques. The
molecular and electronic structures of the investigated compounds (HL ) were also studied using quantum
n
chemical calculations. Molecular docking was used to predict the binding between azo compounds with the re-
ceptor of prostate cancer 2q7k-Hormone and 3hb5-oxidoreductase receptor of breast cancer. The proton–ligand
n
dissociation constant of the azo compounds (HL ) and metal–ligand stability constants of their complexes with
metal ions (Mn , Co , Ni and Cu ) have been determined by potentiometric technique in 0.1 M KCl and
Keywords:
Azo phenols
Theoretical calculations
Molecular docking
Potentiometry
2
+
2+
2+
2+
40% (by volume) DMF–water mixture. For the same ligand at constant temperature, the stability constants of
the formed complexes increase in the order Mn2+, Co , Ni and Cu . The effect of temperature was studied
at 303, 313 and 323 K and the corresponding thermodynamic parameters (ΔG, ΔH and ΔS) were derived and
discussed. The dissociation process is non-spontaneous, endothermic and entropic ally unfavorable. The forma-
tion of the metal complexes has been found to be spontaneous, endothermic and entropic ally favorable.
2+
2+
2+
©
2015 Elsevier B.V. All rights reserved.
1
. Introduction
widely used to predict protein–ligand [9,10] and to screen large libraries
for molecules that will modulate the activity of a biological receptor. In
continuation of our previous work [11–15], we report herein the disso-
Aminophenols have aroused interest owing to their utility as
starting materials for many azodyes [1], corrosion inhibitors [2],
bactericides [3] and anti-inflammatory agent [4]. From the complexing
point of view, many have taken interest in studying aminophenol as po-
tential ligands [5]. Azo colorings are the most versatile class of dyes [6].
The dyes have been most widely used in fields such as dying textile
fibers, biomedical studies, advanced applications in organic synthesis
and high technology areas like lasers, liquid crystalline displays, electro-
optical devices and ink-jet printer [7]. The presence of\\N_N\\group
can lead to increase the solubility of low valent metal oxidation states
due to its π acidity and presence of low lying azo centered π* molecular
orbitals [8].
ciation constant of (HL
n
) and the stability constants of their complexes
with Mn2 , Co , Ni
+
2+
2+
and Cu
2+
at different temperatures. The
corresponding thermodynamic functions are evaluated and discussed.
Moreover, the molecular and electronic structures of the investigated
compounds (HL ) are also studied using quantum chemical calcula-
n
tions. Molecular docking was used to predict the binding between azo
compounds and the receptors of prostate cancer and breast cancer.
2. Materials and methods
2.1. Measurements
Potentiometry is one of the most convenient and successful
techniques employed for metal complex equilibrium measurements.
In recent years the use of protein–ligand docking has become a standard
method in potentiometric studies. The protein groups surrounding the
ligand can highly influence the local pH, so that a different protonation
could be favored in the bound state. To account for this effect, the ideal
case would be to use multiple protonations in the docking and have the
algorithm automatically pick the correct state. Molecular docking is
All the compounds and solvents used were purchased from Aldrich
and Sigma and used as received without further purification. Elemental
microanalyses of the separated ligands for C, H, and N were determined
on Automatic Analyzer CHNS Vario ELIII, Germany. FT-IR spectra (KBr
discs, 4000–400 cm ) by Jasco-4100 spectrophotometer. The calcula-
tions of geometry optimization were performed using Perkin Elmer
ChemBio 3D software by HF method with 3-21G basis set [16,17].
Geometry optimization option was employed to obtain the most stable
structure. The pH measurements were performed with a Metrohm 836
Titrando (KF & Potentiometric Titrator) equipped with a combined
porolyte electrode. The pH-meter readings in the non-aqueous medium
−
1
⁎
Corresponding author.
E-mail address: abindary@yahoo.com (A.A. El-Bindary).
Abstracted from her Ph.D. Thesis.
1
http://dx.doi.org/10.1016/j.molliq.2015.06.070
167-7322/© 2015 Elsevier B.V. All rights reserved.
0

A.A. El-Bindary et al. / Journal of Molecular Liquids 211 (2015) 256–267
257
3
were corrected [18]. The electrode system was calibrated according to
the method of Irving et al. [19]. The temperature was controlled to with-
in ± 0.05 K by circulating thermostated water (Neslab 2 RTE 220)
through the outer jacket of the vessel.
