Molecular Docking, Potentiometric and Thermodynamic Studies of Some Azo Compounds

Article abstract of DOI:10.1007/s10953-016-0486-6

The proton-ligand dissociation constant of 5-(4′-alkylphenylazo)-3-phenylamino-2-thioxothiazolidin-4-one (HL_n) (n?=?1, R?=?–CH₃; n?=?2, –H and n?=?3, –Cl) and metal–ligand stability constants of its complexes with metal ions (Mn

Full text of DOI:10.1007/s10953-016-0486-6

J Solution Chem
DOI 10.1007/s10953-016-0486-6
Molecular Docking, Potentiometric and Thermodynamic
Studies of Some Azo Compounds
1
2
1
•
A. A. El-Bindary
1
A. Z. El-Sonbati
•
M. M. Ghoneim
1
•
•
M. A. Diab
M. K. Abd El-Kader
1
•
A. F. Shoair
Received: 28 November 2015 / Accepted: 26 April 2016
Ó Springer Science+Business Media New York 2016
0
Abstract The proton-ligand dissociation constant of 5-(4 -alkylphenylazo)-3-phenylamino-
-thioxothiazolidin-4-one (HL ) (n = 1, R = –CH ; n = 2, –H and n = 3, –Cl) and metal–
2
ligand stability constants of its complexes with metal ions (Mn , Co , Ni and Cu ) have
n
3
2?
2?
2?
2?
-
3
been determined potentiometrically in 0.1 molÁdm KCl and 40 % (by volume) DMF–
water mixture and at 298, 308 and 318 K. The stability constants of the formed complexes
2?
2?
2?
2?
increase with the order Mn \ Co \ Ni \ Cu . The effect of temperature was
studied and the corresponding thermodynamic parameters (DG°, DH° and DS°) were derived
and discussed. The dissociation process of the ligands is endothermic and entropically
unfavorable. The formation of the metal complexes has been found to be endothermic and
entropically favorable. Molecular docking was used to predict the binding mode between azo
rhodanine derivatives (HL ) with the 3hb5-oxidoreductase receptor of breast cancer. The
n
values of binding constants (K ) of the azo rhodanine derivatives (HL ) are correlated with
i
n
R
Hammett’s constant (r ).
Keywords Azo rhodanine Á Potentiometry Á Thermodynamics Á Molecular docking
1
Introduction
The formation of complexes in aqueous solutions is a matter of great importance not only
in inorganic and analytical chemistry, biochemistry and other scientific and industrial fields
[
1, 2]. Azo rhodanine and its derivatives have wide industrial applications as intermediates
in the synthesis of dyes, antioxidants and brightening additives in silver electroplating, as
well as pharmacological [3], and biological activities [4–6]. Another interesting aspect of
&
A. A. El-Bindary
abindary@yahoo.com
1
2
Department of Chemistry, Faculty of Science, Damietta University, Damietta 34517, Egypt
Department of Chemistry, Faculty of Science, Tanta University, Tanta, Egypt
123

