Spectroscopic investigation, DFT, fluorescence, molecular docking and biological studies of divalent and trivalent binuclear complexes prepared from benzoyl thiosemicarbazide derivative of 2-benzylmalonohydrazide

Article abstract of DOI:10.1002/aoc.4871

The binuclear Cr (III), Mn (II) and Fe (III) complexes of N,N′-(2,2′-(2-benzylmalonyl)bis (hydrazine-1-carbonothioyl))dibenzamide (H₄BPCD), which derived from the combination of 2-benzylmalonohydrazide suspension with benzoyl-isothiocyanate, ha

Full text of DOI:10.1002/aoc.4871

Received: 7 December 2018
DOI: 10.1002/aoc.4871
Revised: 21 January 2019
Accepted: 27 January 2019
F U L L P A P E R
Spectroscopic investigation, DFT, fluorescence, molecular
docking and biological studies of divalent and trivalent
binuclear complexes prepared from benzoyl
thiosemicarbazide derivative of 2‐benzylmalonohydrazide
Reham M. El‐Morshedy1 | Mohammed M. El‐Gamil2
Gaber M. Abu El‐Reash1
| Mohamed Mahmoud Abou‐Elzahab1 |
1 Department of Chemistry, Faculty of
The binuclear Cr (III), Mn (II) and Fe (III) complexes of N,N′‐(2,2′‐(2‐
benzylmalonyl)bis (hydrazine‐1‐carbonothioyl))dibenzamide (H4BPCD),
Science, Mansoura University, Mansoura,
P.O.Box 70, Mansoura, Egypt
2 Department of Toxic and Narcotic Drug,
Forensic Medicine, Mansoura Laboratory,
Medico legal Organization, Ministry of
Justice, Egypt
which derived from the combination of 2‐benzylmalonohydrazide suspension
with benzoyl‐isothiocyanate, have been isolated and investigated by the neces-
sary analytical and spectroscopic techniques. The IR studies show that
H4BPCD dispose as a mono‐negative hexadentate ligand (NOS)2 towards Mn
(II) ion and tetra‐negative hexadentate (NOS)2 towards both Cr (III) and Fe
(III) ions. The values of molar conductance in DMSO suggested the non‐
electrolytic nature for all complexes. The magnetic measurements and the elec-
tronic transitions data confirmed the hexa‐coordinate geometry of complexes.
The DFT geometry optimization of all compounds and IR comparative study
of both theoretical and experimental of H4BPCD were carried out. Moreover,
the H4BPCD and its Cr (III) complex displayed intra ligand (π → π*) fluores-
cence emission spectra which corroborate their photoactive nature. The coordi-
nated and crystalline water molecules have been investigated by (TG/DTG)
studies. The kinetic and thermodynamic parameters were computed using
Horowitz‐ Metzger, Coats‐Redfern and Broido methods. Biological studies of
DNA binding, minimum inhibitory concentration, in vitro determination of
SOD‐like activity and MTT‐cytotoxicity assay as well as molecular docking
studies were tested for the ligand and its complexes.
Correspondence
Gaber M. Abu El‐Reash, Department of
Chemistry, Faculty of Science, Mansoura
University, Mansoura, P.O.Box 70,
Mansoura, Egypt.
Email: gaelreash@mans.edu.eg
KEYWORDS
DNA binding, molecular docking, MTT‐cytotoxicity assay, spectral characterization,
thiosemicarbazide
1 | INTRODUCTION
stereochemistries and bonding behaviors that produce
diverse structures and properties.[1–3] Several studies have
The N‐, O‐ and S‐ containing ligands of dihydrazide
derivatives that can chelate with two metal ions have
become highly important because of symmetric and
asymmetric binuclear complexes exhibited a variety of
been carried out on the binuclear complexes because their
interesting applications like creation of supramolecular
structures to mimic metalloproteins,[4] DNA binding,[5]
specific and selective catalysis,[6,7] sequestering of metal
Appl Organometal Chem. 2019;e4871.
wileyonlinelibrary.com/journal/aoc
© 2019 John Wiley & Sons, Ltd.
1 of 24
https://doi.org/10.1002/aoc.4871