For each mixture, the volume was made up to 50 cm with bidistilled
water before the titration. These titrations were repeated for the
temperatures of 308 and 318 K. All titrations have been carried out
between pH 4.0–11.0 and under nitrogen atmosphere.
2
.2. Preparation of the ligands
3. Results and discussion
The ligands 5-amino-2-(phenyldiazenyl)phenol and its derivatives
n
3.1. Characterization of the ligands (HL )
(
(
HL
10 mmol) in conc. H
an ice–salt bath with a solution of sodium nitrite (0.8 g, 10 mmol, 30 ml
distilled H O). The diazonium salt was coupled with an alkaline solution
n
) were prepared by dissolving aniline or its p-substituted derivatives
2
SO . The compound was diazotized below −5 °C in
4
The chemical structures of the ligands were elucidated by elemental
analyses Table 1. The infrared spectra of ligands shows a broad band
−
1
2
located at the region 2946–3158 cm
bands appear at the region 3320–3359 cm
The ν(N_N) group appeared at 1481–1623 cm
due to ν(OH) group. The two
−
1
of 3-aminophenol (1.0 g, 10 mmol) in 20 ml of ethanol. The precipitate
was filtered and dried after through washing with water and ethanol.
The crude product was recrystallized from ethanol and the microcrystals
were obtained in a yield of 94–97% (Fig. 1). The resulting formed
are due to ν(NH
2
).
region. The bands
region are assigned to ν(C–H) vibrations of the
−
1
−
1
at 2603–2711 cm
aromatic system.
ligands are 5-amino-2-((4-methylphenyl)diazenyl)phenol (HL
-amino-2-(phenyldiazenyl)phenol (HL and 5-amino-2-((4-
chlorophenyl)diazenyl)phenol (HL ).
1
),
5
2
)
3.2. Molecular structure
3
n
The optimized structures, bond length and bond angles of the (HL )
2
.3. Potentiometric studies
A ligand solution (0.01 M) was prepared by dissolving an accurately
ligands are presented in Fig. 2 and Tables 2 and 3. Both the highest
occupied molecular orbital (HOMO) and lowest unoccupied molecular
orbital (LUMO) are the main orbital which take part in chemical stabil-
ity. The HOMO represents the ability to donate an electron; LUMO as an
electron acceptor represents the ability to obtain an electron as shown
weighted amount of the solid in DMF. Metal ion solutions (0.001 M)
were prepared from metal chlorides in bidistilled water and standard-
ized with EDTA [20]. Solutions of 0.01 M HCl and 1 M KCl were also
prepared in bidistilled water. A carbonate-free NaOH solution in 40%
n
in Fig. 3. Quantum chemical parameters of the ligands (HL ) are obtain-
ed from calculations such as energies of the highest occupied molecular
orbital (EHOMO) and the lowest unoccupied molecular orbital (ELUMO) as
listed in Table 4. Additional parameters such as HOMO–LUMO energy
gap, ΔE, absolute electronegativities, χ, chemical potentials, Pi, absolute
hardness, η, absolute softness, σ, global electrophilicity, ω, global
softness, S, and additional electronic charge, ΔNmax, are calculated
using the following equations [15,21–23]:
(
by volume) DMF–water mixture was used as titrant and standardized
against oxalic acid.
The apparatus, general conditions and methods of calculation
were the same as in previous work [11–15]. The following mixtures
(
i)–(iii) were prepared and titrated potentiometrically at 298 K against
standard 0.02 M NaOH in a 40% (by volume) DMF–water mixture:
3
3
3
i) 5 cm 0.01 M HCl + 5 cm 1 M KCl + 20 cm DMF.
ΔE ¼ ELUMO−EHOMO
ð1Þ
ð2Þ
3
3
3
3
ii) 5 cm 0.01 M HCl + 5 cm 1 M KCl + 15 cm DMF + 5 cm 0.0 l M
ligand.
3
3
3
3
iii) 5 cm 0.01 M HCl + 5 cm l M KCl + 15 cm DMF + 5 cm 0.01 M
−ðEHOMO þ ELUMO
Þ
3
χ ¼
ligand + 10 cm 0.001 M metal chloride.
2
NaNO2
-5
H 2 SO4
C
+
N
-
R
NH 2
R
N Cl
o
0
Diazonium Salt
HO
alkaline solution
o
NH2
0-5
C
N
NH 2
R
N
H O
3
1 2 3
R = -CH (HL ), -H (HL ) and -Cl (HL ).
n
Fig. 1. Structure of the azo phenols (HL ).