J Solution Chem
the chemistry of these compounds is their donating power to metal ions, which makes them
strong ligands in coordination compounds [7, 8]. These compounds are also used in
analytical chemistry as highly sensitive reagents for heavy metals [9, 10]. Many binary
complexes of transition and inner transition metals have been studied potentiometrically
[
11, 12]. Metal complexes of rhodanine have been extensively studied because rhodanine
possess good synthetic flexibility, selectivity and sensitivity towards the central metal atom
13–15].
Breast cancer now represents the most common female malignancy in both the
developing and developed world, and is the primary cause of death among women globally
16]. Cancer can be described as the uncontrolled growth of abnormal cells. At the 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.
In the present paper, we describe the dissociation constant of azo rhodanine derivatives
2?
2
?
2?
2?
(
HL ) and the stability constants for its complexes with Mn , Co , Ni and Cu ,
n
which were obtained by potentiometric studies. Also, the corresponding thermodynamic
functions of the dissociation and stability constants are derived and discussed. Also, we
discuss the binding ability of azo rhodanine derivatives (HL ) with the 3hb5-oxidore-
n
ductase receptor of breast cancer.
2
Experimental
2
.1 Measurements
Elemental microanalyses of the separated ligands for C, H, and N were determined on an
1
Automatic Analyzer CHNS Vario ELIII (Germany). The H NMR spectra was obtained by
a Bruker WP 300 MHz using DMSO–d as a solvent containing TMS as the internal
6
-
1
standard. IR spectra (KBr discs, 4000–400 cm ) were measured by a Jasco-4100 spec-
trophotometer. Mass spectrum was recorded by the EI technique at 70 eV using a MS-5988
GS–MS (Hewlett–Packard). The pH measurements were carried out using VWR Scientific
Instruments Model 8000 pH-meter accurate to ± 0.01 units. The pH–meter readings in the
non-aqueous medium were corrected [17]. The electrode system was calibrated according
to the method of Irving et al. [18]. The temperature was controlled to within ± 0.05 K by
circulating thermostated water (Neslab 2 RTE 220) through the outer jacket of the vessel.
All titrations have been carried out between pH = 3.5 and 12.0, under nitrogen
atmosphere.
The study simulates the actual docking process in which the ligand–protein pairwise
interaction energies were calculated using Docking Server [19]. The MMFF94 force field
was used for energy minimization of the 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 a 3hb5–
OXIDORDUCTASE–Hormone protein model. Essential hydrogen atoms, Kollman united
atom type charges, and solvation parameters were added with the aid of AutoDock tools
˚ ˚ ˚ ˚
20]. Affinity (grid) maps of 20 A9 20 A9 20 A grid points and 0.375 A spacing were
[
generated using the Autogrid program [21]. AutoDock parameter set- and distance-de-
pendent dielectric functions were used in the calculation of the van der Waals and the
electrostatic terms, respectively.
1
23

J Solution Chem
2
.2 Materials
All chemicals used in this investigation were chemically pure grade derived from BDH.
2
They include chlorides of Mn , Co , Ni and Cu , sodium hydroxide (NaOH) (97 %),
?
2?
2?
2?
sodium nitrite (NaNO ) (97 %), and hydrochloric acid (HCl) (37 %), purchased from
2
BDH. The standard chemicals aniline (99 %) and 4-alkylanilines (alkyl: CH (99 %) and
3
Cl (98 %)) purchased from Aldrich, Fluka and Merck were used without any further
purification. Water used was bidistilled water; the distillation process was carried out using
both condensation process and ion exchange technique.
2
.3 Preparation of Azo Rhodanine Derivatives
0
Preparation of 5-(4 -alkylphenylazo)-3-phenylamino-2-thioxothiazolidin-4-one (HL ): in
n
-
3
typical preparation, 25 mL of distilled water containing hydrochloric acid (12 molÁdm
.68 mL, 32.19 mmol) was added to aniline (0.979 mL, 10.73 mmol) or a 4-alkyl-aniline.
To the resulting mixture stirred and cooled to 273 K, a solution of sodium nitrite (740 mg,
0.73 mmol, in 20 mL of water) was added dropwise. The so-formed diazonium chloride
was consecutively coupled with an alkaline solution of 3-phenylamino-2-thioxothiazolidin-
-one (10.73 mmol) in 20 mL of pyridine. The precipitate, which formed immediately,
,
2
1
4
was filtered and washed several times with water. The crude products were purified by
recrystallization from hot ethanol [22]. The elemental analyses data for ligands are given in
Table 1.
The resulting formed ligands are:
0
HL = 5-(4 -methylphenylazo)-3-phenylamino-2-thioxothiazolidin-4-one.
1
0
0
HL = 5-(4 -phenylazo)-3-phenylamino-2-thioxothiazolidin-4-one.
2
HL = 5-(4 -chlorophenylazo)-3-phenylamino-2-thioxothiazolidin-4-one.
3
2
.4 pH Titration
The experimental procedure involved the titration of the following solutions (total vol-
-
3
ume = 50 mL) against a standard CO free (0.002 molÁdm ) NaOH solution. The fol-
2
lowing mixtures (i)–(iii) were prepared and titrated potentiometrically at 298 K against
-
3
standard 0.002 molÁdm NaOH in a 40 % (by volume) DMF–water mixture:
3
-3
3
-3
3
(
i) 5 cm 0.001 molÁdm HCl ? 5 cm 1 molÁdm KCl ? 20 cm DMF.
3
-3
3
-3
3
3
(
ii) 5 cm 0.001 molÁdm HCl ? 5 cm 1 molÁdm KCl ? 15 cm DMF ? 5 cm
-
3
0
.00 l molÁdm ligand.
Table 1 Elemental analyses
data of the ligands (HLn)
Compound
% Exp. (calc.)
C
H
N
HL
HL
HL
1
2
3
56.0
4.1
(4.1)
16.4
(16.4)
(
55.8)
54.9
54.8)
49.7
49.6)
3.7
(3.6)
17.1
(16.9)
(
3.1
(3.0)
15.5
(15.4)
(
123

