Synthesis, Structural characterization, thermal, molecular modeling and biological studies of chalcone and Cr(III), Mn(II), Cu(II) Zn(II) and Cd(II) chelates

Article abstract of DOI:10.1016/j.molstruc.2020.128742

A number of new Cr(III), Mn(II), Cu(II) Zn(II) and Cd(II) chelates of (E)-3-(4-(dimethyl-amino)phenyl)-1-(pyridin-2-yl)prop-2-en-1-one were synthesized. The structures were elucidated by elemental and thermal analysis as well as spectral techniques (mass, IR, and electronic spectra) and magnetic measurements. The IR data suggested that the investigated chalcone acted as a bidentate ligand via the O and N atoms of the C[dbnd]O and C[dbnd]N groups, respectively. The spectral plus magnetic data revealed the formation of octahedral structures for all chelates while Cu(II) chelate has the square planar geometry. The kinetic and thermodynamic parameters of the thermal decomposition stages have been evaluated. Molecular orbital calculations have been performed to confirm the geometry of the isolated compounds. The in vitro antimicrobial activities of the chalcone and its metal chelates have been performed against some bacterial strains. The data indicated that all the metal chelates demonstrated a higher activity than the free chalcone. The anticancer activity of the mentioned metal chelates is evaluated against MCF7 cell. These compounds exhibited a moderate and weak activity against the tested cell line. The results were correlated with the experimental data.

Full text of DOI:10.1016/j.molstruc.2020.128742

Journal Pre-proof
Synthesis, Structural characterization, thermal, molecular modeling and biological
studies of chalcone and Cr(III), Mn(II), Cu(II) Zn(II) and Cd(II) chelates
Tarek A. Fayed, M. Gaber, Marwa El-Nahass, H.A. Diab, Mohammed M. El-Gamil
PII:
S0022-2860(20)31067-X
DOI:
https://doi.org/10.1016/j.molstruc.2020.128742
MOLSTR 128742
Reference:
To appear in: Journal of Molecular Structure
Received Date: 17 March 2020
Revised Date: 15 June 2020
Accepted Date: 22 June 2020
Please cite this article as: T.A. Fayed, M. Gaber, M. El-Nahass, H.A. Diab, M.M. El-Gamil, Synthesis,
Structural characterization, thermal, molecular modeling and biological studies of chalcone and
Cr(III), Mn(II), Cu(II) Zn(II) and Cd(II) chelates, Journal of Molecular Structure (2020), doi: https://
doi.org/10.1016/j.molstruc.2020.128742.
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Credit Author Statement
1. Tarek. A. Fayed, Professor of Physical Chemistry, Chemistry
Department, Faculty of Science, Tanta University, Egypt. His research
interests include the design of optical chemical sensors for selective
discrimination of toxic metal ions.
2. M.Gaber, Professor of Inorganic Chemistry, Chemistry Department,
Faculty of Science, Tanta University, Egypt. His research interests include
synthesis and characterization of ligands and their metal complexes.
3. Marwa N. El-Nahass, Associate Professor of Physical Chemistry,
Chemistry Department, Faculty of Science, Tanta University, Egypt. Her
interests include the design of chemosensors for optically selective, sensing
and colorimetric detections of pollutants for environmental cleanup of
toxic heavy metal ions.
4. H. A. Diab, Ph.D student, Chemistry Department, Faculty of Science,
Tanta University, Egypt
5. Mohammed M. El-Gamil, recieved his Ph.D from Chemistry Department.
Faculty of Science, Tanta University, Egypt. He works at Department of
Toxic and Narcotic Drug, Forensic Medicine, Mansoura Laboratory,
Medico legal Organization, Ministry of Justice, Egypt.

1
Synthesis, Structural characterization, thermal, molecular modeling and
biological studies of chalcone and Cr(III), Mn(II), Cu(II) Zn(II) and Cd(II)
chelates
Tarek A. Fayed*a, M. Gaber*,a, Marwa. El-Nahassa, H. A. Diaba, Mohammed M. El-Gamilb
aDepartment of Chemistry, Faculty of Science, Tanta University, 31527, Tanta, Egypt.
bDepartment of Toxic and Narcotic Drug, Forensic Medicine, Mansoura Laboratory, Medico legal
Organization, Ministry of Justice, Egypt.
Abstract:
A number of new Cr(III), Mn(II), Cu(II) Zn(II) and Cd(II) chelates of (E)-3-(4-
(dimethyl-amino)phenyl)-1-(pyridin-2-yl)prop-2-en-1-one were synthesized. The
structures were elucidated by elemental and thermal analysis as well as spectral
techniques (mass, IR, and electronic spectra) and magnetic measurements. The IR
data suggested that the investigated chalcone acted as a bidentate ligand via the O
and N atoms of the C=O and C=N groups, respectively. The spectral plus magnetic
data revealed the formation of octahedral structures for all chelates while Cu(II)
chelate has the square planar geometry.The kinetic and thermodynamic parameters of
the thermal decomposition stages have been evaluated. Molecular orbital calculations
have been performed to confirm the geometry of the isolated compounds. The in
vitro antimicrobial activities of the chalcone and its metal chelates have been
performed against some bacterial strains. The data indicated that all the metal chelates
demonstrated a higher activity than the free chalcone. The anticancer activity of the
mentioned metal chelates is evaluated against MCF7 cell. These compounds exhibited
a moderate and weak activity against the tested cell line. The results were correlated
with the experimental data.
Keywords: Chalcone; Metal chelates; Thermal behavior; Antimicrobial, Molecular
modeling, Anticancer.
* E-mail:
mabuelazm@science.tanta.edu.eg, tfayed2013@science.tanta.edu.eg,
marwa.elnahas@science.tanta.edu.eg.