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EL‐MORSHEDY ET AL.
ions and other of both biological and industrial applica-
tions. In vitro and in vivo tests[8] proved that dihydrazides
possess non‐genotoxic, anti‐inflammatory, antioxidant
and anticancer activities.[9–12] Also, their derivatives in
the field of analytical chemistry used as reagents for spe-
cific chemical separations,[13–15] spectrophotometric
microdetermination of some metal ions[16–18] and used
for polymer industry.[19,20] Furthermore, luminescent
compounds are very interesting because of their many
applications for photocatalysis.[21–24]
Because the promotive application studies of malono
hydrazide derivatives and their complexes[25] we have
prepared N,N′‐(2,2′‐(2‐benzylmalonyl)bis (hydrazine‐1‐
carbonothioyl))dibenzamide (H4BPCD) and its Cr (III),
Mn (II) and Fe (III) complexes. The necessary studies of
analytical, spectral, thermal, fluorescence and magnetic
were carried out.
spectrophotometer. The electronic spectra of the com-
plexes have been measured in the range 200–900 nm in
DMSO solution on a Perkin Elmer Lamda 25 UV/Vis Spec-
trophotometer, at Mansoura University. The effective
magnetic moment, μeff, per metal atom was measured by
Gouy method on Sherwood scientific magnetic suscepti-
bility balance at room temperature. The photoluminescent
properties of all compounds were studied using a LS50B
Jenway 6270 Fluorimeter. The TG and DTA in the temper-
ature region (20‐1000 °C) is carried out by Shimadzu ther-
mogravimetric analyzer at a heating rate of 15 °C/min and
nitrogen flow rate of 20 ml/min.
2.2 | Synthesis of N,N′‐(2,2′‐(2‐
benzylmalonyl)bis (hydrazine‐1‐
carbonothioyl))dibenzamide (H4BPCD)
We apply geometry optimization (using Materials Stu-
dio package[26]) and conformational analysis to the
H4BPCD and all their possible structural isomers and
have got the more stabilized. The proposed structures
were upheld by DFT molecular modeling of the prepared
compounds. Other studies carried out such as spectro-
The ligand was prepared in two main steps: Step1, of
preparation the hydrazide by mixing 1: 2 molar ratio of
diethyl 2‐benzylmalonate (2.35 g, 0.01 mol) and hydra-
zine (0.486 g, 0.02 mol) with stirring for 2 minutes then
adding 30 ml ethanol to the mixture followed by reflux
for 2–3 hr, then the contents were poured in a beaker
and left overnight. The solvent is removed by filtration
and the residue washed by diethyl ether. Step 2, of prep-
aration of H4BPCD where ethanolic solution of benzoyl
isothiocyanate (3.2778 g, 2.7 ml) is added to ethanolic sus-
pension of hydrazide obtained (2.0891 g) and the mixture
is refluxed for 3–4 hr. The obtained precipitate washed by
diethyl ether and checked by TLC (Figure 1). The melting
points of the hydrazide and H4BPCD found to be 167 and
220 °C respectively.
1
scopic (IR,UV–vis, fluorescence, H and 13C NMR), mag-
netic calculations and thermal kinetics of the isolated
complexes as well as its MIC efficacies as anti‐bacterial
and as anti‐fungal microorganism were tested. Several
transition metal complexes with flexible geometric trans-
formation around the metal center especially Mn, Cu or
Zn exhibit SOD activity[27,28] so, the determination of
SOD‐like activity and DNA‐binding affinity are discussed.
While, Molecular Docking was a powerful approach for
structure‐based drug discovery so, molecular docking
studies carried out.
2.3 | Synthesis of Cr (III), Mn (II) and Fe
(III) complexes
2 | EXPERIMENTAL
The chloride salt of each concerning metal (1.02 mmol)
dissolved in hot ethanol (30 ml) and then added to a
hot ethanolic suspension of H4BPCD (1.02 mmol,10 ml).
2.1 | Instrumentation and materials
The diethyl 2‐benzylmalonate and hydrazine were pur-
chased from Cambrian and Fluka and used as received.
The analysis of C, H and N is carried out with a “Perkin–
Elmer 2400 series II analyzer”. The metal and chloride
contents in prepared complexes were determined by tradi-
tional methods.[29] “Fisher‐Johns melting point apparatus”
is used for melting points (°C) determination and are
1
uncorrected. The H and 13C NMR spectrum of H4BPCD
at room temperature was recorded on a Varian Gemini
spectrometer (400 MHz) in d6‐DMSO at Faculty of Sci-
ence, Kafr Elsheikh University using tetra methyl silane
as an internal standard. IR spectra (4000–400 cm−1) with
KBr discs were recorded on a Mattson 5000 FTIR
FIGURE 1 Preparation of H4BPCD ligand

