In silico, In Vitro and docking applications for some novel complexes derived from new quinoline derivatives

Article abstract of DOI:10.1016/j.molstruc.2019.06.053

The new quinoline derivatives: 2-oxo-1,2-dihydroquinoline-4-carbohydrazide (1), 2-(allyloxy) quinoline-4-carbohydrizde (2), 1-allyl-2-oxo-1,2-dihydroquinoline-4-carbohydrazid (3) and 2-(allyl-thio)quinoline-4-carbohydrazide (4) and their Cu(II), Ni(II) and Co(II) complexes were synthesized and characterized by using elemental analysis (CHNM%), FTIR, UV/Vis, ¹H NMR, ¹³C NMR spectra, DTA, TGA, magnetic susceptibility and the conductivity of 0.001 M in DMSO. The obtained results revealed the formation of the Cu(II) complexes in the square planar form, meanwhile Ni(II) and Co(II) complexes as octahedral structure. The FTIR spectra of the synthesized ligands and their complexes were giving the characteristic stretching vibration bands. The weight loss which appeared in the TG analysis indicates that there are different types of water molecules in the formed complexes. The theoretical calculations which are carried out using different computer programs permit proposing an optimized geometry for the formed complexes. The molecular modeling for the free ligands and their complexes were evaluated and discussed. The energy of the HOMO and LUMO was calculated and discussed. The most stable structure of the synthesized compounds was suggested and its energy was evaluated. The most benefit properties, which play a very important role in drug synthesis with reference to the surface properties of the compounds, were evaluated and discussed. The application of the DFT on the target compounds, gave dipole value around 1.73 D. This result turns out well with the requirement properties of the new drug. Docking the synthesized compounds with HepG2-code: 5EQG protein; e.g. liver carcinoma cell, gave a promising inhibition in Silico level. The antimicrobial activity of the target compounds with E. Coli, B. Subtils and Asp. Niger, in Vitro level, gave promising result. The interaction of the compounds with the microorganisms was tested in Silico level. E. Coli was used as an example for the target microorganism. The protein used for docking process was 5C9T.