2
1. Introduction
Chalcones are a class of flavonoid natural products consisting of two aryl rings linked
by α,β-unsaturated ketone moiety. Chalcones have proved to be versatile extensive
applications in wide ranging of biological area such as antimalarial, antibacterial,
antitumor, antioxidant, anti-inflammatory,antihyperglycemic,and anti-HIV [1-8]. This
class of compounds had been extensively used as fluorescent probes for metal ions
detection [9-11] or DNA [12]. Chalcone compounds played animportant role in the
development of coordination chemistry, as they readily form stable chelates with most
transition metals.Thus, the chalcone metal chelates and related compounds have been
studied, due to their interesting behavior in catalytic and biological applications [13-
22].
In continuation to our research which aimed at synthesis and characterization of
chalcones and their chelates [23-27], Cr(III), Mn(II), Cu(II), Zn(II) and Cd(II)
chelates of chalcone compound namely, (E)-3-(4-(dimethylamino)phenyl)-1-(pyridin-
2-yl)prop-2-en-1-one (Structure 1) have been prepared. The synthesized chalcone and
its metal chelates have been characterized by different techniques like elemental
analyses, spectral studies, TGA, magnetic and conductance measurements. In vitro
antimicrobial and anticancer activities of the free chalcone and its metal chelates
involved in this study have also been assessed. Molecular orbital calculations have
been performed for the investigated metal chelates.
2. Experimental
2.1. Materials
All compounds used in the present study were of pure grade available from BDH,
Aldrich or Sigma. The metal salts, Mn(CH3COO)2.4H2O, Cr2(CH3COO)4(H2O)2,
Cd(CH3COO)2, Cu(NO3).3H2O, Zn(CH3COO)2.2H2O, and ZnCl2 were used. The
solvents used for the spectral study were spectroscopic grade from Aldrich.
Section 2.2. Preparation of solid compounds
The titled chalcone, (E)-3-(4-(dimethylamino)phenyl)-1-(pyridin-2-yl)prop-2-en-1-
one structure was prepared and characterized as previously described [25].
For the preparation of metal complexes, firstly, a hot methanolic solution of chalcone
compound (0.01 mol & 20 ml) was prepared. Then a hot methanolic solution (0.01

3
mol & 20 ml) of the hydrated metal salts was added. The resulting solutions were
refluxed under stirring for 4 hrs. The solid products thus separated out on hot, filtered
off, washed several times with methanol and finally dried in a vacuum desiccator over
anhydrous calcium(II) chloride.
2.2.
Physical measurements
Perkin-Elmer 2400 CHN Elemental analyzer were performed for the elemental
microanalysis of the prepared compounds in the microanalytical center, Cairo
University. The Perkin-Elmer 1430 IR spectrophotometer was used for recording the
Infrared spectra (as KBr discs) within the range 4000-200 cm-1. TheNujol mull
electronic spectra have been measured using a Shimadzu UV-Vis 240
spectrophotometer.The magnetic susceptibility of the solid chelates was carried out at
room temperature by the Gouy's technique for magnetic susceptibility instrument.The
Schimadzu TG-50 thermogravimetric analyzer was used for the thermogravimetric
analysis (TGA) of the solid chelates with heating rate 10°C /min under nitrogen
atmosphere, in the range 25-800°C.
2.3. Quantum chemical computations
The DFT computations with periodic boundary environments were accomplished
applying the well-known DMol3 module [28], by means of Materials Studio set [29].
The tasks were utilized as a part of combination together with the specific dual
mathematical and polarization principle set DNP that is precise as Gaussian basis sets
[30-32]. The RPBE (GGA) functions [33] is up to now the greatest exchange-
correlation function [34] is applied to consider the exchange properties of the
electrons.
2.4. Antimicrobial activity
For screening the antimicrobial activity for the tested chelates disc diffusion method
was employed [35].
Freshly prepared spore suspension of different test microorganisms (0.5ml of
about 106 cells/ml) was mixed with 9.5ml of melting sterile Sabouraud's dextrose
medium (for fungi) or nutrient agar medium (for bacteria) at 45°C, poured on sterile
Petri dishes, and left to solidify at room temperature. Regular cellulose filter paper