258
A.A. El-Bindary et al. / Journal of Molecular Liquids 211 (2015) 256–267
Table 1
Analytical data of the azo phenols (HL
1
S ¼ 2
η
ð6Þ
n
).
Compound Empirical formula Yield % M.P. °C Exp. (calc.) %
2
C
H
N
Pi
ω ¼
2η
ð7Þ
ð8Þ
HL
HL
HL
1
2
3
C
13
H
13
N
3
3
O
O
94
97
96
172
215
211
68.72
(68.82) (5.33) (19.35)
67.60 5.16 19.72
(67.67) (5.26) (19.42)
58.18 4.04 16.96
(58.32) (4.24) (17.27)
5.16
19.72
Orange
C H N
12 11
Pi
η
Dark orange
OCl
Pale orange
ΔNmax ¼ −
:
12 10 3
C H N
3.3. Molecular docking
ELUMO−EHOMO
Cancer can be described as the uncontrolled growth of abnormal
η ¼
ð3Þ
2
cells. Prostate cancer is the most common non-skin malignancy in
men. Except for lung cancer, it is responsible for more deaths than any
other cancer. The American Cancer Society (ACS) estimated 1 man in
will be diagnosed with prostate cancer during his lifetime. A little
over 1.8 million men in the United States are survivors of prostate
cancer [24].
σ ¼ 1
ð4Þ
ð5Þ
η
6
Pi ¼ −χ
HL1
HL2
HL3
Carbon atom
Oxygen atom
Nitrogen atom
Hydrogen atom
Chlorine atom
n
Fig. 2. The calculated molecular structures of the azo phenols (HL ).

A.A. El-Bindary et al. / Journal of Molecular Liquids 211 (2015) 256–267
259
Table 2
The bond length for (HL
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.
n
).
Bond length (Å)
Docking study showed the binding affinity, number of hydrogen
bonds. It is interesting to note that the binding affinities have
negative values. This reveals the high feasibility of this reaction.
Molecular docking is a key tool in computer drug design [26,27].
The focus of molecular docking is to simulate the molecular recog-
nition process. Molecular docking aims to achieve an optimized
conformation for both the protein and drug with relative orienta-
tion between them such that the free energy of the overall system
is minimized.
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 used for energy minimization
of ligand molecules 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 and 3hb5-oxidoreductase–Hormone 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 0.375 Å spacing were generated using
the Autogrid program [30]. AutoDock parameter set- and distance-
dependent dielectric functions were used in the calculation of the van
der Waals and the electrostatic terms, respectively.
HL
1
HL
2
HL
3
C(17)–H(30)
C(17)–H(29)
C(17)–H(28)
O(14)–H(27)
N(13)–H(26)
N(13)–H(25)
C(12)–H(24)
C(11)–H(23)
C(9)–H(22)
C(8)–H(21)
C(6)–H(20)
C(3)–H(19)
C(2)–H(18)
N(15)–N(16)
C(11)–C(12)
C(10)–C(17)
C(10)–C(11)
C(9)–C(10)
C(8)–C(9)
C(7)–N(16)
C(7)–C(12)
C(7)–C(8)
C(5)–O(14)
C(5)–C(6)
C(4)–N(15)
C(4)–C(5)
C(3)–C(4)
1.114
1.114
1.113
0.971
1.049
1.049
1.103
1.103
1.103
1.105
1.104
1.105
1.103
1.251
1.343
1.510
1.344
1.343
1.342
1.269
1.347
1.347
1.363
1.347
1.270
1.354
1.349
N(15)–N(16)
O(14)–H(27)
N(13)–H(26)
N(13)–H(25)
C(12)–H(24)
C(11)–H(23)
C(11)–C(12)
C(10)–H(22)
C(10)–C(11)
C(9)–H(21)
C(9)–C(10)
C(8)–H(20)
C(8)–C(9)
N(16)–C(7)
C(7)–C(12)
C(7)–C(8)
C(6)–H(19)
C(5)–O(14)
C(5)–C(6)
C(4)–N(15)
C(4)–C(5)
C(3)–H(18)
C(3)–C(4)
C(2)–H(17)
C(2)–C(3)
C(1)–N(13)
C(1)–C(6)
1.248
0.972
1.050
1.050
1.100
1.100
1.420
1.100
1.420
1.100
1.420
1.100
1.420
1.456
1.420
1.420
1.100
1.355
1.420
1.456
1.420
1.100
1.420
1.100
1.420
1.462
1.420
N(15)–N(16)
O(14)–H(27)
N(13)–H(26)
N(13)–H(25)
C(12)–H(24)
C(11)–H(23)
C(11)–C(12)
C(10)–Cl(17)
C(10)–C(11)
C(9)–H(22)
C(9)–C(10)
C(8)–H(21)