J Solution Chem
3 3
3
-3
3
-3
(
iii) 5 cm 0.001 molÁdm HCl ? 5 cm l molÁdm KCl ? 15 cm DMF ? 5 cm
-
3
3
-3
0
.001 molÁdm ligand ? 10 cm 0.0001 molÁdm metal chloride.
For each mixture, the volume was made up to 50 cm with bidistilled water before the
3
titration. These titrations were repeated for temperatures of 308 K and 318 K.
NH
S
O
HN
S
OH
N
N
N
N
N
N
S
S
R
(
A)
(B)
R
O
H
O
HN
HN
S
H
N
N
N
N
S
N
N
S
S
R
(
D)
(C)
R
R
N
H
S
H
N
S
N
O
N
N
N
O
S
H
N
NH
S
R
(
E)
R = -CH (HL ), -H (HL ) and -Cl (HL )
3
1
2
3
0
Fig. 1 Intramolecular and intermolecular hydrogen-bonded structure of 5-(4 -alkylphenylazo)-3-
n
phenylamino-2-thioxothiazolidin-4-one (HL )
1
23

J Solution Chem
-
3
The ligands solutions (0.001 molÁdm ) were prepared by dissolving an accurately
-
3
weighed amount of the solid in DMF. Metal ion solutions (0.0001 molÁdm ) were pre-
pared from analar metal chlorides in bidistilled water and standardized with EDTA [23].
-
3
-3
Solutions of 0.001 molÁdm HCl and 1 molÁdm KCl were also prepared in bidistilled
water. A carbonate free sodium hydroxide solution in 40 % (by volume) DMF–water
mixture was used as titrant and standardized against analar oxalic acid [24–27].
3
Results and Discussion
3
.1 Structure of the Ligands
IR spectra provide valuable information regarding the nature of the functional group
attached to the metal atom. The spectra of ligands do not show absorption characteristic of
the N=N function owing to the formation of the hydrazone (Fig. 1). The ligand IR spectra
give interesting results and conclusions; thus, the three bands around 823–882 and
-
1
3
205–3210 cm
in the ligands are assigned to t(CS) and –NH(3-phenylamine),
(
a)
O
HN
S
N
NH
N
O
N
-C
6
H
5
N
2
C3H2N2OS2
N
S
S
S
m /z = 77
m /z = 224
Structure II
Structure I
m /z = 328
(b)
2
Fig. 2 a Mass spectrum and b fragmentation patterns of HL ligand
123