4
discs of 6 mm diameter were prepared under aseptic conditions. Each disc was
saturated with 20 mg of each tested suspended material. For each test three replicas
were made. All plates were incubated at 27°C for 48 hours for fungi, and at 32°C for
24 hrs for bacteria. The average diameters of inhibition zones were recorded in
millimeters. All experiments were carried out in triplicate and the mean results are
evaluated.
2.5. MIC determination
Half-fold serial dilutions were made for selected chelates in order to prepare
concentrations of 6.25, 12.5, 25, 50 and 100 mg/ml in distilled water, zero
concentration was considered as a negative control. A previously prepared pure spore
suspension of each test microorganism (0.5ml of about 106 cells/ml) was mixed with
9.5 ml of each concentration in sterile test tubes, incubated at 27°C for 3 days for
fungi, and at 32°C for 24 hours for bacteria, then optical density of growth was
measured by spectrophotometer (Optima SP-300, Japan) at 620 nm for each
incubated mixture, results were represented graphically, and MIC was recorded for
each tested material [36].
2.6. Measurement of Potential cytotoxicity
The human cancer cell line used for in vitro screening experiment is breast cancer
cell line (MCF7). It was obtained frozen in liquid nitrogen (-180oC) from the
American Type Culture Collection. The tumor cell lines were maintained in the
National Cancer Institute, Cairo, Egypt, by serial sub-culturing. Potential
cytotoxicity of the compounds was tested using Skehan method [37]. Cells were
plated in 96-multiwell plate (104 cells/well) for 24 hrs before treatment with the
compound to allow attachment of cell to the wall of the plate. Different
concentration of the compounds under test (0, 5, l0, 12, 25 and 50 µg/ml) were
added to the cell monolayer triplicate wells were prepared for each individual dose.
Monolayer cells were incubated with the compounds for 48 h at 37 °C and in
atmosphere of 5% CO2. After 48 h, Cells were fixed, washed and stained with Sulfo-
Rhodamine-B stain. Excess stain was washed with acetic acid and attached stain was
recovered with Tris EDTA buffer. Color intensity was measured in an ELISA reader.
The relation between surviving fraction and drug cone is plotted to get the survival
curve of each tumor cell line after the specified compound. An Elisa reader (TECAN

5
SUNRISE), Potential cytotoxicity of the compounds was measured in
(Pharmacology Unit, Cancer Biology Department, National Cancer Institute, Cairo
University). Doxorubicin was used as standard cytotoxins.
3. Results and discussion
3.1. Characterization of the investigated chalcone and its metal chelates
The stoichiometry and formulation of the investigated chalcone, namely; (E)-3-(4-
(dimethylamino)phenyl)-1-(pyridin-2-yl)prop-2-en-1-one and its metal chelates,
[CrL2(OAc)2].2H2O.AcO, C1, [MnL2(OAc)2].2H2O, C2, [CuL2].2NO3.H2O, C3,
[ZnL2(OAc)2].H2O, C4, [ZnL2Cl2]. H2O, C5, and [CdL2(OAc)2], C6 are based on
their elemental, molar conductivity and IR spectral data. The results of elemental
analysis and molar conductance are collected in Table 1. The isolated solid chelates
are stable in air and soluble in DMF and DMSO. The low molar conductance values
of all chelates except C3-Chelate (C3) revealed that these chelates are non-
electrolytes in DMF [38]. The presence of Cl- ions outside the coordination sphere
was confirmed by the chemical reaction with AgNO3 where the white precipitate of
AgCl was observed. The addition of FeCl3 solution to the acetato chelates solution
gave the red brown coloration, confirming the presence the of acetate ions outside the
coordination sphere. Our efforts to obtain crystalline samples of the compounds of X-
ray crystal structure were unsuccessful, we decided to carry out molecular modeling
studies in order to gain a better understanding of the structures of the metal
complexes.
3.2. IR spectra
In order to study the binding mode of chalcone to the metal ions, the IR spectrum of
the free chalcone was compared with the spectra of the corresponding metal chelates.
The important infrared bands exhibited by the organic chalcone and its chelates are
given in Table 2. A cursory glance on the data reported in Table 1, it was found that
the strong and intense chalcone band at 1648cm-1 which was due to υC=O, showed shift
to lower frequencies (40-62 cm-1) in the case of chelates. This shift is due to
coordination of carbonyl oxygen to the metal center. The coordination of oxygen
atom to the metal center has been supported by the appearance of non-chalcone bands

6
within the range 520-596 cm-1, due to υM-O. The υC=N of the pyridine ring of the free
chalcone appeared at 1519 cm-1, was shifted to higher value on chelate formation, due
to the coordination of nitrogen atom to the central metal ion. This observation was
confirmed by the appearance of a new band (υM-N) at 403- 447cm-1.The presence of
lattice or coordinated water molecules in metal chelates has been indicated by the
band appearing within the range 3424-3338cm-1, corresponding to υOH of water
molecules. The IR spectrum of C3-chelate exhibits three bands at 1460 (υ5), 1375
(υ1) and 1222 (υ2) cm-1 corresponding to monodentate coordination of nitro group
[39]. New two bands appearing in the spectra of chelates (C1-C4) located within the
ranges 1444-1477and 1315-1330cm-1 are assigned to υCOO (asy) and υCOO(sym),
respectively. The difference between these two bands (Δυ)indicated the coordination
nature of the acetate as a mondentate chalcone [40].
3.3. Electronic spectra and magnetic moments
The magnetic moment C1-chelate (μeff=3.77 BM) corresponded to the spin only
value for three unpaired electrons due to the absence of any orbital contribution [41].
The electronic spectrum of C1-chelate shows bands at bands at 17391and 25317 cm-
1assignable to 4A2g → 4T2g (F) ν1 and4A2g → 4T1g (F) ν2,respectively,in an octahedral
geometry [42].The three spin allowed transitions of Cr(III) in an octahedral field are
as follows:
4
4
4
4A2g (F)→4T2g(F)(ν1), A2g (F) → T1g(F)(ν2),4A2g (F) → T1g(P)(ν3).
The ν1transitions is a direct measurement of the chalcone field parameter
10Dq.From ν1 and ν2, the value of B and β can be calculated.The B value is calculated
by [43]
2
2
B =[2ν1 -3 ν1 ν2+ ν2 ][15 ν1-27 ν1]
and the value of β is computed is B=(B│BO) where BO =918 cm-1.
The calculated values of Dq (1786 ),B , β and ν2 ∕ ν1 values as well as the
magnetic moments confirm an octahedral environment.
B =835.4
β=0.91 ν2 ∕ ν1=1.456
ν1=10Dq
The Nujol mull spectrum of C2-chelate exhibited four absorption bands at
17857, 24390, 28571,and 29412 cm-1. These bands may assigned to the transition:
4
6
4
4
6A1g → T1g (4G), A1g→ Eg,4A1g → (4G) (10B+5C),6A1g → Eg (4D) (17B+5C)