Full text of DOI:10.1016/j.molstruc.2019.06.053

Accepted Manuscript
In silico, In Vitro and docking applications for some novel complexes derived from
new quinoline derivatives
Ibrahim A.I. Ali, Sahar S.A. El-Sakka, Mohamed H.A. Soliman, Omayma E.A.
Mohamed
PII:
S0022-2860(19)30777-X
DOI:
https://doi.org/10.1016/j.molstruc.2019.06.053
MOLSTR 26695
Reference:
To appear in: Journal of Molecular Structure
Received Date: 4 February 2019
Revised Date: 10 June 2019
Accepted Date: 13 June 2019
Please cite this article as: I.A.I. Ali, S.S.A. El-Sakka, M.H.A. Soliman, O.E.A. Mohamed, In silico, In Vitro
and docking applications for some novel complexes derived from new quinoline derivatives, Journal of
Molecular Structure (2019), doi: https://doi.org/10.1016/j.molstruc.2019.06.053.
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ACCEPTED MANUSCRIPT
In Silico, In Vitro and Docking applications for some Novel
Complexes Derived from new Quinoline Derivatives
1
2*
2
3
Ibrahim A. I. Ali , Sahar S. A El-Sakka , Mohamed H. A. Soliman and Omayma E. A. Mohamed
1
Suez Canal University, Faculty of Science, Chemistry Department, Ismailia, Egypt
2
Suez University, Faculty of Science, Chemistry Department, Suez, Egypt
3
Chemistry Administrations, Suez, Egypt
*Corresponding author
Email address: saharelsakka@hotmail.com; sahar.alsakka@suezuniv.edu.eg
Abstract
The new quinoline derivatives: 2-oxo-1,2-dihydroquinoline-4-carbohydrazide (1), 2-(allyloxy)
quinoline-4-carbohydrizde (2), 1-allyl-2-oxo-1,2-dihydroquinoline-4-carbohydrazid (3) and 2-(allyl-
thio)quinoline-4-carbohydrazide (4) and their Cu(II), Ni(II) and Co(II) complexes were synthesized
1
13
and characterized by using elemental analysis (CHNM%), FTIR, UV/Vis, H NMR, C NMR spectra,
DTA, TGA, magnetic susceptibility and the conductivity of 0.001 M in DMSO. The obtained results
revealed the formation of the Cu(II) complexes in the square planar form, meanwhile Ni(II) and Co(II)
complexes as octahedral structure. The FTIR spectra of the synthesized ligands and their complexes
were giving the characteristic stretching vibration bands. The weight loss which appeared in the TG
analysis indicates that there are different types of water molecules in the formed complexes. The
theoretical calculations which are carried out using different computer programs permit proposing an
optimized geometry for the formed complexes. The molecular modeling for the free ligands and their
complexes were evaluated and discussed. The energy of the HOMO and LUMO was calculated and
discussed. The most stable structure of the synthesized compounds was suggested and its energy was
evaluated. The most benefit properties, which play a very important role in drug synthesis with
reference to the surface properties of the compounds, were evaluated and discussed. The application of
the DFT on the target compounds, gave dipole value around 1.73 D. This result turns out well with the
requirement properties of the new drug. Docking the synthesized compounds with HepG2-code:
5
EQG protein; e.g. liver carcinoma cell, gave a promising inhibition in Silico level. The antimicrobial
activity of the target compounds with E. Coli, B. Subtils and Asp. Niger, in Vitro level, gave promising
result. The interaction of the compounds with the microorganisms was tested in Silico level. E. Coli
was used as an example for the target microorganism. The protein used for docking process was 5C9T.
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Keywords: Antimicrobial; Docking; Complexes; In Silico; Quinoline; Hydrazide.
1
. Introduction
The synthesis of quinoline and its derivatives have attracted considerable attention of organic and
medicinal chemists for many years [1]. The structural core of quinoline is frequently associated with
medicinal applications [2–5]. The intensive efforts to find effective therapeutic agents with antiviral
and antitumor activities have directed many researchers to synthesize a series of quinoline derivatives
or their analogues.
The prevalence of the quinoline ring system in a vast range of medical and industrial setting scan is
ascribed mainly to its versatility and broad potential for functionalization. In fact, this versatility which
earned it the designation of “privileged scaffold” in medicinal chemistry, a term coined by Evans in
1
988 which refers to simple structural subunits present in diverse therapeutic compounds with
distinctive receptor affinities [6]. Consequently, the synthesis of variously substituted quinolines has
been a recurring endeavor for nearly a century and a half [7]. A multitude of synthetic methods has
been established over this timeframe, which constructs the quinoline ring from diverse starting
materials and result in products with nearly limitless combinations of functionality.
Quinoline and its analogs represent privileged moieties in the field of synthetic and medicinal
chemistry because of its diverse chemical and pharmacological properties. The broad spectrum of
biological and biochemical activities has been further facilitated by the synthetic versatility of
quinoline, which allows the generation of a large number of structurally diverse derivatives [8].
Compounds containing the quinoline ring system were found to be the oldest chemicals for the
treatment of various diseases [8]. The extremely drug resistant tuberculosis is a worldwide public
health problem in recent years. The wide spread of this disease is primarily due to the development of
resistance to the existing drugs that has concerned researchers throughout the world. There is an urgent
requirement of improvement in new drug molecules with newer targets and with an alternative
mechanism of action [9,10].
It is evident from the literature that quinoline-based hydrazone scaffolds are known to exhibit
excellent anti-TB properties [11,12]. This broad spectrum of biological and biochemical activities has
been further aided by the synthetic flexibility of quinoline hydrazones, which allows the generation of
a large number of structurally diverse derivatives and their metal complexes [13]. Further, various
types of hydrazones have attracted continued interest in the medicinal field due to their broad-
spectrum biological activities [14]. Among the ligand systems, quinoline hydrazone derivatives are
highly important because, these ligands developed due to their diverse chelating ability, structural
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flexibility and pharmacological activities like antitumoral, antifungal, antibacterial, antituberculosis,
antimalarial, and antiviral [10].
Recently, it is reported that quinoline hydrazones and their Zn(II) complexes showed significant
activity against the Mycobacterium tuberculosis strain, at low micro-molar levels [15–17].
Recent years have witnessed an unprecedented progress in biological applications of metal
coordination compounds of biologically active ligands because of their key role in clinical therapy.
Transition metals are particularly suitable for this purpose because they can adopt a wide variety of
coordination numbers, geometries and oxidation states in comparison with other main group elements.
One of the characteristics of metals is their potential to undergo redox processes, as determined by