C(8)–C(9)
C(7)–N(16)
C(7)–C(12)
C(7)–C(8)
C(6)–H(20)
C(5)–O(14)
C(5)–C(6)
C(4)–N(15)
C(4)–C(5)
C(3)–H(19)
C(3)–C(4)
C(2)–H(18)
C(2)–C(3)
C(1)–N(13)
C(1)–C(6)
1.251
0.971
1.049
1.049
1.103
1.103
1.343
1.727
1.342
1.103
1.341
1.105
1.342
1.269
1.348
1.348
1.104
1.363
1.347
1.270
1.354
1.105
1.349
1.103
1.341
1.267
1.341
Docking simulations were performed using the Lamarckian genetic
algorithm (LGA) and the Solis & Wets local search method [31]. Initial
position, orientation, and torsions of the ligand molecules were set
randomly. All rotatable torsions were released during docking. Each
docking experiment was derived from 10 different runs that were set
to terminate after a maximum of 250,000 energy evaluations. The
population size was set to 150. During the search, a translational step
of 0.2 Å, and quaternion and torsion steps of 5 were applied.
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 [25]. At global level, it accounted for more than
In this context, the docked ligands were analysis with the prostate
cancer mutant 2q7k-Hormone and breast cancer 3hb5 as shown in
Fig. 4(A, C, E) and (B, D, F) and Fig. 5(A
, C , E ) and (B , D , F ). The
1 1 1 1 1 1
Table 3
The selected geometric parameters bond angle for (HL
n
).
study simulates the actual docking process in which the ligand–protein
pair-wise interaction energies are calculated in Tables 5 and 6. Accord-
ing to our results, HB plot curve indicates that, azo compound binds to
Bond angles (°)
HL
1
H
2
HL
3
H(26)–C(15)–C(16)
H(26)–C(15)–C(14)
C(16)–C(15)–C(14)
C(15)–C(14)–C(13)
H(25)–C(13)–C(14)
C(14)–C(13)–C(12)
H(27)–C(16)–C(9)
H(27)–C(16)–C(15)
C(9)–C(16)–C(15)
H(24)–C(12)–C(13)
C(13)–C(12)–C(9)
C(16)–C(9)–C(12)
C(16)–C(9)–N(10)
C(12)–C(9)–N(10)
N(11)–N(10)–C(9)
H(21)–N(7)–C(6)
C(1)–C(6)–C(5)
C(1)–C(6)–N(7)
C(5)–C(6)–N(7)
C(6)–C(5)–C(4)
C(3)–N(11)–N(10)
C(5)–C(4)–C(3)
C(5)–C(4)–O(8)
C(3)–C(4)–O(8)
C(4)–C(3)–C(2)
119.435
119.296
121.27
117.919
119.983
120.824
121.85
117.101
121.049
118.209
121.53
117.408
125.954
116.637
119.84
120.107
118.987
120.399
120.614
122.406
121.157
118.569
117.646
123.785
118.657
127.28
114.063
122.092
120.833
119.878
119.289
109.265
119.181
118.414
120.033
119.644
120.323
119.392
120.289
119.982
121.886
117.026
121.088
120.124
121.479
117.736
125.829
116.436
119.902
120.3
118.988
120.409
120.603
122.405
121.129
118.571
117.639
123.79
119.326
120.487
120.188
119.509
120.73
119.847
121.799
117.009
121.191
118.139
121.583
117.682
125.849
116.469
119.87
120.111
118.991
120.401
120.609
122.404
121.153
118.566
117.658
123.776
118.663
127.253
114.084
122.087
120.835
119.876
119.289
109.299
119.187
118.409
n
the two proteins with hydrogen bond interactions of ligands (HL )
with 2q7k and 3hb5 as shown in Figs. 6 and 7. The calculated efficiency
is favorable, 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, 3hb5 receptors and the ligands (HL
2D plot curve of docking with ligands (HL ) is shown in Figs. 8 and 9.
This interaction could activate apoptosis in cancer cell energy of interac-
tions with ligands (HL ). From the analysis of the values, it is evident
that the binding energy of (HL ) decreases. So that is decrease in
binding energy of HLn on transpiration of mutation for prostate cancer
q7k whereas increase with HLn for breast cancer. Binding energies
n
) is possible.
n
n
n
2
are most widely used mode of measuring binding affinity of a ligand.