7
and6A1g
→
4T1g (4p) (7B+7C),respectively, corresponding to the octahedral
geometry.The second and third transitions are free from the crystal field splitting [44].
Thus, the parameters B and C were calculated from these transitions. The calculated
Dq, B, C and B are 1786, 597, 3684 cm-1 and 0.76, respectively. The value of β
indicated the appreciable covalent character of metal chalcone σ-bond. The magnetic
properties calculated for C2-chelate show strikingly subnormal values (2.43 BM) has
been ascribed to anti-ferromagnetism.
The effective magnetic moment value of C3-chelate (1.92 BM) indicated that
Cu(II) chelate is monomeric in nature and the absence of Cu-Cu interaction. C3-
chelate shows an intense broad band at 16667 cm-1which may be assigned to2B1g →
2Eg. This suggest the distorted octahedral geometry for C3-chelate. The broadness of
this band may be due to Jahn-Teller distortion of the octahedral geometry [45]. The
band observed at 28735 cm-1 refers to chalcone-metal charge transfer transition.
3.4. Thermal analysis
The thermal behavior of metal chelates was studied by means of TGA techniques. The
data including the stages of decomposition, temperature ranges, peak temperatures,
decomposition product loss, found and the calculated mass loss percentages are listed
in Table 3. The obtained data indicated that all the metal chelates underwent thermal
decomposition within two, three or four stage decomposition processes.
C1-chelate decomposed in four successive decomposition steps. The first step
appeared within the temperature range 28-65oC which assigned to the loss of lattice
water. The second step appeared within the range 113-218oC was assigned to the
elimination of lattice OAc anion. The third step of decomposition appeared within the
ranges 218-311oC, corresponded to the elimination of coordinated OAc anion. The
last step of decomposition (311-4420C) corresponded to further decomposition of the
organic chalcone. The final product of decomposition left behind assigned as the
thermally stable Cr2O3 +C.
The metal chelates C2-C5 gave three-stage decomposition processes. The first
step of decomposition appeared within the temperature ranges19-118, 24-75, 24-80
and 25-80oC, respectively and assigned to the loss of lattice water. The second step
appeared within the temperature ranges 128-274, 171-226, 116-243, and 161-234oC
for chelates C2, C3, C4 and C5, respectively, corresponding to the loss of coordinated
anions. The third step of decomposition appeared at temperature ranges 282-491, 226-

8
384, 243-536 and 234-656oC for chelates C2,C3, C4, C5, respectively, due to the
decomposition of organic chalcone and resulting in the formation of MnO, CuO +
2Cu, Zn and ZnO, as final product for chelates C2,C3, C4 and C5, respectively.
The metal chelate C6 gave two-step decomposition diagram. The first one of
decomposition within the temperature ranges 87-258oC corresponded to the loss of
coordinated acetate anion. The last one of decomposition within the temperature at
258-630o Ccorresponded to the further decomposition of the organic chalcone with the
formation of CdO as a final product.
The kinetic parameters of activation energy (E), reaction order (n) and Arrhenius
pre-exponential factor (A) as well as the thermodynamic parameters were calculated
from the integral method proposed by Coats-Redfern [46], Figure S1
The thermodynamic parameters of activation (ΔH*, ΔS* and ΔG*) were estimated
according to the previous methods with the aid of the following expressions:
ΔH*= E –RT, ΔS* =R ln ( hA /KBT),
ΔG* = ΔH* - TΔS*
where ΔH* is the activation enthalpy (kjmol-1), ΔS* is the activation entropy
(Jmol-1k-1), ΔG* is the Gibbs activation free energy (kjmol-1), h is the Plank constant,
KB is the Boltzmann constant and T is the observed peak temperature.
From the results listed in Table 4, one can pointed out the following remarks:
i.
The thermodynamic parameters (∆H*, ∆G*, and ∆S*) of the decomposition
steps are affected by the nature of the metal ion in the formed chelate.
ii.
iii.
iv.
The positive sign of
endothermic processes.
The high values of E revealed high stability of the chelates due to their
covalent bond character.
∆H* indicates that the decomposition stages are
The positive sign of ∆G* for most investigated chelates revealed that all the
decomposition steps are non-spontaneous processes. Also, the values of ΔG*
increases significantly for the subsequent decomposition stages of a given
chelate. This is due to increasing the values of TΔS from one step to another
which overrides the values of ΔH*.
v.
The negative values of entropy of activation indicated that the activated
chelates have a more ordered structure than the reactants.
3.5. Molecular orbital calculations
3.5.1. IR analysis
Theoretical and experimental IR spectra Figure S2 were scaled to produce the
spectroscopic signs of chalcone which displays that υC=O band (measured: 1648 cm-