their redox potentials. Transition metal ions, in particular, are usually able to switch between several
oxidation states. Due to the redox activity of metals and, therefore, a possible disturbance of the
sensitive cellular redox homeostasis, a tight regulation of the metal and redox balance is crucial for
health [18].
On the other hand, over production of activated oxygen species, generated by normal metabolic
process, is considered to be the main contributor to oxidative damages to biomolecules such as DNA,
lipids and proteins, thus accelerating cancer, aging, inflammation, cardiovascular and
neurodegenerative diseases. The potential value of antioxidants has already prompted investigators to
search for the cooperative effects of metal complexes and natural compounds for improving
antioxidant activity [18].
Depending on their structure, on the one hand, and the source of the oxidative stress, on the other,
metal complexes might act as antioxidants or prooxidants. The current review provides insight into the
interaction between the reactive oxygen species and the transition metals and their complexes. It will
focus on a novel approach to design synthetic antioxidant metal-based compounds and to study their
activities in the oxidation processes. This work underlines some important features for the research on
metal complexes of biologically active ligands and supports future evaluation of some of these
compounds as possible therapeutic agents [18].
Efthimiadou et.al., have prepared and characterized nine metal complexes of the quinolone
2
+
2+
3+
2+
2+
2+
2+
2+
antibacterial agent N-propyl-norfloxacin with VO , Mn , Fe , Co , Ni , Zn , MoO , Cd and
2
2
+
UO2 . The antimicrobial activity of the complexes has been tested on three different microorganisms
[
19]. The interaction of the complexes with calf-thymus (CT) DNA has also been studied.
According to the history of the important applications of the quinoline derivatives and their metal
2
+
2+
2+
complexes, this work introduce some new quinoline derivatives and their Cu , Ni and Co
complexes. The new view of the synthesized compounds in the level of in Vitro and in Silico was
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attained to a deep prospective view which facilitates determining which one could be used as drug and
which could be toxic.
2
. Materials and Methods
2
.1.Materials
All chemicals used in this study were of analytical grade. The primitive chemicals (Koch-Light and
Sigma-Aldrich) were used as received. The metals nitrate salts (Cu(II), Ni(II), Co(II)) were purchased
from the Sigma-Aldrich and used without extra treatment.
2
.2.Apparatus
Thin layer chromatography (TLC) was carried out on silica gel type 60-F254 aluminum sheets (E.
Merck, layer thickness= 0.2 mm) using the following solvent systems, S : petroleum ether/ethyl
1
acetate (5:1); S : petroleum ether/ethyl acetate (2:1); S : petroleum ether/ethyl acetate (1:1).
2
3
o
The obtained spots were detected by UV lamp. Melting points were determined on 300 C melting
point apparatus and the values are used without extra correction. The infrared spectra were obtained in
−
1
1
13
the 4000–400 cm region by using Bruker Alpha instrument with KBr discs. H and C NMR spectra
were recorded on Bruker spectrometer operating at 300 and 75.0 MHz uses CDCl as solvent and TMS
3
as internal standard. Elemental analysis was carried out by element arvario instrument. The electronic
absorption spectra were obtained on UV-1601PC Shimadzu spectrophotometer in 1 cm quartz cell.
TGA and DTA were recorded on Shimadzu 60 thermal analyzer under a dynamic flow of nitrogen (30
mL/min) and heating rate 10 °C/min with open platinum sample holder. Electrical conductivity
measurements were carried out at room temperature on freshly prepared 1 mM DMSO solution using
WTW conductivity.
2
.3. Antimicrobial Activity
The antimicrobial activities of the synthesized compounds have been screened using different strains
of bacteria (Bacillis subtilis and Escherichia coli) and pathogenic fungi (Aspergillus fumigatus).
The disc diffusion method technique was adopted for antibacterial activity [20] while the well
technique was used for antifungal activity [21].
Mean zone of the inhibition in mm ± standard deviation beyond well diameter (6 mm) produced on a
range of environmental and clinically pathogenic microorganisms using (30 mg/L) concentration of
the tested samples. The test was done using the diffusion agar technique, well diameter: 6.0 mm (30
µL was tested). Ampicillin and Fluconazole were used as positive control while methanol was used as
negative control. This test was performed in the Center of Mycology and Biotechnology–Suez Canal
University
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2
.4.Synthesis of the Target Complexes
The target complexes were prepared according to the following procedure. The targeted compounds
ligands) (1.0 mmol) were dissolved in 20 mL ethanol. The metal nitrate (0.5 mmol) was dissolved in
0 mL ethanol, which was added dropwise with stirring to the ligand solution. The obtained mixture
(
1
was refluxed with stirring for 5 h. The formed precipitate was filtered, washed with hot ethanol and
dried under vacuum over anhydrous CaCl2.
2
.5.Synthesis of the Target Quinoline derivatives
General Methods
Hydrazine hydrate was added to a solution of esters in ethanol or methanol. The reaction mixture was
o
refluxed at 85 C for 6 hr. After cooling to room temperature the precipitated hydrazides were filtered
off, washed with water and ethanol followed by recrystallization from aqueous ethanol or methanol to
yield the quinolone derivatives (Scheme 1).
2
.5.1. 2-oxo-1,2-dihydroquinoline-4-carbohydrazide (1)
o
1
Faintly beige powder (1.59 g, 88.3%), mp > 300 C, R = 0.90 (S ), H NMR (300.0 MHz, CDCl ) δ =
f
2
3
9
.96 (2H, br, 2NH), 7.75 (1H, d, J= 9.0 Hz, ArH), 7.54 (1H, t, J= 9.0 Hz, ArH), 7.36 (1H, d, J= 6.0,
13
ArH), 7.19 (1H, t, J= 9.0 Hz, ArH), 6.48 (1H, s, ArH), 4.55, 3.45 (2H, br, NH ). C NMR (75.0 MHz,
2
CDCl ) δ= 165.5 (CO), 161.6 (Ar-CO), 145.5, 139.6, 131.3, 126.4, 122.4, 120.5, 116.8, 116.1 (Ar-C).
3
Anal. Calcd. for C H N O (203.20): C, 59.11; H, 4.46; N, 20.68. Found: C, 59.34; H, 4.18; N, 20.45.
1
0
9
3
2
2
.5.2. 2-(allyloxy)quinoline-4-carohydrazide (2)
o
1
White powder (1.2 g, 75.0%), m.p 168 C, R = 0.67 (S ). H NMR (300.0 MHz, CDCl ) δ= 9.88 (1H,
f
2
3
br, NH), 8.05 (1H, d, J= 9.0 Hz, ArH), 7.80 (1H, d, J= 9.0 Hz, ArH), 7.72-7.67 (1H, m, ArH), 7.48-
7
.43 (1H, m, ArH), 6.97 (1H, s, ArH), 6.25-6.12 (1H, m, CH=), 5.52, 5.34 (2H, 2d, J= 18.0, 12.0 Hz,
1
3
=
CH ), 5.06 (2H, d, CH O), 4.66 (2H, br, NH ). C NMR (75.0 MHz, CDCl ) δ= 165.8 (CO), 161.5
2 2 2 3
(
Ar-CO), 146.8, 144.6 (Ar-C), 133.3 (CH=), 130.5, 127.5, 125.9, 124.9, 122.1 (Ar-C), 117.8 (=CH2),
11.7 (Ar-C), 67.7 (OCH ). Anal. Calcd. for C H N O (243.27): C, 64.4; H, 5.39; N, 17.27. Found:
1
2
13 13
3
2
C, 64.02; H, 5.69; N, 17.46.
.5.3. 1-allyl-2-oxo-1,2-dihydroquinoline-4-carbohydrazid (3)
2
o
1
Yellow crystals (0.65 g, 54.2%), m.p 267-269 C, R = 0.50 (S ). H NMR (300.0 MHz, CDCl ) δ=
f
3
3
9
.90 (1H, s, NH), 7.82 (1H, d, J= 9.0 Hz, ArH), 7.63 (1H, t, J= 9.0 Hz, ArH), 7.50 (1H, d, J= 9.0 Hz,
ArH), 7.28 (1H, t, J= 9.0 Hz, ArH), 6.61 (1H, s, ArH), 6.00-5.88 (1H, m, CH=), 5.16, 5.00 (2H, 2d, J=
1
3
1