EL‐MORSHEDY ET AL.
3 of 24
DNA‐binding affinity
The contents were boiled for 4 hr. The fine formed precip-
itate was filtered and washed with ether and then desic-
cated over CaCl2. Complexes powders in varying yields
(80–91%) and the proposed structures are supported by
analytical and spectroscopic data.
Colourimetric assay for DNA active compound were
tested using the method reported by Burres N. et al.[36]
MTT‐cytotoxicity assay[37]
HePG‐2 cells were seeded in a 96‐well plate at a density of
1.0x104 cells/well[38] at 37 °C for 24 hr under 5% CO2. The
samples were dissolved in DMSO and diluted with phos-
phate buffer solution (PBS) to form concentration of
500, 200, 100, 50, 10 and 3 μmol/l. 5‐fluorouracil was used
as a standard anticancer drug for comparison. The differ-
ent concentration of prepared samples were added to
each well and were cultured for 48 hr. The treated cells
were washed with (PBS) and 100 μl of MTT solution
(5 mg/ml MTT stock in PBS diluted to 1 mg/ml with
10% RPMI‐1640 medium) was added to each well and
incubated for 4 h at 37 ° C. Finally, 100 μL of DMSO
was added and optical densities at 540 nm were measured
using a plate reader (EXL 800). The relative cell viability
in percentage was calculated as:
2.4 | Computational details
So as to get insight to the structural stabilities of the pre-
pared compounds, DFT calculations with periodic bound-
ary conditions were performed with the DMol3[30] code,
using Materials Studio package.[26] All the functions were
used in conjunction with the precise double numerical
plus polarization basis set DNP which is overweight the
accuracy of than Gaussian basis sets.[31] The RPBE func-
tional[32] is so far the best exchange‐correlation func-
tional,[33] in the light of the summed up gradient
approximation (GGA), is utilized to assess the exchange
and relationship effects of electrons. The geometric opti-
mization is done with no symmetry limitation.
A540 of treated samples
A540 of untreated sample
Relative cell viability% ¼
× 100
2.5 | Biological studies and molecular
docking
2.5.1 | Biological studies
Minimum inhibitory concentration (MIC)
2.5.2 | Molecular docking
The potencies of H4BPCD and it's complexes as antibacte-
rial and antifungal were examined by diffusion method of
agar and potato dextrose, respectively.[34] The examina-
tion was carried out in DMSO at 100, 200 and
500 μg/ml by using two bacteria (Escherichia coli as
Gram‐negative bacteria and Staphylococcus aureus as
Gram‐positive bacteria) and one fungi (Candida albicans)
by the MIC method.[35] These bacterial strains were incu-
bated for 24 h at 37 °C while fungi strain were hatched
for 48 hr, at 37 °C. The Ampicillin and Clotrimazole as
standerds were utilized for examination at the same con-
ditions. Efficacy was estimated by diameter measuring of
complete inhibition zone (mm).
Protein preparation
The three‐dimensional complex structure of E. coli (PDB
ID: 1C14‐chain A) was downloaded from the Protein
Data Bank.[39] The protein structures were prepared
using the protein preparation wizard program from the
Schrödinger suite[40] in which water molecules (> 5A
radius) and small molecules present were removed from
the structure part, disulphide bonds were created and
hydrogens were added to the PDB structures. Restrained
impref minimization with default settings was performed
on the structure with optimized potentials for liquid sim-
ulations (OPLS‐2005) force field. The resulting structures
were used for receptor grid generation for docking.
Antioxidant activity (determination of SOD‐like
activity)
Ligand preparation
Free ligand (H4BPCD) and it's complexes were investi-
gated for Superoxide dismutase (SOD)‐like activity using
well‐known method.[27] The solutions of H4BPCD
and/or its isolated complexes were prepared in DMSO.
The response was started by phenazine methosulfate
(PMS) addition, and the expansion in absorbance at
560 nm was recorded by the spectrophotometer for
The ligand compound (H4BPCD) intended to be used for
docking were prepared using default protocol of the
Ligprep program[41] in the Schrödinger's suite. Glide pro-
gram[42] in the Schrödinger's suite was used for docking
studies. All compounds and reference drug (ampicillin)
were docked to the target protein using the glide dock
XP protocol without using perform post‐docking minimi-
zation. Glide E‐Model was used as ranking criteria for the
best‐docked compound.[43]
5 minutes. For relative purposes, the activity of native ‐
L
Ascorbic acid has also been resolved.