Thus, the decrease in binding energy due to mutation will increase the
binding affinity of the azo phenol towards the receptor. The charac-
teristic feature of azo phenols represents the presence of several ac-
tive 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 results confirm that,
the azo ligand derived from 3-aminophenol is an efficient inhibitor of
prostate cancer mutant 2q7k-Hormone and 3hb5-oxidoreductase
breast cancer.
118.655
127.271
114.074
122.092
120.487
117.422
119.29
C(4)–C(3)–N(11)
C(2)–C(3)–N(11)
C(3)–C(2)–C(1)
H(18)–C(1)–C(6)
H(18)–C(1)–C(2)
C(6)–C(1)–C(2)
H(23)–O(8)–C(4)
H(20)–C(5)–C(6)
H(20)–C(5)–C(4)
3.4. Potentiometric studies
The average number of the protons associated with ligands (HL
n
) at
different pH values, nA , was calculated from the titration curves of

260
A.A. El-Bindary et al. / Journal of Molecular Liquids 211 (2015) 256–267
LUMO
HOMO
HL
1
HL
HL
2
3
n
Fig. 3. The highest occupied molecular orbital (HOMO) and the lowest unoccupied molecular orbital (LUMO) of the azo phenols (HL ).
the acid in the absence and presence of ligands (HL
following equation:
n
) by applying the
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 Rossotti and Rossotti
[35]. 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):
ꢁ
ꢁ
ðV1−V2ÞðN þ E Þ
nA ¼ Y ꢀ
ꢁ
ð9Þ
ꢁ
ðV −V1ÞTC
L
where Y is the number of available protons in ligands (Y = 1) and V
and V 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 cm ) of the mixture, TC is the total concentration
L
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
1
ꢁ
ꢁ
ðV3−V2ÞðN þ E Þ
n ¼
ꢁ
ð10Þ
2
ꢁ
ðV −V2Þ ꢂ nA ꢂ TC
M
3
°
and
!
n
(nA vs. pH) for the proton–ligand systems were constructed and found
Xn¼J
1
H
n
β
ꢀ
ꢁ
to extend between 0 and 1 in the nA scale. This means that azo
aminophenol has one ionizable proton (the enolized hydrogen ion of
þ
H
ꢁ
n¼o
V þ V3
pL ¼ log10
ꢁ
L
ꢁ
:
ð11Þ
ꢁ
H
TC −n ꢂ TC
V
the phenolic –OH group, pK ). Different computational methods were
M
applied to evaluate the dissociation constant [32]. Three replicate titra-
tions were performed; the average values obtained are listed in Table 7.
°
where TC
M
is the total concentration of the metal ion present in the
H
The completely protonated form of ligands (HL
n
) has one dissociable
n 1 2
solution, β is the overall proton-reagent stability constant. V , V
proton, that dissociates in the measurable pH range. The deprotonation
of the hydroxyl group most probably results in the formation of stable
intramolecular H-bonding with nitrogen of the azo group. Such an
interaction decreases the dissociation process of phenolic –OH group,
3
and V 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 computa-
H
i.e. increases the pK value [33,34].
tional methods [36,37]. The values of the stability constants (log K
1
Table 4
n
The calculated quantum chemical parameters for the azo phenols (HL ).
Compound
E
HOMO
E
(eV)
LUMO
ΔE
(eV)
χ
(eV)
η
(eV)
σ
(eV)
Pi
(eV)
S
(eV)
ω
(eV)
ΔNmax
−
1
−1
(
eV)
HL
HL
HL
1
2
3
−3.061
−3.218
−2.733
−1.841
−1.838
−1.836
1.22
1.38
0.89
2.451
2.528
2.285
0.61
0.69
0.45
1.639
1.449
2.229
−2.451
−2.528
−2.285
0.819
0.725
1.115
4.924
4.631
5.818
4.0180
3.664
5.094

A.A. El-Bindary et al. / Journal of Molecular Liquids 211 (2015) 256–267
261
HL
1
A
B
HL
2
C
D
HL
3
E
F
n
Fig. 4. The azo phenols (HL ) (green in (A, C, E) and blue in (B, D, F)) 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.)
and log K
be pointed out:
2
) are given in Table 8. The following general remarks can
n
Stepwise dissociation constants for all ligands (HL ) and the step-
2
+
2+
2+
wise stability constants of their complexes with Mn , Co , Ni
and Cu2 have been calculated at 298, 308 and 318 K. The correspond-
+
(
i) The maximum value of nA was ~2 indicating the formation of 1:1
and 1:2 (metal:ligand) complexes only [11,38].
ii) The metal ion solution used in the present study was very dilute
ing thermodynamic parameters (ΔG, ΔH and ΔS) were evaluated.