2.0, 18.0 Hz, =CH ), 4.93 (2H, d, J= 6.0 Hz, CH N), 4.63 (2H, s, NH ). C NMR (75.0 MHz,
2 2 2
CDCl ) δ= 165.4 (CO), 160.6 (Ar-CO), 144.8, 139.5 (Ar-C), 132.8 (CH=), 131.6, 127.2, 122.6, 119.6,
3
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1
17.9 (Ar-C), 117.0 (=CH ), 116.0 (Ar-C), 44.1 (NCH ). Anal. Calcd. for C H N O (243.27): C,
2
2
13 13
3
2
6
4.4; H, 5.39; N. 17.27. Found: C, 64.27; H, 5.55; N, 17.41
2
.5.4. 2-(allylthio)quinoline-4-carbohydrazide (4)
o
1
Beige powder (1 g, 83.3%), m.p 156-158 C, R = 0.64, (S ). H NMR (300.0 MHz, CDCl ) δ= 8.50
f
1
3
(
1H, d , NH↔OH), 8.09 (1H, d, J= 6.0 Hz, Ar-H), 7.93 (1H, d, J= 9.0 Hz, ArH ), 7.75 (1H, t, J= 6.0
Hz, ArH), 7.54 (1H, t, J= 6 Hz, ArH), 7.35 (1H, s, ArH), 6.10-5.95 (1H, m, CH=), 5.45, 5.15 (2H, 2d,
1
3
J= 15.0, 9.0 Hz , =CH ), 4.30 (2H, br, NH ), 4.02 (2H, d, J= 6.0 Hz, SCH ). C NMR (75.0 MHz,
2
2
2
CDCl ) δ= 165.7 (CO), 158.4 (CS), 148.3 , 141.3 (Ar-C), 134.2 (CH=), 130.7, 128.3, 126.4, 126.0,
3
1
5
22.9, 14.1 (Ar-C), 118.5 (=CH ), 32.3 (SCH ). Anal. Calcd. for C H N OS (259.33): C, 60.21; H,
2 2 13 13 3
.05; N; 16.20. Found: C, 60.32; H, 5.17; N, 16.43.
Scheme 1: The stepwise formation of the synthesized ligands 1-4.
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3
. Results and Discussion
The obtained complexes which were formed from the reaction of the target ligands (1-4) with the
M(II) ions (M= Cu, Ni and Co) were purified and characterized by using different tools, which were
depicted as follows:
3
.1.Elemental Analysis and Physical Properties:
The elemental analysis of the complexes which were formed from the ligand 1 and M(II) ions was
listed in Table 1. The postulated formula could be represented as follows: [Co(C H N O ) (H O) ]
1
0
9
3
2 2
2
2
(
NO ) , [Ni(C H N O ) (H O) ](NO ) and [Cu(C H N O ) ](NO ) .(H O) . Co(II) complexes are
3 2 10 9 3 2 2 2 2 3 2 10 9 3 2 2 3 2 2 2
formed as cream non-hygroscopic crystals, Ni(II) as ice blue crystals and Cu(II) as green crystals.
The interaction of the ligand 2 (C H N O ) with the Co(II), Ni(II) and Cu(II) ions gave the
13
13
3
2
corresponding complexes which could be formulated as: [Co(C H N O ) (H O) ](NO ) ,
1
3
13
3
2 2
2
2
3 2
[
Ni(C H N O ) (H O) ](NO ) and [Cu(C H N O ) ](NO ) .(H O) , respectively. The obtained
13 13 3 2 2 2 2 3 2 13 13 3 2 2 3 2 2 4
elemental analysis (N and M%) goes well with the postulated formula (Table 1). All the complexes
were crystalline and non-hygroscopic. Co(II) complex has brown fine crystals, Ni(II) complex gave
green crystal and Cu(II) complex has green crystals.
The complexes which derived from the ligand 3 and the target metals ions gave elemental analysis as
shown in Table 1. The obtained results revealed the following postulated formula:
[
(
Co(C H N O ) (H O) ](NO ) , [Ni(C H N O ) (H O) ](NO ) and [Cu(C H N O ) ](NO ) .
13 13 3 2 2 2 2 3 2 13 13 3 2 2 2 2 3 2 13 13 3 2 2 3 2
H O) . All the complexes have fine crystal structure and non-hygroscopic behavior. Co(II) complex
2
2
has orange color, Ni(II) complex was ice blue meanwhile Cu(II) was turquoise.
The interaction of the ligand 4 (C H N OS) with the Co(II) ions gave brown, non-hygroscopic
1
3
13
3
crystals with the molecular formula: [Co(C H N OS) (H O) ](NO ) .(H O) . Ni(II) ions gave brown
1
3
13
3
2
2
2
3 2
2
4
crystals with the formula:[Ni(C H N OS) (H O) ](NO ) .(H O) . The brown crystals also formed
1
3
13
3
2
2
2
3 2
2
2
with Cu(II) ions with the formula:[Cu(C H N OS) ](NO ) (Table 1).
1
3
13
3
2
3 2
3
.2. Conductivity of the Complexes:
The conductivity of the formed complexes was measured in DMSO (0.001 M). All the formed
-1
2
-1
complexes gave conductivity in the range 140-179 µS (ohm .cm .mol ), which indicates the
electrolytic behavior of the complexes [22], which could be formulated generally as [A](NO ) form
3
2
(
Table 1)[23–25]. Generally, the conductivity of the formed complexes has the following order:
Ligand 4 > Ligand 3 ≈ Ligand 2 > Ligand 1
Cu(II) complexes gave the lowest conductivity, meanwhile Co(II) and Ni(II) complexes were close to
each other. The obtained result is manifested in the following points:
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1
. Cu(II) complex has a structure different from the other complexes,
. Co(II) and Ni(II) complexes could have a similar structure.
2
3
.3.FTIR Spectra:
The FTIR spectra of the target ligands and their complexes were listed in Table 2 and shown in
Figures 1–4 as representative examples.
-1
Ligand 2 gave a broad and strong band centered at wavenumber 3454 cm which could be attributed
to the stretching vibrational motion for O-H group with some inter and/or intra hydrogen bond [22].
The obtained result strongly indicated the presence of some tautomerism from the type keto↔enol
-1
form. The band which appeared at 3277 cm as strong band could be due to υN-H moiety. The
-1
stretching vibrational bands which appeared at 1640 and 1604 cm as medium and strong bands,
respectively could be attributed to the stretching vibration of the C=O and C=N bonds, respectively
-1
[
26]. Strong and broad band clearly appeared for all complexes, which ranged at 3632-2700 cm ,
-1
-1
3
665-2765 cm and 3651-2804cm for Cu(II), Ni(II) and Co(II) complexes, respectively, could be
assigned as stretching vibration of the water molecules which could be present in the formed
complexes as water of coordination and water of crystallization. The broadness could be due to: (1)
the presence of strong inter and/ or intra hydrogen bond, (2) the presence of partial overlapping of the
wave number of ν and ν of the water molecules [27]. The stretching vibration band of C=O were
1
3
shifted in all formed complexes. This indicates the ligation behavior of this group in complex
formation (Table 2). The vibration bands of the nitrate group appeared at the wave number range
-
1
1
381-1396 cm as strong band, which strongly revealed the ionization nature of this group in the
-1
formed complexes [28]. The stretching vibration band of the M-O bond appeared at 586-657 cm
-
1
range for all complexes, while M-N appeared at 514-520 cm as weak band [29]. The stretching
vibration value is different from metal to another, where it depends on the electronegativity, electronic
structure and the mass of the metal ions [28].
-1
The IR spectrum of the third ligand was listed in Table 2. The band which appeared at 3438 cm as
shoulder and broad could be due to the presence of the keto↔enol tautomerism with some inter and/
-
1
or intra hydrogen bond interaction. The strong band which appeared at 3347 and 3270 cm could be
assigned as the stretching vibration band due to the NH and NH . The ν
appeared at 1634 and 1581
2
C=O
-1
-
1
-1
-1
cm as strong bands. The band which centered at 3431 cm , 3425 cm and 3439 cm for Cu(II),
Ni(II) and Co(II) complexes, respectively could be due to the stretching vibration of the water
molecules which could be present in the formed complexes. The νN-H of the ligand completely
disappeared in Cu (II) complexes or gave red shifted (decreasing in wavenumber) in Ni (II) and Co
(
II) complexes enhanced the ligation postulation of the nitrogen of the hydrazine moiety in the
complexation process. Correspondingly, the variation of the stretching vibration of the C=O, indicates
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8)