4 of 24
EL‐MORSHEDY ET AL.
of the same band is accompanied by appearance of a
broad vibration at 1630 cm−1 assigned to new υ(C=N)3
due to the thiolization and deprotonation of (SH) group.
The broadness at 1630 cm−1 may be attributed to overlap-
3 | RESULTS AND DISCUSSION
The elemental composition of the isolated compounds in
addition to their physical properties are scheduled in
Table 1, which are in a decent concurrence with the pro-
posed chemical formulae. Sadly, single crystals of the
studied compounds cannot be isolated. The complexes
were found to be non‐hygroscopic and hardly soluble in
most organic solvents except DMSO and DMF.
*
*
ping of υ(C=N)3 with υ(C=N)1 .
The appearance of new bands at 1573 and 1562 cm−1
belongs to new (C=N)2* in both Cr (III) and Fe (III) com-
plexes respectively as a result of enolization and depro-
tonation of (C=O)2 group. The behavior is different in
Mn (II) complex where one of both (C=O)2 groups coor-
dinate as carbonyl and its vibration is shifted to higher
wavenumber (1677 cm−1) with reduction of intensity
while the other (C=O)2 enolized and coordinated with
deprotonation thereby new absorption band appeared at
3.1 | IR spectra
The IR spectral data provide us by the valuable informa-
tion regarding functional groups. The main characteristic
frequencies of H4BPCD (Figure 2) and its concerned
metal complexes (Figure S1–S3, supplementary materials)
are summarized in Table 2. Because the symmetrical
nature of both sides in the ligand and complexes, one
absorption band is observed for most of the functional
groups except when the environment varies because of
chelation.
1582 cm−1 assigned to υ(C=N)2 . The new low frequency
*
non‐ligand bands in the region 426–584 cm−1 and
observed in the spectra of complexes can be attributed
to υ(M‐S), (M‐O) and (M‐Cl).[46,47]
3.2 | 1H and 13C NMR of H4BPCD
The H4BPCD (Figure 3) exhibits broad band of
medium intensity at 3223 cm−1 assigned for υ (OH) and
sharp intense band at 1687 cm−1 may be due to overlap-
ping of υ(C=O)1 and υ(C=O)2 bands. Appearance of
υ(C‐O) band at 1252 cm−1 in addition of two mentioned
bands pointed to the presence of H4BPCD in the two
forms (keto and enol, Figure 4) which confirmed also by
1H and 13C NMR spectral analysis. The vibrations of
(NH)a and (NH)b lies at 3191 and 3061 cm−1 and the band
at 1602 cm−1 referred to υ(C=N)1 remains around the
same position in Cr (III) and Mn (II) complexes.[44,45]
The δ(C=S) band, observed at the 850 cm−1 not
The 1H NMR spectrum of H4BPCD (Figure 8) shows three
singlet signals at δ = 10.17, 11.19 and 11.81 ppm relative to
TMS that disappear upon deuteration (Figure S4, supple-
mentary materials). These signals attributed to (NH)a,
(NH)b and (OH) protons respectively.[48,49] The signals of
NH groups appeared in high downfield frequencies
because of formation of two hydrogen bond between
N(36)‐H(81) and N(11)‐H(48). Appearance of (OH) signal
at high frequency is additional evidence that the ligand
present in enol form. The multiplets at 7.15–7.95 ppm
belong to the protons of phenyl ring.[50] Doublet and
triplet signals at 3.15–3.20 and 3.92–3.98 ppm refereed to
(‐CH2) and (‐CH) groups respectively.
change
in
[Cr2(BPCD)Cl2(H2O)4].H2O
complex
(Figure 5), because its un‐participation in coordination
and undergoing blue shifted in [Mn2(H3BPCD)
Cl3(H2O)3].3H2O spectrum (Figure 6). In [Fe2(BPCD)
Cl2(H2O)4].5H2O (Figure 7) complex, the dissaperance
The 13C NMR spectrum of H4BPCD (Figure 9) shows
two signals belong to (C=O)1 and (C=O)2 groups appear
at δ = 172.01 and 164.55 ppm, and also a signal at
δ = 175.45 ppm assigned to (C=S) group. The aromatic
TABLE 1 Analytical and physical data of H4BPCD and its metal complexes
Found (Calcd.) %
Compound Empirical
Formula (F.Wt.)
Colour M.P. (°C) Yield (%)
C
H
N
M
Cl
H4BPCD C26H24N6O4S2 (548.64) white
220
210
95
80
56.81 (62.99) 4.45 (4.22) 15.54 (15.32) ‐ ‐
‐ ‐
[Fe2(BPCD)Cl2(H2O)4].5H2O
C26H38Cl2Fe2N6O13S2 (889.33)
Black
35.13 (35.11) 4.29 (4.31) 9.07 (9.08) 12.59 (12.56) 7.95 (7.97)
35.75 (35.81) 4.15 (4.05) 9.58 (9.64) 12.15 (12.20) 12.25 (12.60)
38.40 (38.57) 3.66 (3.74) 10.58 (10.38) 12.25 (12.85) 8.85 (8.76)
[Mn2(H3BPCD)Cl3(H2O)3].3H2O Paige
C24H35Cl3Mn2N6O10S2 (871.94)
230
250
91
86
[Cr2(BPCD)Cl2(H2O)4].H2O
C26H30Cl2Cr2N6O9S2 (807.97)
Olive