9
1, predicted: 1660 cm-1) and υC=N band (measured: 1519 cm-1, predicted: 1578 cm-1).
The small differences among the measured frequencies is due to the predicted
spectrum was performed in vacuum, while the measurements were refined for solid
state. The lower symmetry is the main reason for the chelateity of the vibrational
modes of the investigated chalcone. Especially, torsion, all plane modes are difficult
to allocate due to decipher by the ring modes besides the imitative. Nevertheless, the
existence of some obvious vibrations supportive to depict in the obtained figure.
3.5.2.Geometry optimization
For the optimized structural models, Figures S3-S9, inspection of the bond distances
and angles Tables 5 and 6, the following remarks could be outlined:
1. The active groups (C=O and C=Npy) are elongated upon coordination with metal
ion. This is referred to the formation of M-N and M-O bonds [27], which let the
C=N and C=O bonds become weaker.
2. The M-N and M-O bond distances are in a good agreement with the sum of
covalent radii for M and N or O atoms and similar to values repeated earlier [47].
3. In all chelates, the bond distances of M-Cl and/ or M-OAc are longer than M-N
and M-O.
4. The length of Zn-Cl bond in chelate C5 are longer than that of Zn-OAc bond in
C4 chelate.
5. The bond angles of C1, C2, C4, C5 and C6 are similar to that reported for an
octahedral chelate with d2sp3 or sp3d2 hybrid orbitals and a square planar
geomtery with sp2d hybrid orbitals [48] for C3 chelate.
3.5.3. Chemical reactivity
3.5.3.1. Global reactivity descriptors
Highest Occupied Molecular Orbitals "HOMO level" is defined as is the one which
essentially shows an electron donation behavior. While, the Lowest Unoccupied
Molecular Orbital "LUMO" is one which significantly acts as an electron acceptor.
Both named frontier molecular orbitals (FMOs) (Figures 1-7, supplementary
materials) estimate the electric optical properties, electronic transitions and kinetic
stability [49]. The FMOs hypothesis anticipate sites of coordination (electrophilic
attack) on an aromatic compound. The interaction between HOMO of one moiety
with LUMO on another one is a major reason in most of the reactions. We can

10
demonstrate from the computation that the oxygen of the C=O group have the largest
values of molecular orbital coefficients showing that it is a suitable site of chelation.
The energy gap (ΔE= EHOMO - ELUMO), chemical descriptors as softness (S),
hardness (η), electronegativity (χ), chemical potential (μ) and (electrophilicity) (ω),
softness (ϭ) and additional electronic charge (ΔNmax) for the isolated compounds was
done as illustrated in Table 7. These descriptors can be estimated using the equations
described previously [50], as well as the inverse value of the global hardness, (which
is designed as the softness, ϭ , ϭ =1/ η) and the maximum number of electrons
transferred in a chemical reaction (ΔNmax=- μ /η), have been calculated as mentioned
previously [51]:
According to the obtained results as summarized in Table 8, it was exhibited that:
i. The EHOMO and ELUMO are almost negative showing the stability of the isolated
compounds [52, 53].
ii. Gutmann’s variation rules, "the bond strength increases as the neighboring bonds
become weaker" such as found by Linert et al. [54]. This interpretation agrees
well with the resultant as the increase of the EHOMO is convoyed by a weakness
(elongation) of the metal–chalcone bond, which prompts a reinforcing (shortness)
of the sites next to the metal chalcone centers.
iii. A hard molecule is represented by large HOMO-LUMO difference, while a soft
and more active framework has a small energy difference. Chemical potential 'μ'
that estimates the escaping capability of electrons from its equilibrium framework
diminishes as follow C2 (-3.027) > C1 (-3.076) > chalcone (-3.608) > C3 (-3.647)
> C4 (-3.758)> C5 (-3.804)> C6 (-3.811).
iv. The importance of η and ϭ is to measure the molecular stability and reactivity. In a
chelate formation system, metal ions are Lewis acid (soft acids) and thus Lewis
base (soft base) chalcones are most effective for chelate formation. Accordingly, it
is concluded that the investigated chalcone with a proper ϭ value has a good
tendency to chelate metal ions effectively [55].
v. ΔNmax is a reactivity index that measures the stabilization in the energy of the
compound. The calculation of ΔNmax displayed that C1 and C2 have the higher
values (14.578 e and 12.480 e), respectively than chalcone and other chelates