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the entrance of this group in the complexation process. The stretching vibration band, which centered
-1
at 1388, 1387 and 1379 cm as strong band for the Cu(II), Ni(II) and Co(II) complexes, respectively,
enhanced the ionic behavior of the nitrate group. The M-O and M-N were listed in Table 2 as weak
bands.
The IR spectrum of the ligand 1 gave the characteristic bands for the function groups. The broad and
-1
medium band which centered at 3438 cm could be due to the keto↔enol tautomerism. Meanwhile,
-1
-1
the NH and NH appeared at 3270 and 3202 cm . The ν
and νC=N appeared at 1653 and 1517 cm ,
C=O
2
respectively. The IR spectra of the complexes (1-Cu, 1-Ni and 1-Co) strongly enhanced the ligation
properties of the C=O and NH groups [22,27,28].
2
The IR spectra of the ligand 4 and their complexes (4-Cu, 4-Ni and 4-Co) revealed the close similarity
with the ligand 2 and their complexes (2-Cu, 2-Ni and 2-Co) (Table 2).
1
00
5
0
0
4000 3500 3000 2500 2000 1500 1000
500
-1
(cm
Wavenumber
)
Figure 1: FTIR sprum of the ligand 3.
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9)

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8
0
0
6
40
4000 3500 3000 2500 2000 1500 1000
500
-
1
Wavenumber
(cm
)
Figure 2: FTIR spectrum of compound 3-Co.
100
75
5
0
25
4000 3500 3000 2500 2000 1500 1000
500
Wavenumber
(
cm-1)
Figure 3: FTIR spectrum of compound 3-Ni.
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80
60
40
4000 3500 3000 2500 2000 1500 1000
500
-1
Wavenumber (cm )
Figure 4: FTIR spectrum of compound 3-Cu.
3
.4.Uv-Vis Spectra:
The Uv-Vis absorption spectra which were produced due to the electronic transitions from the highest
occupied molecular orbital (HOMO) to the lowest unoccupied molecular orbital (LUMO) [30], were
carried out in ethanolic solution as listed in Table 3 and showed in Figures 5-8.
Generally, the obtained spectra exhibit ligands bands due to π → π* and n → π* transitions, which in
consequently undergo some red and blue shifts on complexation. The bathochromic (red) and
hypthochromic (blue) effect strongly revealed the formation of the target complexes. The d-d
transition need extra elucidation due to the very small value of the molecular absorptivity (ε) of this
type of transition [31,32].
3
.5.Magnetic measurements
Magnetic susceptibilities of metal complexes were investigated by the Gouy method which involves
weighing a sample of the complex in the presence and absence of a magnetic field and observing the
difference in weight. The measurements were carried out using Sherwood Scientific's Magnetic
Susceptibility Balance [22]. The mass magnetic susceptibility (X ) was calculated by
g
9
Χ = LC(R – R ) / m x 10
g
o
Where L = sample length in centimeters
m = sample mass in grams
(
11)

ACCEPTED MANUSCRIPT
C = balance calibration constant (printed on the back of the instrument)
R = reading from the digital display when the sample (in the sample tube) is in the balance.
R = reading from the display when the empty sample tube is in the balance
o
The number of unpaired electrons was evaluated by magnetic susceptibility, where paramagnetic
metal complexes arise inherent magnetic moment from the spins of unpaired electrons. The effective
magnetic moment value of metal complex, ꢀ , was given by the sum of spin moments:
eff
ꢀeff = ꢀspin
=
=
where spin moments S = 1/2 n and n is the number of unpaired electrons [33,34].
Also, the effective magnetic moment was calculated from the molar susceptibility by the following
equation:
ꢀeff = 2.83
where X is the molar susceptibility which equal mass susceptibility multiplied by mole weight and T
M
is the absolute temperature [35–37].
The magnetic moment measurements of metal complexes are given in Table 3. The Cu (II) complexes
(
2-Cu, 3-Cu, 1-Cu and 4-Cu) have magnetic moment value lying in the range of the planar structure.
Ni(II) and Co(II) complexes have magnetic moment value in the range of the octahedral structure
Table 3).
(
2.5
2.0
1.5
1.0
0.5
0.0
Ligand 1
1
1
1
-Co
-Ni
-Cu
200
250
300
350
400
Wavelength (nm)
Figure 5: Uv-Vis spectra of the ligand 1 and its complexes.
12)
(

ACCEPTED MANUSCRIPT
4
3
2
1
0
Ligand 2
2
-Co
-Ni
-Cu
2
2
200
250
300
350
400
Wavelength (nm)
Figure 6: Uv-Vis spectra of the ligand 2 and its complexes.
4
Ligand 3
3
3
3
3
-Co
-Ni
-Cu
2
1
0
200
250
300
350
400
Wavelength (nm)
Figure 7: Uv-Vis spectra of ligand 3 and its complexes.
(
13)

ACCEPTED MANUSCRIPT
4
3
2
1
0
Ligand 4
4
4
4
-Co
-Ni
-Cu
200
250
300
350
400
450
Wavelength (nm)
Figure 8: Uv-Vis spectra of ligand 4 and its complexes.
3
.6.Thermal analysis
o
The target complexes were subjected to TG-DTA analysis in ambient temperature up to 800 C under
nitrogen atmosphere. The decomposition temperature ranges, the percentage of mass losses and the
thermal effects accompanying the decomposition process are given in Table 4–7. Representative
thermal curves TG/DTG-DTA of the complexes under consideration are given in Figures 9-11 as
representative examples and the remaining figure is presented in a supplementary file.
The thermal decomposition behavior of the complexes derived from ligand 1 was listed in Table 4.
The obtained metal % goes well with the postulated complexes formula and the residual product was
found as MO structure. The thermal decomposition of the 1-Ni was proceeding through three steps;
meanwhile 1-Cu and 1-Co were carried out through four steps. The water of crystallization was
o
liberated at DTA temperature= 62 C for 1-Cu as endothermic behavior with weight loss revealed two
moles of water. Water of coordination was liberated with the same exothermic behavior for 1-Ni and
1
-Co complexes. The weight loss in TG analysis indicates liberation 2H O. The thermal
2
decomposition of the ligand proceeds through two steps for all target complexes. The first
decomposition step has the following trend: 1-Co > 1-Ni > 1-Cu with exothermic behavior (Table 4).
The TGA/DTG and DTA thermogram of the complexes derived from ligand 2 are listed in Table 5.
The 2-Cu complex was thermally decomposed through different steps, where the first step starts at 40
o
o
o
C and finished at 100 C accompanied with DTA peak as endothermic one at 77 C. The weight loss
accompanied with step, according to the TG diagram= 9.82, which go well with the calculated value
(
14)