EL‐MORSHEDY ET AL.
5 of 24
FIGURE 2 IR spectrum for H4BPCD a) Experimental, b) Theoretical IR for H4BPCDketo, c) Theoretical IR for H4BPCDenol
carbons were observed at δ = 126.92–138.66.[51] Moreover
3.3 | Electronic spectra and magnetic
appearance of carbon resonance signal of (N=C‐OH) at
168.68 in addition of (C=O)1 signal suggest the presence
of keto‐enol tautomers of in solution. Since the more
available enol form leads to a decrease in polarization
causing the downshift in the resonance of (C=O)1 from
172.01 to 168.68. This suggestion is confirmed by energy
gap (EHOMO ‐ELUMO) calculations where of enol form
(0.897 ev) less than that for keto form (1.157 ev) which
mean that it is more reactive, and hence that explains
why chelation with metal ions takes place in enol form
in all prepared complexes.
behavior
The spectral data of H4BPCD and its complexes are illus-
trated in Table 3. The ligand H4BPCD shows two intense
bands around 307 nm (32573 cm−1) and 342 nm
(29240 cm−1) in DMSO solution, because of the intramo-
lecular transitions (π–π*) and (n–π*) respectively. These
transitions shifted to slightly higher wavenumbers in
the complexes.[52,53]
The spectrum of the iron compound displays multiple
bands belong to Oh environment at 17483, 23585, 24994

6 of 24
EL‐MORSHEDY ET AL.
FIGURE 4 Keto/enol form of the title compound H4BPCD
FIGURE 3 Molecular modeling of H4BPCDenol form (1)
6
4
and 27933 cm−1 which are attributed to A1g → T1g(G),
6A1g → T2g(G), A1g → Eg(G) and A1g → T2g(D) tran-
sitions, respectively.[54] The measured μeff is found to be
5.6 B.M. which suggested the sp3d2 hybridization in Fe
(III) ion.[55]
4
6
4
6
4
The diffused reflectance spectrum of the Mn (II) com-
plex shows three bands at 17036, 19960 and 22696 cm−1
6
6
assignable to A1g
→ →
4T1g, A1g 4T2g(G) and
FIGURE 5 Molecular modeling of [Cr2(BPCD)Cl2(H2O)4].H2O
6A1g → Eg(G) transitions, respectively.[56] The magnetic
moment value 4.8 B.M. indicates the occurrence of Mn
(II) complex in Oh geometry.[54] However, the lowering
of magnetic moment value than normal value may be
due to the sharing of high diamagnetic sulphur atom of
CS group in coordination. As noticed, there is no sextet
spin multiplicity in any excited state, where the transi-
tions from the ground state (6A1g) are expected to be
spin‐forbidden and both the band intensities and Molar
absorptivity values (ε) are low.
4
4
4A2g(F) → T1g(p) transitions, separately, affirmed the
octahedral geometry.[57] We could not observe υ1 band
which expected to be at ca. 451 nm (22163 cm−1) for the
4
4A2g(F) → T2g(F) transition. The estimated values of
Dq, β and B also coincident with Oh geometry.[58]
3.4 | Fluorescence studies
The electronic spectrum of Cr (III) complex (μeff = 2.6
B.M.) demonstrates two bands at 25510 cm−1 (υ2) and
The emission spectra of H4BPCD and its Cr (III) complex
were measured upon the excitation wavelength around
4
4
28902 cm−1 (υ3) allude to A2g(F) → T1g(F) and
TABLE 2 Assignment of the IR spectral bands of H4BPCD and its metal complexes
*
Compound
υ(O‐H) υ(C=N)1 υ(C‐O) δ(C=S) υ(C=O)2 υ(C=N)2 υ(C=C) υ(N‐N) υ (NH)a υ (NH)b
H4BPCD (experimental)
3223
obs.
1602
1630
1604
1605
1252
1231
1257
1255
850
‐
1687
‐
1562
1580
1573
1527
1494
1495
1495
980
942
950
961
3191
Obs.
3193
Obs.
3061
[Fe2(BPCD)Cl2(H2O)4].5H2O
‐
1677
‐
‐
3062
‐
[Mn2(H3BPCD)Cl3(H2O)3].3H2O obs.
[Cr2(BPCD)Cl2(H2O)4].H2O
876
851
‐