11
which confirm that both chelates C1 and C2 have the higher facility to accept
electrons (electrophiles).
The calculations of the total energy, Table 8, revealed that the increase of the
value of the calculated binding energy of chelates compared to that of the chalcone
indicates that the stability of the formed metal chelates is higher than that of chalcone.
The dipole moment values of the chelates are larger than the chalcone value except
the dipole moment of chelates (C3) and (C4) has a lower value than that of chalcone.
The structure activity relationship studies were investigated to correlate the
antimicrobial properties of the studied compounds that related to physico-chemical
properties. The dipole moments are the property of interest which gives some insight
on the degree of hydrophobicity/hydrophilicity of the compounds. As dipole moment
decreases the polarity decreases. Thus, the lipophilic nature of the compound
increases, which favors its permeation through the lipid layer of the microorganism,
then destroying them.
3.5.3.2. Local reactivity descriptors
The most relevant local descriptor of reactivity is the Fukui function (FF). The Fukui
function shows the propensity of the electronic density to deform at a given position
upon accepting or denoting electrons [56-58] which are more prone to undergo a
nucleophilic or an electrophilic attack, respectively. The Fukui function is defined as
[56];
f (r) = ꢀꢁ(ꢂ) ꢄ
ꢀꢃ
where ρ(r) is the electronic density, N is the number of electrons and r is the
+
external potential exerted by the nucleus. The local (condensed) Fukui functions (f k
,
-
o
f k , fk ) are calculated using the following equations:
+
f k = [qk(n+1) – qk(N)]
for nucleophilic attack
for electrophilic attack
for radical attack
-
f k = [qk(N) – qk(N-1)]
o
fk = 1/2 [qk(N+1) +qk(N-1)]
Where qk is the atomic charge (evaluated from Mulliken population analysis,
electrostatic derived charge, etc.) at the kth atomic site is the neutral (N), anionic
(N+1) or cationic (N-1) chemical species.
+
-
o
+
-
o
Also local softness(Sk , Sk , Sk ) and electrophilicity indices (ωk , ωk , ωk ) are
calculated [59] using the following equations:

12
+
+
-
-
o
o
Sk =S f k ,
Sk =S f k
,
Sk =S fk
+
+
-
-
o
o
ωk =ω f k ,
ωk =ω f k
,
ωk =ω fk
Where +, -, 0 signs show nucleophilic, electrophilic and radical attack
respectively.
-
o
The reactivity indexes (f k +, f k , fk ) are directly disturbed with the selectivity
of the molecule to specific chemical events. The Fukui functions are calculated for
chalcone and its chelates as shown in Tables (S1-S7, supplementary materials). The
ordering of the nucleophilic, electrophilic and radical attack sites for chalcone
chalcone and its chelates is shown in Table 9. It is clear that the substitutions of OAc
group and Cl atom in the chelates leads to a redistribution of electron density.
From the values reported in Table S1, supplementary materials
,
the reactivity
-
order for the nucleophilic case as O(14)>N(18)>C(16). The calculated f
value
k
predicts that the possible sites for electrophilic attack is O(14)>C(2)>C(13) site and
the radical attack was predicted as O(14)>N(18)>C(20) site. t has been found that the
i
+
-
o
results for chalcone predict the highest f k , f k and f k value for O(14) indicates the
most favored site for all attacks. Thus, a profound dual descriptor Δf(r) which is the
difference between the nucleophilic and electrophilic Fukui functions is explained by
the following equation [60]:
+
-
Δf(r)= fk - f k
If Δf(r)>0, then the site is favored for a nucleophilic attack, whereas If Δf(r)<0,
then the site is favored for an electrophilic attack. So, the calculation of Δf(r) for
O(14) is smaller than zero indicate that O(14) is most favored site for electrophilic
+
attack. The reflection of the reactive sites by Sk for chalcone and its chelates are
found almost identical to f +. Even though the values are numerically less, the
k
+
ordering of the reactivity for Sk has not changed.
3.5.4. Molecular electrostatic potential (MEP)
It is considered as a graph of electrostatic potential charted onto the constant electron
density surface. It is additionally remarkably valuable in research of sub-atomic
structure with its physiochemical property association and hydrogen bonding
interactions [61-63]. The electrostatic potential V(r) at a given point r (x, y, z) is
characterized as a function of the interaction energy between the electrical charge
produced from the electrons, nuclei and protons placed at r [64]. Calculation of

13
electrostatic potential is feasible for atoms utilizing the Γ-point and various k-points.
In the current investigation, 3D plots of molecular electrostatic potential (MEP) of
chalcone and its metal chelates (Figures 8-14) have been figured. The largest negative
part, which desired site for electrophilic attack indications as red covering, the largest
positive area that desired site for nucleophilic attack designated by the blue color. The
potential decreases as follow: red < green < blue, where blue demonstrates the most
favored site for the attraction while the red one reveals the greatest site for the
repulsion. Areas having the negative potential are over the electronegative molecules
while the regions having the positive potential are over the hydrogen atoms.
3.5.5. Mulliken atomic charges
Mulliken atomic charge estimation of chalcone and its chelates, Figure 15 and
Tables S8-S14 in the supplementary materials shows a significant role in the
procedure of theoretical estimation of the molecular framework. Figure 15 explains
the charge distribution of chalcone. Oxygen and nitrogen atoms having negative
values due to their giving capacity. In contrast, hydrogen atoms and most of carbon
atoms displayed positive values because of its accepting capacity. According to the
above results, the structures of the chelates were shown in Scheme 1.
3.6. Biological screening
The investigated metal chelates, C1-C6 were evaluated for their antimicrobial activity
in comparison with the organic chalcone using agar diffusion technique [35]. The
tested organisms are Gram-negative bacteria (E. coli),Gram-positive bacteria ( S.
aureus) and Fungi (C. albicans&A. niger). The screening results are summarized in
the Table 10 and represented in Figure S10. Generally, the investigated chelates have
lower activity than the chalcone.
In the present case, the activity is dependent on the central metal ion and its ability
to diffuse into the cell membrane of the organism. The antimicrobial activity of the
chelates can be ordered as C5> C1 > C2, suggesting that the lipophilic behavior
increases in the same order. Zn(II) chelate had a higher activity against the bacteria
and fungi strains. C5 and C2 chelates showed better antimicrobial activity against
Gram negative bacteria. Chalcone and its C1 chelate showed a highest activity
towards positive bacteria.