H
The dissociation constants (pK ) for (HL
n
), as well as the stability
constants of their complexes with Mn2 , Co , Ni
+
2+
2+
and Cu
2+
have
(
−
4
(
2 × 10
M), hence there was no possibility of formation of
been evaluated at 298, 308 and 318 K, and are given in Tables 7 and 9,
respectively. 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 graphical representation of van't Hoff Eqs. (12) and (13):
polynuclear complexes [39,40].
(
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 with
the ligand. The large decrease in pH for the metal titration curves
relative to ligand titration curves points to the formation of
strong metal complexes [41,42].
ΔG ¼ −2:303 RT logK ¼ ΔH–TΔS
ð12Þ
(
iv) For the same ligand at constant temperature, the stability of the
or
chelates increases in the order Mn2 , Co , Ni
+
2+
2+
and Cu
2+
2
+
[
43,44]. This order largely reflects that the stability of Cu com-
ꢂ
ꢃꢂ ꢃ
plexes is considerably larger than those of other metals of the 3d
−ΔH
:303R
1
T
ΔS
log K ¼
þ
2:303R
ð13Þ
series. Under the influence of both the polarizing ability of the
2
2
+
metal ion and the ligand field [45] Cu will receive some extra
stabilization due to tetragonal distortion of octahedral symmetry
in its complexes. The greater stability of Cu2 complexes is
produced by the well known Jahn–Teller effect [46].
+
where R is the gas constant = 8.314 J·mol−1·K−1, K is the dissociation
constant for the ligand stability and T is the temperature (K).

262
A.A. El-Bindary et al. / Journal of Molecular Liquids 211 (2015) 256–267
HL
1
B
1
A
1
HL
2
C
1
D
1
HL
3
E
1
F
1
Fig. 5. The azo phenols (HL ) (green in (A , C , E ) and blue in (B , D , F )) in interaction with receptor breast cancer mutant 3hb5. (For interpretation of the references to color in this figure
n 1 1 1 1 1 1
legend, the reader is referred to the web version of this article).
Table 5
Energy values obtained in docking calculations of azo phenols with receptor prostate cancer mutant 2q7k.
Ligand
Est. free energy of binding
kCal/mol)
Est. inhibition constant
Ki (uM)
vdW + Hbond + desolv energy
(kCal/mol)
Electrostatic energy
(kCal/mol)
Total intermolec. energy
(kCal/mol)
Interact
surface
(
HL
HL
HL
1
2
3
−6.91
−2.76
−6.76
8.55
9.46
11.17
−8.04
−3.70
−7.69
−0.02
−0.15
−0.06
−8.06
−3.85
−7.75
477.708
288.127
483.220
Table 6
Energy values obtained in docking calculations of azo phenols with receptor breast cancer mutant 3hb5.
Ligand
Est. free energy of binding
kCal/mol)
Est. inhibition constant
Ki (uM)
vdW + Hbond + desolv energy
(kCal/mol)
Electrostatic energy
(kCal/mol)
Total intermolec. energy
(kCal/mol)
Interact
surface
(
HL
HL
HL
1
2
3
−6.72
−6.78
−6.54
11.86
10.76
16.07
−7.35
−7.51
−7.87
−0.11
−0.11
−0.17
−7.46
−7.61
−8.04
687.618
613.179
696.115

A.A. El-Bindary et al. / Journal of Molecular Liquids 211 (2015) 256–267
263
HL
1
HL
2
HL
3
Fig. 6. HB plot of interaction between the azo phenols and receptor prostate cancer mutant 2q7k.

264
A.A. El-Bindary et al. / Journal of Molecular Liquids 211 (2015) 256–267
HL1
HL2
HL3
Fig. 7. HB plot of interaction between the azo phenols and receptor breast cancer mutant 3hb5.

A.A. El-Bindary et al. / Journal of Molecular Liquids 211 (2015) 256–267
265
HL1
HL
1
HL2
HL
2
HL3
HL
3
Fig. 8. 2D plot of interaction between the azo phenols and receptor prostate cancer mutant
Fig. 9. 2D plot of interaction between the azo phenols and receptor breast cancer.