J Solution Chem
respectively. The splitting of the t(N=N) band into two bands in the ranges 1435–1520 and
-
1
*
vides evidence that the hydrazone N participate in the chelation after deprotonation leading
1230 cm due to t(HC=N) and t(=N–NH) hydrazone, respectively, for ligands pro-
to a covalent linkage. The IR spectral data of the ligands (HL ) exhibit a band at
n
-
727–1754 cm due to C=O [22]. There are broad bands, which can be attributed to
1
1
different types of intramolecular hydrogen-bonded –NH groups (Fig. 1c, d) and inter-
molecular hydrogen bond (Fig. 1e).
1
The H NMR spectra of the ligands were recorded in DMSO–d solution using TMS as
6
internal standard. The broad signal exhibited by the ligands can be assigned to an
intramolecularly hydrogen bonded proton of NH (hydrazone)/OH (enol) at *11.5 ppm
and NH (3-phenylamine) at *9.0 ppm, which were not affected by dilution and disap-
peared in the presence of D O. The aromatic rings give a group of multi-signals at
6.5–8.0 ppm. The singlet peak observed at 2.3 ppm can be assigned to the proton of the
CH group.
2
3
The mass spectrum fragmentation mode of ligand (HL ) shows the exact mass of 328
2
corresponding to the formula C H N OS as shown in Fig. 2a. The ion of m/z = 328
1
5
12
4
2
undergoes fragmentation to a stable peak at m/z = 224 by losing the C H N (structure
6 5 2
I) as shown in Fig. 2b. The loss of C H N OS leads to the fragmentation with m/z = 77
2
3
2
2
(structure II).
3
.2 Potentiometric and Thermodynamic Studies
From the titration curves of the acid in the absence and presence of ligands (HL ), the
n
average number of the protons associated with ligands (HL ) at different pH values, nꢀ A,
n
was calculated from Eq. 1:
o
o
ðV1 À V2ÞðN þ E Þ
nꢀ A ¼ Y Æ
ð1Þ
o
o
L
ðV À V1ÞTC
where Y is the number of available protons in the ligand (HL ) (Y = 1) and V and V are
the volumes of alkali required to reach the same pH on the titration curve of hydrochloric
n
1
2
n
Table 2 Thermodynamic functions for the dissocation of ligands (HL ) in 40 % (by volume) DMF–water
-3
mixtures and 0.1 molÁdm KCl at different temperatures
Compound Temperature Dissociation Gibbs energy
Enthalpy change
-1
Entropy change
-1 -1
-
1
(K) constant
H
(kJÁmol
)
(kJÁmol
)
(JÁmol ÁK
)
pK
1
DG°
DH°
-DS°
HL
HL
HL
1
2
3
298
8.58 (± 0.02)
8.43 (± 0.03)
8.30 (± 0.05)
8.37 (± 0.04)
8.21 (± 0.03)
8.08 (± 0.02)
8.19 (± 0.05)
8.05 (± 0.04)
7.90 (± 0.03)
48.96 (± 0.11)
49.71 (± 0.17)
50.54 (± 0.30)
47.76 (± 0.22)
48.42 (± 0.17)
49.20 (± 0.12)
46.73 (± 0.28)
47.47 (± 0.23)
48.10 (± 0.18)
79 (± 3)
79 (± 3)
79 (± 3)
72 (± 2)
72 (± 2)
72 (± 2)
69 (± 2)
69 (± 2)
69 (± 2)
3
08
18
25 (± 3)
26 (± 2)
26 (± 2)
3
298
3
08
18
3
298
3
08
18
3
1
23

J Solution Chem
123

J Solution Chem
o
3
acid and reagent, respectively, V° is the initial volume (50 cm ) of the mixture, TC , is the
L
total concentration of the reagent, N° is the normality of the sodium hydroxide solution and
E° is the initial concentration of the free acid. Thus, the formation curves ( nꢀ A against pH)
for the proton–ligand systems were constructed and found to extend between 0 and 1 in the
nꢀ A scale. This means that ligands (HL ) have one ionizable proton (the enolized hydrogen
n
H
ion of the –OH group, pK ). The dissociation constants were evaluated by different
computational methods [28]. Three replicate titrations were performed; the average values
obtained for ligands HL are listed in Table 2. The completely protonated form of the
n
ligands (HL ) has one proton that dissociates in the measurable pH range. The deproto-
n
nation of the enol group most probably results in the formation of stable intramolecular H–
bonding with the nitrogen of the N=N group. Such an interaction increases the dissociation
H
process of enolic OH group and decreases the pK value in the order HL [ HL [ HL
1
2
3
[
29, 30].
The formation curves for the metal complexes were obtained by plotting the average
number of ligands attached per metal ion ( nꢀ ) against the free ligands exponent (pL),
according to Irving and Rossotti [31]. The average number of the reagent molecules
attached per metal ion, nꢀ , and free ligands exponent, pL, can be calculated using Eqs. 2 and
3:
o
o
ðV3 À V2ÞðN þ E Þ
nꢀ ¼
ð2Þ
ð3Þ
o
o
M
ðV À V2Þ Á nꢀ A Á TC
and
8
>
:
9
>
;
ꢀ
ꢁ
n¼J
n
P
>
H
1
>
>
<
bn
>
=
½HþŠ
o
V þ V3
n¼o
pL ¼ log10
Á
o
o
M
o
>
TC À nꢀ Á TC
V
>
L
where TCo is the total concentration of the metal ion present in the solution, and b is the
H
n
M
overall proton–reagent stability constant. V , V and V are the volumes of alkali required
1
2
3
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 sta-
bility constants were determined using different computional methods [32, 33]. The values
of the stability constants (log10 K and log K ) are given in Table 3. The following
1
10
2
general remarks can be made:
(
i) The maximum value of nꢀ is *2 indicating the formation of 1:1 and 1:2 (metal:
ligand) complexes [34].
ii) The metal ion solution used in the present study was very dilute (2 9 10
-5
(
-3
molÁdm ), hence there was no possibility of formation of polynuclear complexes
[35, 36].
(
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 [37, 38].
(
iv) For the same ligand at constant temperature, the stability of the chelates increases
2
?
2?
2?
2?
with the order Mn \ Co \ Ni \ Cu [39–41]. This order largely reflects
the considerably greater the stability of Cu complexes compared to those of
2
?
1
23