14
The variation in the activity of different chelates against different microorganisms
depends either on the impermeability of the cells of the microbes or differences in
ribosomes in microbial cells [65]. The data listed in Table 10 indicated that all the
tested compounds showed a moderate to good antimicrobial activity against the tested
microorganisms when compared with the standard drugs, except for A. niger.
The tested chalcone and its C1 chelate were more active against Gram-positive
than Gram-negative bacteria, while C2 and C5 chelates have more activity against
negative than positive bacteria. It may be concluded that the antimicrobial activity of
the compounds is related to cell wall structure of the bacteria. It is possible because
the cell wall is essential to the survival of bacteria and some antibiotics are able to kill
bacteria by inhibiting a step in the synthesis of peptidogly can. Gram-positive bacteria
possess a thick cell wall containing many layers of peptidogly can and teichoic acids,
but in contrast, Gram negative bacteria have a relatively thin cell wall consisting of a
few layers of peptidogly can surrounded by a second lipid membrane containing
lipopolysaccharides and lipoproteins. These differences in cell wall structure can
produce differences in antibacterial susceptibility and some antibiotics can kill only
Gram-positive bacteria and is infective against Gram-negative pathogens [66].
Furthermore, the minimum inhibitory concentrations (MIC) of chalcone against
microorganisms are show in Table 11.
3.7. Antitumor measurements
The cytotoxic effect of the different concentration of the chalcone and its metal
chelates in the concentration rang of 0, 5, 12.5, 25 and 50 μg/mg was tested against
human breast cancer cell line (MCF7). The IC50 (half maximal inhibitory
concentration value) which measures the effectiveness of a compound to inhibit
biological or biochemical functions, is derived from the experimental data. For
comparison,the cytotoxicity of the standard doxorubicin antitumor drug was evaluated
under the same conditions
The results obtained are presented in Figure S11. This figure shows that the
proliferation of MCF7 is decreased upon increasing the concentration of the chalcone
and its chelates. i.e the toxicity of these compounds was found to be concentration
dependent. The data indicate that the in vitro IC50 values for the metal chelates are
higher than the free chalcone, therefore the free chalcone possess better antitumor

15
activity than the metal chelates. This means the chelates failed to cause significant
inhibitory action on the tumor cell as is evident from its high cell IC50value.
From the data obtained, it is possible to exhibit the relation between IC50value and the
nature of the metal ion. However, the toxicity of the metal complexes can be related
to the strength of metal-ligand bonds in addition to other factors such as the size of the
metai ion . The higher the size of the metal ion, the higher the value of IC50. [69]
Cr(III) complex exhibited more potential anticancer activity than the other metal
complexes. Thus, Cr(III) chelate is more effective than the other chelates towards
cancer cell line.
[ 69 ]R.R.ZakyaT.A.Yousefb K.M.Ibrahima Co(II), Cd(II), Hg(II) and U(VI)O2
complexes of o-hydroxyacetophenone[N-(3-hydroxy-2-naphthoyl)] hydrazone:
Physicochemical study, thermal studies and antimicrobial activity, Spectrochimica
Acta Part A: 97 (2012) 683-694
According to Shier [70] compounds with IC50 within the range of 10-25 µg/ml are
considered weak anticancer drugs, while those of IC50 between 5 and 10 µg/ml are
moderate and compounds of activity below 5.00 µg/ml are considered strong agents.
Based on these facts, it is clear that the C1 chelate has a moderate anticancer activity,
the chalcone exhibited strong activity while the other chelates exhibited a weak
antitumor activity according to Shier scale. Also, the results showed that the chelates
under investigation give higher IC50 values [71-74] or lower [75] for breast cell MCF7
than the reported for cytotoxic metal (II) chelates for the same cell .
The crucial aim of structure activity relationship(SAR)[76] is to correlate the
biological properties with different quantum chemical descriptors such as the energy
gap (ΔE= EHOMO - ELUMO), hardness (η), electronegativity (χ), chemical potential (μ)
and (electrophilicity) (ω), softness (ϭ) and additional electronic charge (ΔNmax). These
values showed no clear direct correlation with the anticancer activity.
A property of interest is the dipole moment. The highest dipole moment value of the
Cr(III) complex should be a considerable factor fot its highest cytotoxicity[77]
compared to the other complexes. The results were correlated with the experimental