EL‐MORSHEDY ET AL.
7 of 24
3.5 | Molecular modeling
3.5.1 | IR
Frequency calculation analyses have been performed for
H4BPCD possible forms in order to ensure the most prev-
alent form/forms. Because of large size of the molecule,
calculated modes of vibrations are complex especially,
the in plane, out of plane and torsion modes. The last
kind is the most difficult to assign due to interference
with the ring modes. However, there are some intense
frequencies, useful for characterization in the IR spec-
trum. The little difference between that experimental
wavenumbers and the calculated one is may due to that
the experimental wavenumbers were carried out for solid
samples, while the calculations were processed in a vac-
uum for a free molecule as shown in Figures 1b and 1c
and Table 4. It was found that the values of wavenumbers
of calculated frequencies are with good agreement with
experimental one, especially combination with the two
graphs of form 1 (enol form) and form 3 (keto form)
which confirm the presence of the two forms in the solid
form of the title compound.
FIGURE
Cl3(H2O)3].3H2O
6
Molecular
modeling
of
[Mn2(H3BPCD)
The corresponding graphic described harmony
between the experimental and theoretical wavenumbers
(Figure 11) since the relations between them are linear
and can be expressed by the next equations:
For the enol form υcal ¼ 0:99425 υexp
þ 11:352 with correlation coefficients
À
Á
× R2 ¼ 0:99977 :
FIGURE 7 Molecular modeling of [Fe2(BPCD)Cl2(H2O)4].5H2O
For the keto form υcal ¼ 1:01121 υexp
þ 23:899 with correlation coefficients
their maximum absorption. The spectra were recorded in
DMSO at room temperature and depicted in Figure 10.
Because the fluorescence intensities of the Mn (II) and
Fe (III) complexes are much too weak therefore they can-
not be discussed in our present work. The fluorescence
spectrum of ligand displayed an emission band at
432 nm when excited at 309 nm that was attributed to
the intra‐ligand π → π* transitions, while that for Cr
(III) complex shows one emission band at 503 nm
followed the excitation at 347 nm. It is noteworthy that
the emission wavelength of Cr (III) complex is slightly
longer than that of the free ligand, which is may be due
to the chelation of the ligand to the metal center. Such
chelation enhances the rigidity of the ligand and thus
reduces the loss of energy by radiation less decay of the
intra‐ligand emission excited state. Thus, the ligand and
its chromium complex may be used in further photo-
chemical applications which are with great interest lately.
À
Á
× R2 ¼ 0:99918 :
3.5.2 | Geometry optimization with DFT
method
For ligand and its possible forms
The DFT/DMoL3 method has been used for a complete
study of the molecular structures of all the possible
conformations of H4BPCD (Figure 12) in order to obtain
their stability order according to the calculated energy
components in addition of spin polarization as listed in
Table 5. It was found that H4BPCD form (1) has the low-
est total energy and highest binding energy which mean
that form (1) is the most stable conformation and that
clarifies why all coordination modes takes place in this
form.