J Solution Chem
other metals of the 3d series. Under the influence of both the polarizing ability of
2?
the metal ion [42] and the ligand field [43], Cu will receive some extra
stabilization due to tetragonal distortion of octahedral symmetry in its complexes.
2
The greater stability of Cu complexes is produced by the well known Jahn–
?
Teller effect [43].
H
The dissociation constant (pK ) for ligands (HL ), as well as the stability constants of
n
2?
2?
its complexes with Mn , Co , Ni and Cu have been evaluated at 298, 308 and
2?
2?
3
ciation and complexation process was calculated from the slope of the plot pK or log
18 K, and are given in Tables 2 and 3, respectively. The enthalpy (DH°) for the disso-
H
K
0
1
-
against T (Fig. 3) using the graphical representation of van’t Hoff, Eqs. 4 and 5:
1
ꢀ
ꢀ
ꢀ
DG ¼ À2:303 RTlog10 K ¼ DH ÀT DS
ð4Þ
ð5Þ
or
ꢀ
ꢀ
log10 K ¼ ðÀDH =2:303RÞ:ð1=TÞ þ ðDS =2:303RÞ
From the DG° and DH° values one can deduce the entropy DS° using the well known
relationships 4 and 6:
ꢀ
ꢀ
ꢀ
DS ¼ ðDH À DG Þ=T
ð6Þ
All thermodynamic parameters of the dissociation process of ligands (HL ) are
n
recorded in Table 2. From these results the following conclusions can be made:
H
i) The pK values decrease with increasing temperature, i.e. the acidity of the ligand
increases [20].
(
(
ii) A positive value of DH° indicates that the process is endothermic.
(iii) A large positive value of DG° indicates that the standard state dissociation process
is not spontaneous [44].
(
iv) A negative value of DS° is obtained due to the increased order as a result of the
solvation process.
H
Fig. 3 van’t Hoff plot pK of
ligands (HL ) against 1/T
8.7
8.4
8.1
7.8
n
HL1
HL2
HL3
0.0031
0.0032
0.0033
0.0034
-1
1
/T (K )
123