ACCEPTED MANUSCRIPT
which obtained from the liberation of 4 molecules from water, which classified as water of
o
crystallization. The ligand decomposition was preceded through exothermic peaks start at 173 C.
Also, liberation of the nitrate group carried out with exothermic peaks. The residue % goes well with
the calculated value of the CuO %. The 2-Ni complex liberates the two molecules from coordinated
o
water at temperature range finished at 135 C. The ligand decomposition start decomposed at DTA
o
peak= 150 C. The residue % goes well with the calculated value as NiO moiety. 2-Co complex
resemble the thermal decomposition behavior of the 2-Ni complex, where the coordinated water
liberated with weight loss % enhanced the liberation of two molecules of water. The residue %
indicates the presence of the CoO moiety [38,39]. From the obtained data, the results could be
summarized as follows:
•
2-Cu gave thermal decomposition behavior different from the 2-Ni and 2-Co, meanwhile 2-Ni
2-Co.
≈
•
•
The thermal stability of the coordinated water of 2-Ni > 2-Co.
The residual product for all complexes was MO (M = Cu, Ni and Co).
The TGA/DTG and DTA thermogram of the complexes derived from ligand 3 are listed in Table 6.
Generally, the thermal decomposition of the target complexes goes well with the same thermal
process. The liberation of the water of crystallization was carried out at DTA peak temperature= 120
o
C for the 3-Cu complex with endothermic behavior. The thermal stability of the ligand in the target
complex has the following trend: 3-Co> 3-Ni > 3-Cu. The thermal stability of the nitrate group in the
complexes has the following trend: 3-Cu> 3-Co> 3-Ni. The residual % was going well with the
postulated product formula MO (Table 6).
The thermal decomposition behavior of the complexes derived from ligand 4 was listed in Table 7.
The obtained data revealed the distinguishable properties of this ligand more than the other. Each
complex nearly has the special thermal decomposition trend. 4-Co complex gave the largest numbers
of decomposition steps meanwhile 4-Cu the lowest. The liberation of the water of crystallization need
energy has the following trend: 4-Ni ≈ 4-Co. The TG analysis indicates the liberation of 2H O for 4-
2
Ni and 4H O for 4-Co complex. The thermal decomposition of the coordinated water has the
2
following stability trend: 4-Ni> 4-Co. The residual % of 4-Cu strongly indicates the complicated
thermal decomposition process of this complex; meanwhile 4-Ni and 4-Co go well with the MO
formula. The principle difference of ligand 4 with the other ligand, is the presence of Sulphur atom in
its structure, which could play a different role in thermal reactions (Table 7) [40,41].
According to the elemental analysis, conductivity, Uv/Vis spectra, FTIR, magnetic susceptibility and
thermal analysis (DTA/TGA), could formulate obtained complexes as shown in Schemes 2-5.
(
15)

ACCEPTED MANUSCRIPT
100
TGA %
DrTGA
DTA
0.000
6
3
0
0
80
60
40
20
0
-
0.005
0
-0.010
0
100
200
300
400
500
600
700
800
o
Temperature ( C)
Figure 9: The thermogram of the DTA/TG analysis of the Complex 4-Co.
TGA %
DrTGA
DTA
100
0
.000
1
00
8
6
4
2
0
0
0
0
0
-
-
0.003
0.006
50
0
0
100
200
300
400
500
600
700
800
o
Temperature ( C)
Figure 10: The thermogram of the DTA/TG analysis of the Complex 4-Ni.
(
16)

ACCEPTED MANUSCRIPT
TGA %
DrTGA
DTA
100
60
8
6
4
2
0
0
0
0
0
0.000
-0.002
-0.004
3
0
0
0
100
200
300
400
500
600
700
800
o
Temperature ( C)
Figure 11: The thermogram of the DTA/TG analysis of the Complex 4-Cu.
(
17)

ACCEPTED MANUSCRIPT
Table 1: The physico-chemical properties of the target ligands and their complexes
Elemental analysis
N%
F.
>300 20.68 20.90 -
Conductivity
a
Compound Formula
M.wt. Color
m.p
M%
C. F.
Ω (µS)
C.
C H N O
Beige
1
1
1
1
10
9
3
2
203.20
-
-
[
[
[
Cu(C H N O ) ](NO ) .(H O)
Green
-Cu
-Ni
-Co
10
9
3
2 2
3 2
2
2
629.98
283 17.79 17.66 10.09 9.98 140
298 17.93 17.87 9.39 9.50 155
290 17.92 17.70 9.42 9.36 160
Ni(C H N O ) (H O) ](NO )
Ice blue
10
9
3
2 2
2
2
3 2
625.13
Co(C H N O ) (H O) ](NO )
Cream
10
9
3
2 2
2
2
3 2
625.37
C H N O
White
2
2
2
2
13 13
3
2
243.27
166 17.27 17.30 -
-
-
[
[
[
Cu(C H N O ) ](NO ) .(H O)
Green
-Cu
-Ni
-Co
13 13
3
2 2
3 2
2
4
746.14
110 15.02 15.21 8.52 8.37 166
170 15.89 15.95 8.32 8.64 170
135 15.88 15.63 8.35 8.22 173
Ni(C H N O ) (H O) ](NO )
Green
13 13
3
2 2
2
2
3 2
705.26
Co(C H N O ) (H O) ](NO )
Brown
13 13
3
2 2
2
2
3 2
705.50
C H N O
Yellow
3
3
3
3
13 13
3
2
243.27
267 17.27 17.13 -
-
-
[
[
[
Cu(C H N O ) ](NO ) .(H O)
Turquoise
-Cu
-Ni
-Co
13 13
3
2 2
3 2
2
2
710.11
292 15.78 15.92 8.95 8.72 151
270 15.89 15.71 8.32 8.11 177
218 15.88 15.79 8.35 8.40 169
Ni(C H N O ) (H O) ](NO )
Ice blue
13 13
3
2 2
2
2
3 2
705.26
Co(C H N O ) (H O) ](NO )
Orange
13 13
3
2 2
2
2
3 2
705.50
C H N OS
Beige
4
4
4
4
13 13
3
259.33
156 16.20 16.29 -
-
-
[
[
[
Cu(C H N OS) ](NO )
Brown
-Cu
-Ni
-Co
13 13
3
2
3 2
706.22
160 15.87 15.61 9.00 8.79 160
106 14.49 14.58 7.59 7.56 169
140 13.84 13.61 7.28 7.33 179
Ni(C H N OS) (H O) ](NO ) .(H O)
Brown
13 13
3
2
2
2
3 2
2
2
773.42
Co(C H N OS) (H O) ](NO ) .(H O)
Brown
13 13
3
2
2
2
3 2
2
4
809.69
a
-3
-1
2
-1
M.wt.= molecular weight
m.p= melting point
C= calculated
F= found
10 M in DMSO, ohm .cm .mol
(
18)