2q7k.

266
A.A. El-Bindary et al. / Journal of Molecular Liquids 211 (2015) 256–267
Table 7
Table 9
n
Thermodynamic functions for the dissociation of (HL ) in 40% (by volume) DMF–water
mixture and 0.1 M KCl at different temperatures.
Thermodynamic functions for ML and ML
DMF–water mixture and 0.1 M KCl.
2
complexes of (HL
n
) in 40% (by volume)
Compound
Temperature
K)
Dissociation
constant
pK
Gibbs
energy
Enthalpy
change
kJ mol
Entropy
change
Comp.
Mn+
T/K
Gibbs energy
Enthalpy change
Entropy change
(
(kJ mol−
1
)
(kJ mol
−1
)
(J mol
−1 −1
K
)
H
−1
−1
J mol K−1
−1
kJ mol
ΔG
−
−ΔG
1
−ΔG
2
ΔH
1
ΔH
2
ΔS
1
ΔS
2
1
ΔH
1
ΔS
1
HL
1
Mn2+
Co2+
Ni2+
Cu2+
Mn2+
Co2+
Ni2+
Cu2+
Mn2+
Co2+
Ni2+
Cu2+
298
37.54
39.57
41.71
38.12
40.10
42.20
38.57
40.57
42.56
39.31
41.22
43.35
36.80
38.92
40.92
37.37
39.51
41.46
37.77
39.81
41.83
38.51
40.63
42.56
36.29
38.27
40.25
36.80
38.80
40.67
37.26
39.39
41.34
37.89
39.92
42.01
32.12
34.03
35.92
32.52
34.38
36.35
32.98
34.79
36.78
33.55
35.50
37.45
31.44
33.32
35.19
31.90
33.85
35.62
32.35
34.26
36.05
33.09
35.15
37.20
30.81
32.85
34.77
31.33
33.26
35.19
31.78
33.56
35.68
32.52
34.26
36.47
24.48
22.66
20.87
20.83
24.52
23.62
22.68
21.81
22.68
20.89
23.62
23.58
24.50
24.48
23.56
24.50
24.50
23.62
22.70
28.12
28.14
26.31
26.25
26.23
208.12
207.95
208.13
203.95
203.78
203.96
199.46
199.49
199.46
201.82
201.47
201.83
205.77
205.97
205.76
204.67
204.97
204.67
202.87
202.89
202.87
202.41
202.72
202.41
197.89
197.91
197.89
193.59
193.81
193.59
204.29
204.59
204.28
206.26
206.18
206.27
190.00
190.01
190.00
191.28
191.10
191.28
189.73
189.46
189.74
194.79
194.80
194.79
187.70
187.72
187.70
186.29
186.59
186.28
184.75
184.95
184.74
205.43
205.43
205.43
197.84
198.03
197.83
193.41
193.41
193.41
194.74
194.18
194.75
197.16
196.41
197.18
HL
HL
HL
1
2
3
298
9.15
9.02
8.90
9.02
8.91
8.81
8.85
8.73
8.62
52.21
53.19
54.19
51.47
52.55
53.64
50.50
51.48
52.49
99.08
99.06
99.08
108.76
108.73
108.77
99.42
3
3
08
18
3
3
08
18
22.68
19.05
20.87
298
298
3
3
08
18
3
3
08
18
298
298
3
3
08
18
3
3
08
18
99.40
99.42
298
3
3
08
18
From the ΔG and ΔH values, one can deduce the entropy ΔS using
the well known relationships (12) and (14):
HL2
298
308
3
18
298
08
3
ΔS ¼ ðΔH−ΔGÞ=T:
ð14Þ
318
298
3
3
08
18
298
The thermodynamic parameters of the dissociation process of (HL
are recorded in Table 7. From these results the following can be made:
n
)
3
3
08
18
HL
3
298
3
3
08
18
(
i) The pKH values decrease with increasing temperature, i.e. the
acidity of ligand increases [15].
298
3
3
08
18
(
ii) Positive values of ΔH indicate that dissociation is accompanied by
absorption of heat and the process is endothermic.
298
08
(
iii) Positive values of ΔG indicate that the dissociation process is not
3
spontaneous [47].
318
298
(
iv) Negative values of ΔS are due to increased order as result of the
3
3
08
18
solvation processes.