J Solution Chem
Table 4 Thermodynamic functions for ML
n
complexes of ligand (HL ) in 40 % (by volume) DMF–water
n
-3
mixtures and 0.1 molÁdm KCl
n?
M
-1
Compound
T/K Gibbs energy (kJÁmol
)
Enthalpy change
)
Entropy change
-1 -1
-1
(
kJÁmol
(JÁmol ÁK
)
o
o
o
o
o
ÀDS
1
o
2
ÀDG1
ÀDG2
ÀDH1
ÀDH2
ÀDS
2
?
HL
HL
HL
1
2
3
Mn
298 34.29 (± 0.39) 24.42 (± 0.28) 29 (± 2) 21 (± 1) 212 (± 2) 152 (± 1)
3
08 36.38 (± 0.35) 25.94 (± 0.35)
18 38.54 (± 0.30) 27.46 (± 0.36)
212 (± 2) 152 (± 1)
212 (± 2) 152 (± 1)
3
2?
Co
298 34.97 (± 0.28) 25.16 (± 0.34) 24 (± 1) 24 (± 1) 196 (± 1) 164 (± 1)
3
08 36.85 (± 0.29) 26.83 (± 0.41)
18 38.90 (± 0.24) 28.43 (± 0.42)
196 (± 1) 164 (± 1)
196 (± 1) 164 (± 1)
3
2
Ni
?
298 35.83 (± 0.34) 25.79 (± 0.28) 29 (± 1) 23 (± 3) 217 (± 1) 163 (± 3)
3
08 37.86 (± 0.23) 27.42 (± 0.47)
18 40.18 (± 0.42) 29.04 (± 0.48)
217 (± 1) 163 (± 3)
218 (± 1) 163 (± 3)
3
2?
Cu
298 36.51 (± 0.39) 26.53 (± 0.39) 31 (± 1) 22 (± 1) 226 (± 1) 162 (± 1)
3
08 38.68 (± 0.29) 28.18 (± 0.23)
18 41.03 (± 0.36) 29.77 (± 0.42)
226 (± 1) 162 (± 1)
226 (± 1) 162 (± 1)
3
2
Mn
?
298 35.54 (± 0.34) 25.67 (± 0.45) 22 (± 1) 25 (± 3) 192 (± 1) 171 (± 3)
3
08 37.50 (± 0.35) 27.18 (± 0.29)
18 39.39 (± 0.30) 29.10 (± 0.36)
193 (± 1) 171 (± 3)
192 (± 1) 171 (± 3)
3
2?
Co
298 36.28 (± 0.28) 26.36 (± 0.22) 21 (± 2) 21 (± 3) 192 (± 2) 158 (± 3)
3
08 38.15 (± 0.41) 27.95 (± 0.47)
18 40.12 (± 0.42) 29.53 (± 0.42)
192 (± 2) 159 (± 3)
192 (± 2) 158 (± 3)
3
2
Ni
?
298 37.08 (± 0.22) 27.10 (± 0.28) 24 (± 1) 22 (± 1) 204 (± 1) 164 (± 1)
3
08 39.04 (± 0.47) 28.66 (± 0.41)
18 41.16 (± 0.24) 30.38 (± 0.36)
203 (± 1) 164 (± 1)
204 (± 1) 164 (± 1)
3
2?
Cu
298 37.77 (± 0.39) 27.55 (± 0.34) 21 (± 1) 23 (± 1) 197 (± 1) 169 (± 1)
3
08 39.74 (± 0.29) 29.19 (± 0.35)
18 41.70 (± 0.30) 30.93 (± 0.30)
197 (± 1) 168 (± 1)
197 (± 1) 169 (± 1)
3
2
Mn
?
298 37.03 (± 0.34) 26.76 (± 0.39) 23 (± 1) 22 (± 3) 200 (± 1) 163 (± 3)
3
08 38.98 (± 0.41) 28.30 (± 0.29)
18 41.03 (± 0.42) 30.01 (± 0.24)
200 (± 1) 163 (± 3)
200 (± 1) 163 (± 3)
3
2?
Co
298 37.77 (± 0.39) 27.38 (± 0.34) 20 (± 1) 23 (± 1) 194 (± 1) 168 (± 1)
3
08 39.68 (± 0.35) 29.07 (± 0.23)
18 41.64 (± 0.36) 30.74 (± 0.36)
194 (± 1) 168 (± 1)
194 (± 1) 168 (± 1)
3
2
Ni
?
298 38.62 (± 0.34) 28.12 (± 0.39) 21 (± 2) 24 (± 1) 200 (± 2) 174 (± 1)
3
08 40.63 (± 0.41) 29.89 (± 0.29)
18 42.62 (± 0.24) 31.60 (± 0.48)
200 (± 2) 174 (± 1)
200 (± 2) 174 (± 1)
3
2?
Cu
298 38.74 (± 0.28) 28.81 (± 0.45) 22 (± 2) 24 (± 1) 203 (± 2) 176 (± 1)
3
08 40.69 (± 0.29) 30.60 (± 0.35)
18 42.80 (± 0.42) 32.33 (± 0.42)
203 (± 2) 176 (± 1)
203 (± 2) 176 (± 1)
3
1
23

J Solution Chem
All the thermodynamic parameters of the stepwise stability constants of complexes are
recorded in Table 4. The values of DH° and DS° can then be considered as the sum of two
contributions: (a) release of H O molecules, and (b) metal–ligand bond formation.
2
Examination of these values shows that:
(
i) The stability constants (log10 K and log K ) for ligand (HL ) complexes
n
1
10
2
increase with increasing temperature, [45].
(
ii) The negative value of DG° for the complexation process suggests the favorable
nature of the standard state processes [46].
8.7
8.4
8.1
7.8
HL
1
2
3
3
98 K
08 K
18 K
HL
2
HL
3
-0.2
-0.1
0.0
0.1
0.2
R
H
R
Fig. 4 Correlation of pK with Hammett’s constant (r ) at 289, 308 and 310 K
Fig. 5 The ligand (HL
hb5. (For interpretation of the references to color in this figure legend, the reader is referred to the web
version of this article.) (Color figure online)
1
) [green in (a) and blue in (b)] in interaction with receptor breast cancer mutant
3
123