ACCEPTED MANUSCRIPT
Table 2: The most effective IR spectra of the target ligands and their complexes
Comp.
1
νO-H
νN-H
νC=O
νNO3
νM-O
νM-N
3438 br, m
3270 s
1653 s
1517 s
1653 s
-
-
-
3
202 sh
1
1
-Cu
-Ni
364-3354 br, s
3153 m
1381 s
1381 s
657
514
1
582 sh
3638-2649 br, s
1672 s, br
528 w
476 w
1
1
622 s, br
562 s
1
-Co
3645-2675 br, s
1672 br, s
1381 s
528 w
468 w
1
1
622 br, s
562 s
2
3454 s, br
3277 s
1640 m
604 s
-
-
-
1
2
2
-Cu
-Ni
3632-2700 s, br
3665- 2765 s, br
1659 s
1381 s
1394 s
657 w
630 w
514 w
520 w
1656 sh s
1
582 sh, s
2
-Co
3651-2804 s, br
1692 sh
1396 s
586 w
520 w
1
1
656 s
581 s
3
3
3
3
3438 sh.br
3347 s
1634 s
1581 s
1646 s
-
-
-
3
-
270 s
-Cu
-Ni
-Co
3431 s, br
3425 s, br
3439 s, br
1388 s
1387 s
1379 s
553 w
560 w
547 w
540 w
500 w
483 w
1
601 s
324 w
258 w
1646 s
1600 s
1648 s
3
3233 w
1
600 s
1627 s
588 s
1633 sh
4
4
3438 br,s
3296 s
-
-
-
1
-Cu
-Ni
-Co
3625-3179 br, s
1387 s
608 w
553 w
1
1
607 s
536 m
4
4
3651-3088 br, s
3632-3036 br, m
1640 sh
1381 s
1381 s
598 w
602 w
489 w
489 w
1
1
595 sh, m
543 sh, m
1633 sh
1
1
585 sh, m
543 sh, m
s= strong m= medium w= weak sh= shoulder br= broad
(
19)

ACCEPTED MANUSCRIPT
Table 3: The magnetic and electronic spectra of the ligands and their complexes
Comp.
n→π∗ and π→π∗
µeff
Postulated Hybrid
n
transition
(B.M)
Structure
orbitals
1
335, 277, 250, 229
334, 279, 228
-
-
-
-
2
1
1
1
-Cu
-Ni
-Co
1.96
Planar
dsp
1
3
2
2
332, 275, 229
332, 275, 227
2.98
4.87
Octahedral
Octahedral
sp d
2
3
3
sp d
2
2
327, 315, 273
341, 277, 227
-
-
-
-
2
-Cu
-Ni
-Co
1.80
Planar
dsp
1
3
2
2
2
2
327, 315, 273, 239
3.30
5.20
Octahedral
Octahedral
sp d
2
3
3
327, 314, 275, 240, 224
sp d
3
3
336, 277, 250
343, 231, 208
-
-
-
-
2
-Cu
-Ni
-Co
1.91
Planar
dsp
1
3
2
2
3
3
334, 276, 230, 210
334, 280, 230, 207
3.51
4.92
Octahedral
Octahedral
sp d
2
3
3
sp d
4
4
347, 334, 263, 214
350
-
-
-
-
2
-Cu
-Ni
-Co
1.82
Planar
dsp
1
3
2
2
4
4
342, 261, 214
342, 261, 214
3.25
5.08
Octahedral
Octahedral
sp d
2
3
3
sp d
(
20)

ACCEPTED MANUSCRIPT
Table 4: The thermal analysis data for the synthesized ligand 1 and its complexes
Comp. Temp.
DTA peak Peak
Mass loss %
Process
Expected
products
Residue%
Found
o
o
range ( C) temp. ( C)
Type
Found Calcd.
(
Calcd.)
1
1
1
-Cu
-Ni
30-105
62
Endo. 5.50
5.72
Water of crystallization
2H
2
O
12.00
(12.63)
CuO
1
2
3
05-205
05-378
78-504
175
347
432
225
234
443
Exo.
Exo.
Exo.
Exo.
Exo.
Exo.
52.00
13.00
20.00
5.00
51.61
12.90
4.68
Partial ligand decomposition 0.8 L
Partial ligand decomposition 0.2 L
Liberation of NO3
NO3
2H
50-225
5.76
Water of coordination
O
11.60
(11.95)
NiO
2
2
2
25-239
39-447
32.00
52.40
32.51
52.35
Partial ligand decomposition 0.5 L
Ligand decomposition 0.5 L + NO3
Liberation of NO3
Water of coordination
+
-Co
187-215
207
262
397
435
Exo.
Exo.
Exo.
Exo,
-
5.76
2H
2
O
11.40
(11.98)
CoO
2
2
4
15-266
66-433
33-449
12.83
33.00
39.6
13.00
32.50
39.33
Partial ligand decomposition 0.2 L
Partial ligand decomposition 0.5 L
Ligand decomposition +
Liberation of NO3
0.3 L + NO3
L= Total ligand content
(
21)