All the thermodynamic parameters of stepwise stability constants
n
for the complexes of ligand (HL ) are recorded in Table 9. It is known
(b) metal–ligand bond formation. Examination of these values shows
that the divalent metal ions exist in solution as octahedral hydrated
that:
species [11,15] and the obtained values ΔH and ΔS can then be consid-
ered as sum of two contributions: (a) release of H
2
O molecules and
1 2
(i) The stability constants (log K and log K ) for the azo aminophenol
complexes increase with increasing temperature, i.e. its stability
constants increase with increasing temperature.
ii) The negative values of ΔG for the complexes' formation suggest a
Table 8
(
n
Stepwise stability constants for complexes of (HL ) in 40% (by volume) DMF–water
mixtures and 0.1 M KCl at different temperatures.
spontaneous nature of such process [13].
(
iii) The positive values of ΔH mean that the complex formation
processes are endothermic and favored at higher temperature.
iv) The positive values of ΔS confirming that the complex formation
processes are entropically favorable [11,13].
Compound
298 K
Mn+
308 K
318 K
log K
1
log K
2
log K
1
log K
2
log K
1
log K
2
(
+
2
HL
HL
HL
HL
HL
1
2
3
2
3
Mn
6.58
6.68
6.76
6.89
6.45
6.55
6.62
6.75
6.36
6.45
6.53
6.64
6.45
6.55
6.62
6.75
6.36
6.45
6.53
6.64
5.63
5.70
5.78
5.88
5.51
5.59
5.67
5.80
5.40
5.49
5.57
5.70
5.51
5.59
5.67
5.80
5.40
5.49
5.57
5.70
6.71
6.80
6.88
6.99
6.60
6.70
6.75
6.89
6.49
6.58
6.68
6.77
6.60
6.70
6.75
6.89
6.49
6.58
6.68
6.77
5.77
5.83
5.90
6.02
5.65
5.74
5.81
5.96
5.57
5.64
5.69
5.81
5.65
5.74
5.81
5.96
5.57
5.64
5.69
5.81
6.85
6.93
6.99
7.12
6.72
6.81
6.87
6.99
6.61
6.68
6.79
6.90
6.72
6.81
6.87
6.99
6.61
6.68
6.79
6.90
5.90
5.97
6.04
6.15
5.78
5.85
5.92
6.11
5.71
5.78
5.86
5.99
5.78
5.85
5.92
6.11
5.71
5.78
5.86
5.99
2
+
Co
2
+
Ni
2
+
Cu
H
2
+
An inspection of the results in Table 9 reveals that the pK values of
Mn
2
+
Co
(HL
2
) and its substituted derivatives are influenced by the inductive or
has a lower acidic character
. This is quite reasonable because the pres-
group (i.e. an electron-donating effect) will enhance the
2
+
Ni
mesmeric effect of the substituents. HL
higher pK values) than HL
ence of p-CH
electron density by their high positive inductive or mesomeric effect,
whereby a stronger O–H bond is formed. The presence of p-Cl group
i.e. an electron-withdrawing effect) will lead to the opposite effect [15].
1
2
+
Cu
H
(
3
2
+
Mn
2
+
3
Co
2
+
Ni
2
+
Cu
2
+
Mn
(
2
+
Co
2
+
Ni
2
+
4. Conclusion
Cu
2
+
Mn
2
+
Co
5-Amino-2-(phenyldiazenyl)phenol and its derivatives have been
synthesized and characterized by different spectroscopic techniques.
The molecular and electronic structures of the investigated compounds
2
+
Ni
2
+
Cu

A.A. El-Bindary et al. / Journal of Molecular Liquids 211 (2015) 256–267
267
[
[
17] N.A. El-Ghamaz, A.Z. El-Sonbati, M.A. Diab, A.A. El-Bindary, G.G. Mohamed, Sh.M.
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HL
n n
) were studied. The proton–ligand dissociation constant of (HL )
and metal–ligand stability constants of their complexes with metal
ions (Mn , Co , Ni
determined. The stability constants of the formed complexes increase
in the order Mn , Co , Ni
non-spontaneous, endothermic and entropically unfavorable. The
formation of the metal complexes has been found to be spontaneous,
endothermic and entropically favorable. Molecular docking and binding
energy calculations of azo phenols with the receptor of prostate cancer
mutant indicated 2q7k and breast cancer 3hb5-oxidoreductase–
Hormone provide that the presence of the azo phenol is an efficient in-
hibitor of prostate cancer mutant 2q7k-Hormone and breast cancer
2
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