J Solution Chem
(
iii) The DH° values are positive, meaning that these processes are endothermic and so
more favorable at higher temperature.
(
iv) The DS° values for the ligand complexes are positive, confirming that the
complex formation is entropically favorable [19].
H
An inspection of the results in Table 2 reveals that the pK values of (HL ) and its
substituted derivatives are influenced by the inductive or mesmeric effect of the sub-
2
H
stituents. HL has a lower acidic character (higher pK values) than HL . This is quite
1
3
Fig. 6 The ligand (HL
3
version of this article.) (Color figure online)
2
) [green in (a) and blue in (b)] in interaction with receptor breast cancer mutant
hb5. (For interpretation of the references to color in this figure legend, the reader is referred to the web
Fig. 7 The ligand (HL
hb5. (For interpretation of the references to color in this figure legend, the reader is referred to the web
version of this article.) (Color figure online)
3
) [green in (a) and blue in (b)] in interaction with receptor breast cancer mutant
3
1
23

J Solution Chem
reasonable because the presence of a p-CH group (i.e. an electron-donating effect) will
3
enhance the electron density by their high positive inductive or mesomeric effect, whereby
a stronger O–H bond is formed. The presence of a p-Cl group (i.e. an electron-withdrawing
n
Table 5 Energy values obtained in docking calculations of ligands (HL ) with receptor breast cancer
mutant 3hb5
Compound Gibbs
energy of
binding
Inhibition
constant (K
(lmolÁdm
vdW ? H
bond ? desolve energy
Electrostatic Total
Surface
intermolecular interaction
i
)
)
-
3
-1
energy
-1
(kJÁmol
(kJÁmol
)
energy
-1
(kJÁmol
-
1
)
(kJÁmol
)
)
HL
HL
HL
1
2
3
-34.14
-32.55
-29.28
1.05
1.98
7.45
-39.87
-37.15
-35.48
-0.29
-0.08
0.12
-40.1664
-37.2376
-35.3548
917.30
782.03
841.02
1 2 3
Fig. 8 HB plot of interaction between ligands a HL , b HL and c HL with receptor breast cancer mutant
3hb5
123

J Solution Chem
effect) will lead to the opposite effect [47]. The results are also in accordance with
R
H
Hammett’s para-substituent constant values r . Straight lines are obtained on plotting pK
values at different temperature versus r as shown in Fig. 4.
R
3
.3 Molecular Docking
Molecular docking is a key tool in computer drug design [48]. The focus of molecular
docking is to simulate the molecular recognition process. Molecular docking aims to
achieve an optimized conformation for both the protein and drug with relative orientation
between them such that the Gibbs energy of the overall system is minimized.
In this work, we used molecular docking between ligands (HL ) and breast cancer
n
(3hb5). The results showed a possible arrangement between ligands (HL ) and receptor
n
3hb5. The docking study showed a favorable interaction between ligands (HL ) and the
n
receptor 3hb5 as shown in Figs. 5, 6, and 7 and the calculated energy is listed in Table 5.
n
Table 6 Decomposed interaction energies of ligands HL with receptor breast cancer mutant 3hb5
Hydrogen
bonds
Polar
Halogen-
bond
Cation-pi
Hydrophobic
Other
HL
1
VAL188
(
THR190
(-0.7525)
PHE226
(-0.3699)
PHE192
(-2.5937)
SER12
(-0.3769)
-0.659)
TYR155
SER142
(-0.2248)
(-0.8648)
ILE14 (-0.74)
MET193
(-0.5743)
VAL196
(-0.2553)
HL
2
PHE192
VAL196
(-0.6767)
(-1.6761)
TYR155
MET193
(-0.4839)
(-1.2665)
PHE226
SER142
(-0.3868)
(-0.4911)
VAL196
ILE14
(-0.3982)
(-0.3508)
LYS159
(
-0.2634)
ASN152
(
-0.2148)
THR190
(
-0.2019)
HL
3
THR190
-0.7037)
ASN90
(-0.4185)
PHE192
(-1.3762)
TYR155
(-1.0834)
MET193
(-0.632)
(
GLY9
PHE226
(-0.4002)
ILE14
(-0.6416)
(-0.1193)
VAL188
(
-0.5677)
VAL196
-0.1405)
(
1
23