ACCEPTED MANUSCRIPT
Table 5: The thermal analysis data for the synthesized ligand 2 and its complexes
Comp. Temp.
DTA peak Peak
temp. ( C) Type
Mass loss %
Process
Expected
products
Residue%
Found
(Calcd.)
o
range
o
Found Calcd.
(
C)
2
2
2
-Cu
-Ni
40-100
77
173
318┐
Endo. 9.82
9.66
Water of crystallization
Partial ligand
decomposition
Ligand decomposition +
liberation of NO3
4H
0.5 Ligand
0.5 Ligand + NO3 CuO
2
O
11.50
(10.66)
1
2
00-252
52-473
Exo.
32.00 32.61
Exo.┐ 49.00 49.23
3
3
4
-
33│
40│
24┘
Exo.│
Exo.│
Exo.┘
55-135
-
5.00
5.11
Water of coordination
Partial ligand
decomposition
Ligand decomposition +
liberation of NO3
2H
O
10.00
(10.59)
NiO
2
1
1
35-158
58-513
150
392┐
Exo.
53.00 53.00
0.77 Ligand
0.23 Ligand +
NO3
Exo.┐ 33.50 33.57
Exo.┘
4
-
23┘
-Co
50-123
-
5.00
5.11
Water of coordination
Ligand decomposition
Liberation of NO3
2H
2
O
11.50
(10.62)
CoO
1
1
23-176
76-459
166
262┐
Exo.
68.50 68.96
Ligand
NO3
Exo.┐ 18.00 17.58
2
4
98│
04┘
Exo.│
Exo.┘
L= Total ligand content
(
22)

ACCEPTED MANUSCRIPT
Table 6: The thermal analysis data for the synthesized ligand 3 and its complexes
Comp. Temp.
DTA peak Peak
Mass loss %
Process
Expected
products
Residue%
Found
o
range
temp. ( C) Type
Found Calcd.
o
(
C)
(Calcd.)
3
3
-Cu
-Ni
40-147
120
181
436
Endo. 5.00
5.07
Exo. 68.00 68.51
Exo. 17.00 17.46
Water of
2H
2
O
10.50
(11.20)
CuO
1
4
47-44
4-497
crystallization
L
Ligand decomposition NO3
Liberation of NO3
50-132
-
-
5.00
5.11
Water of coordination 2H
O
11.00
(10.59)
NiO
2
1
1
32-151
51-529
139
343
Exo. 69.00 68.99
Ligand decomposition L
Exo. 18.00 17.58
Liberation of NO3
NO3
3
4
76
77
Exo.
Exo.
3-Co
50-203
128
223
357
Endo. 5.00
Exo. 69.50 68.96
Exo 17.50 17.58
5.11
Water of coordination 2H
2
O
10.00
(10.62)
CoO
2
2
03-239
39-423
Ligand decomposition L
Liberation of NO3
NO3
L= Total ligand content
(
23)

ACCEPTED MANUSCRIPT
Table 7: The thermal analysis data for the synthesized ligand 4 and its complexes
Comp. Temp.
DTA peak Peak
Mass loss %
Process
Expected
products
Residue%
Found
o
o
range ( C) temp. ( C)
Type
Found Calcd.
(
Calcd.)
4
4
-Cu
-Ni
40-273
184
402
505
106
142
261
558
-
Exo.
28.00
27.91
30.11
17.56
4.66
Partial ligand decomposition
Partial ligand decomposition
Liberation of NO3
0.38 L
0.41 L
NO3
22.00
2
4
73-475
75-588
Endo. 30.00
CuS (13.54)
CuO (11.26)
10.00
Exo.
Exo.
Exo.
Exo.
Exo.
-
18.00
5.00
32-112
Water of crystallization
Water of coordination
2H O
2
1
1
3
12-155
55-380
80-620
5.50
4.66
2H O
(9.66)
2
38.00
35.00
9.00
37.55
34.81
8.90
Partial ligand decomposition
0.56 L
NiO
Ligand decomposition + liberation of NO3 0.28 L + NO3
4
-Co
50-108
Crystallization Water
4H O
2
9.00
1
1
2
4
08-130
30-279
79-436
36-624
14
Exo.
Exo.
Exo.
Exo.
5.00
4.45
Coordination Water
2H O
(9.25)
CoO
2
225
340
557
12.00
26.00
32.00
12.17
26.26
31.98
Partial ligand decomposition
Partial ligand decomposition
0.4 L
0.41 L
Ligand decomposition + liberation of NO3 0.26 L + NO3
L= Total ligand content
(
24)

ACCEPTED MANUSCRIPT
Scheme 2: The postulated structure of the metal complexes of the ligand 1
(
25)

ACCEPTED MANUSCRIPT
Scheme 3: The postulated structure of the metal complexes of the ligand 2
(
26)

ACCEPTED MANUSCRIPT
Scheme 4: The postulated structure of the metal complexes of the ligand 3
(
27)

ACCEPTED MANUSCRIPT
Scheme 5: The postulated structure of the metal complexes of ligand 4
.7.The Density Function Theory (DFT)
3
The DFT was carried out to calculate and explore the effect of HOMO and LUMO energy on
the compounds which were previously calculated in MM2 level (as representative examples
for the thesis compounds). Each studied compound was undergoing energy minimization
using the force field parameter MMFF94x. The simulation process was carried out using SCF
(
self-consistent field method, also named Hartree–Fock method) calculation. MOPAC system
was used with Hamiltonian PM3 using RHF (restricted Hartree-Fock method).
(
28)

ACCEPTED MANUSCRIPT
3.7.1. The Density Function Calculation for Compound 1
As shown in Figure 12 and listed in Table 8, the application of the DFT on compound 1 gave
representative data. The electron density map indicates the cylindrical density on the aromatic
rings with branched chain nearly present out of plan of aromatic rings. The density= 0 at the
center of the rings (Figure 12.B). The view of the electron density map plays an important
role in selecting the receptor in the drug design process. The π-π stacking and interaction
could be proceeded through the rich electron density poses [42–44]. The HOMO and LUMO
orbitals gave some hints about the target orbitals which were involved in the electronic
migration process that was intricate in the excitation–relaxation pathway. The large number of
occupied and unoccupied orbitals revealed the lower energy which needed to promote
electron from one level to another. The energy of the HOMO, LUMO and ∆E was listed in
Table 8. The dipole value (4.00 D) indicates the polarity of compound 1, which is
unfavorable for drug behavior [45].
A
B
C
D
Figure 12: The DFT simulation for the compound 1
[
A] 3D view, [B] Electron density map, [C] HOMO and [D] LUMO
(
29)