16
data. The antibacterial activity of the chalcone and its chelates have been tested. The
data indicated that all the metal chelates demonstrated a higher activity than the free
chalcone. The results suggested that:(i)Cr(III) complex has an enormous potential as
anticancer agent compared to the other chelates, (ii) All the metal chelates a lower
activity compared to the free chalcone [78]
4.
Conclusion
Cr(III), Mn(II), Cu(II) Zn(II) and Cd(II) chelates of the titled chalcone have been
synthesized and characterized by analytical and spectral methods. The data indicated
that the investigated chalcone acts as a bidentate chalcone coordinated to the metal
ions via the O and N atoms of the C=O and C=N groups, respectively. The spectral
and magnetic data revealed the formation of octahedral chelates for all chelates except
Cu(II) chelate which exhibit the square planar geometry. The thermal properties of the
metal chelates have been investigated by TGA technique. The kinetic and
thermodynamic parameters of the decomposition steps have been calculated.
Molecular orbital calculations have been performed for the chalcone and its chelates.
The antibacterial activity of the chalcone and its chelates have been tested. The data
indicated that all the metal chelates demonstrated a higher activity than the free
chalcone. The results suggested that:(i)Cr(III) complex has an enormous potential as
anticancer agent compared to the other chelates, (ii) All the metal chelates a lower
activity compared to the free chalcone . All chelates exhibited a very weak antitumor
activity except Cr (III) chelate which has a relatively stronger antitumor activity,
while the antitumor activity of these chelates is not as strong as that of chalcone.
Based on the data of the manuscript, the structure of chalcone chelates are represent
as:
OAc
O
N
M
X
O
N
OAc

17
X = 2H2O, AcO for C1; 2H2O for C2; H2O for C4; Zero for C6
Y
O
N
N
Zn
Y
X
O
Y = Zero, X= 2NO3 .H2O for C3; Y = Cl, X= H2O for C5
Scheme 1: The structure of chalcone compoundand its chelates.
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1
Table 1. The physical and analytical data of the chalcone and its chelates.
% Elemental analysis Calc. (found)
Color
Mol.
wt
Metal Content
Compound
Chalcone
C1
Formulae
(Λm)a
C
H
N
Atomic
TGA
.absorption
C16H16N2O
76.16
59.29
6.39
5.89
11.1
----
6.75
----
252.13
769.78
C38H45 CrN4O10
Dark brown
25
7.27
(6.86)
6.65
(58.49) (6.67)
[CrL2(OAc)2].2H2O.AcO
(7.44)
7.70
C36H42 MnN4O8
713.98
710.19
706.18
656.13
735.10
C2
C3
C4
C5
C6
Dark brown
14
60.59
5.89
7.84
(7.41)
6.83
9.5
(60.92) (5.42)
[MnL2(OAc)2].2H2O
(6.86)
8.95
C32H34CuN6O9
Dark blue
179
54.12
5.83
11.83
(53.49) (5.38) (11.01)
[CuL2].2NO3.H2O
(9.84)
9.29
7.93
C36H40ZnN4O7
Dark brown
3
61.23
5.71
(7.6)
----
(61.04) (5.44)
[ZnL2(OAc)2].H2O
(9.62)
9.92
C32H34 ZnCl2N4O3
[ZnL2Cl2]. H2O
Dark brown
1
58.33
5.20
8.53
(8.44)
9.87
(58.69) (4.95)
(8.94)
15.29
(14.37)
C36H38CdN4O6
[CdL2(OAc)2]
Dark brown
5.5
58.82
5.21
7.61
(8.11)
15.19
(58.10) (5.80)

2
Table 2. IR spectra data (cm-1) of chalcone and its chelates
No.
ν OH
νC=O
νC=N
νOAc
νM-O
νM-N
Chalcone
--
1648
1519
--
-
-
1444
1370
1438
1369
--
3437
1594
1530
520
414
C1
3435
3429
3424
3438
3435
1596
1608
1599
1598
1593
1535
1568
1524
1555
1524
562
550
546
596
522
427
403
417
447
425
C2
C3
C4
C5
C6
1465
1377
--
1447
1372

3
Table 3. The Thermal amalysis data of chalcone chelates
Chelates
Temp. oC
Mass Loss %
Estimate Calc.
Assignment
28-65
4.93
4.45
Loss of lattice 2H2O
C1
113-218
218-311
311-442
8.70
8.09
Loss of lattice OAc
15.52
91.00
15.34
91.69
Loss of coordinated 2OAc
Dissociation of the organic chalcone with
formation of Cr2O3+ C as final products.
Loss of lattice 2H2O
19-118
4.39
5.05
C2
C3
C4
C5
C6
128-274
282-491
15.78
93.14
16.84
92.30
Loss of coordinated 2OAc
Dissociation of the organic chalcone with
formation of MnO as final products.
Loss of lattice H2O
24-75
2.79
2.53
171-226
226-384
17.96
84.30
17.46
85.42
Loss of lattice 2 NO3
Dissociation of the organic chalcone with
formation of CuO + 2C as final products.
Loss of lattice H2O
24-80
2.36
2.57
116-243
243-536
16.50
90.38
16.71
90.74
Loss of coordinated 2OAc
Dissociation of the organic chalcone with
formation of Zn as final products.
Loss of lattice H2O
24-80
2.18
2.74
161-234
234-656
10.56
91.06
10.82
90.71
Loss of coordinated Cl ions
Dissociation of the organic chalcone with
formation of ZnO as final products.
Loss of coordinated 2OAc
87-258
16.75
85.63
16.05
84.71
258-630
Dissociation of the organic chalcone with
formation of CdO as final products.