J Solution Chem
According to the results obtained in this study, the HB plot curve indicates that the ligands
(
HL ) bind to the protein with hydrogen bonding interactions. The decomposed interaction
n
-
1
energies, in kJÁmol , between ligands (HL ) with the 3hb5 receptor are shown in Fig. 8
n
and Table 6. The calculation efficiency is favorable where K values estimated by Auto-
i
Dock were compared with experimental K values, when available, and the Gibbs energy
i
change is negative. Also, based on this data, we can propose that interaction between the
3
hp5 receptors and the ligands (HL ) is possible; 2D curves of docking with ligands (HL )
n n
are shown in Fig. 9a–c. This interaction could activate apoptosis in cancer cells. Binding
energies are most widely used as mode of measuring binding affinity of compounds. Thus,
1 2 3
Fig. 9 2D plot of interaction between ligands a HL , b HL and c HL with receptor breast cancer mutant
3hb5
123

J Solution Chem
Fig. 10 The relation between
Hammett’s substitution
8
7
6
5
4
3
2
1
0
R
coefficient (r ) and K
i
of ligands
(3)
(
n
HL )
(
2)
(1)
-0.2
-0.1
0.0
0.1
0.2
0.3
R
the decrease in binding energy due to mutation will increase the binding affinity of the
compounds towards the receptor. The characteristic features of compounds were repre-
sented in the presence of active sites available for hydrogen bonding. This feature gives
them the ability to be good binding inhibitors to the protein and will help in the devel-
opment of augmented inhibitory compounds. As shown in Table 5, the values of K are
i
related to the nature of the para substituent, increasing in the order p-(Cl [ H [ CH ). This
3
can be attributed to the fact that the effective charge increases due to the electron with-
drawing p-substituent HL while it is decreased by the electron donating character of HL .
3
1
R
This is in accordance with that expected from Hammett’s constant (r ), and as shown in
Fig. 10, the K values correlate with r increasing with increasing r . The results confirm
R
R
i
also that the ligands derived from azo rhodanine derivatives (HL ) are efficient inhibitors
n
of 3hb5-oxidoreductase breast cancer. The ligands (HL1–3) showed binding energies of
-
1
-
34.14, -32.55 and -29.28 kJÁmol , respectively, with 3hb5-oxidoreductase breast
cancer using H-bond, electrostatic and van der Waals interactions. On the basis of complex
scoring and interactions with the active site residue and binding ability, it was shown that
ligands (HL ) could be promising inhibitors of 3hb5-oxidoreductase breast cancer. This
n
gives us the conclusion that HL possesses the lowest binding energy (-34.14 kJÁmol) and
1
highest binding ability [49].
4
(
Conclusion
0
1) 5-(4 -Alkylphenylazo)-3-phenylamino-2-thioxothiazolidin-4-one (HL ) compounds
n
have been synthesized and characterized by different spectroscopic techniques.
2) The proton–ligand dissociation constant of ligands (HL ) and metal–ligand stability
(
n
2
?
2?
2?
2?
constants of their complexes with metal ions Mn , Co , Ni and Cu were
determined at different temperatures.
3) The stability constants of the formed complexes increase with the order
(
(
2
?
2?
2?
2?
Mn \ Co \ Ni \ Cu
.
4) The dissociation process is non-spontaneous, endothermic and entropically
unfavorable.
1
23

J Solution Chem
(
(
(
(
5) The formation of the metal complexes has been found to be spontaneous,
endothermic and entropically favorable.
6) The stability constants (log10 K and log K ) for the complexes increase with
1
10
2
increasing temperature.
H
7) The pK values of the ligands decrease in the order of HL [ HL [ HL as
1
2
3
R
expected from Hammett’s constant (r ).
8) Molecular docking and binding energy calculations of azo dye ligands with the
receptor of 3hb5-oxidoreductase breast cancer indicated that the present azo dye
rhodanine ligands are efficient inhibitors of 3hb5-oxidoreductase breast cancer.
(9) The values of binding constant (K ) of the ligands increase in the order
i
HL \ HL \ HL as expected from Hammett’s constant.
1
2
3
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