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EL‐MORSHEDY ET AL.
FIGURE 8 1H NMR spectrum of
H4BPCD
FIGURE 9 13C NMR spectrum of H4BPCD
For ligand in enol form and its metal complexes
For the discussion of optimized molecular geometry of
H4BPCD and its metal complexes, bond lengths and
angles are calculated and the data listed in Table S1, sup-
plementary materials. There are some important
remarks:

EL‐MORSHEDY ET AL.
9 of 24
TABLE 3 Spectral absorption bands, magnetic moments and ligand field parameters of H4BPCD and its metal complexes
λmax
Complex
nm
cm−1
band assignment
Dq
B
β (B/Bo) ε
μeff (B.M) geometry
H4BPCD
342(m) 29240
307(s) 32573
239(sh) 41841(found) (π–π*)
451 22163(calc.)
392(m) 25510(found.) A2g(F) → T1g(F) (υ2)
(n–π*)
‐
‐
‐
‐
‐
‐
‐
‐
‐
‐
‐
‐
‐
‐
‐
‐
‐
‐
(found)
(found)
4
[Cr2(BPCD)Cl2(H2O)4].H2O
4A2g(F) → T2g(F)(υ1) (υ1) 2216 905 0.98
‐
2.6
Oh
4
4
1131
2767.3
4
4
346(s) 28902(found) A2g(F) → T1g(p) (υ3)
4
[Fe2(H2BPCD)Cl4(H2O)2].5H2O 572(w) 17483
6A1g → T1g(G) (υ1)
801.3 728.5 0.76
780.8 709.8 0.74
463.6 5.6
2096
1910
Oh
(found)
6
4
424(s) 23585(found) A1g → T2g(G) (υ2)
6
4
400(s) 24994(found) A1g → Eg(G) (υ3)
6
4
358(s) 27933(found) A1g → T2g(D) (υ4)
2949
6
4
[Mn2(H3BPCD)
Cl3(H2O)3].3H2O
587(w) 17036(found) A1g → T1g (G) (υ1)
30.4
30.42
50.7
4.8
Oh
4
501(m) 19960
441(s) 22696
6A1g → T2g(G) (υ2)
(found)
6A1g → Eg(G) (υ3)
4
(found)
FIGURE 10 The fluorescence spectra of
ligand and its Cr (III) complex
TABLE 4 Theoretical IR comparison of H4BPCD possible forms
υ(O‐ υ(C‐ υ(C‐ υ(S‐
υ(C‐
υ(N‐
υ
υ
Compound
H) υ(C=N)1 O) δ(C=S) S)
H) υ(C=O)1 υ(C=O)2 O)2 υ(C=N)2* υ(C=C) N) (NH)a (NH)b
H4BPCD
(experimental)
3223 1602
1252 850
1266 851
1252 843
‐
‐
‐
‐
‐
‐
‐
‐
‐
1687
1657
‐
‐
‐
1527
1527
1521
1524
1516
1515
980 3196
981 3195
977 3177
981 3182
986 3167
958 3193
3061
3061
3062
3065
3098
3086
H4BPCDenol form1 3195 1605
(theoretical)
‐
‐
‐
H4BPCD form2
(theoretical)
3300 1618
‐
1335 1585
H4BPCDketo form3
(theoretical)
‐
‐
‐
849
1740
1680
1630
1668
‐
‐
H4BPCD form4
(theoretical)
3259 1629
1268 855
1110 1229 ‐
1366 ‐
H4BPCD form5
(theoretical)
‐
‐
‐
‐
1116 1259 1783
‐
‐

10 of 24
EL‐MORSHEDY ET AL.
FIGURE 11 The linear regression between the experimental and theoretical frequencies of H4BPCD a) for keto form and b) for enol form
5. Elongation and weakness of the (C‐O) bond distances
(in all complexes) as a result of formation of the M‐O
bond.[60]
6. As the result of coordination, the angles of ligand
bonds are altered and the great change belong to
N(34)‐C(33)‐O(30) and S(18)‐C(13)‐N(12) angles
which are increased or reduced because the
coordination.[60]
7. In all complexes the angle of bonds found to be in
coincide with Oh geometry range expecting d2SP3 or
SP3d2 hybridization.
8. The M‐N, M‐O and M‐S bonds according to their
FIGURE 12 structure of possible conformations of H4BPCD
lengths
can
be
arranged
as
follows:
S(31)‐Fe(39) > S(18)‐Fe(40) > Cr(40)‐O(19) > O(38)‐
Cr(39) > O(17)‐Cr(40) > O(19)‐Mn(47) > O(30)‐
Mn(39) > O(19)‐Fe(40) = O(30)‐Fe(39) reflecting the
great strength of the Fe‐O and Mn‐O bonds than
the others. Finally for M‐X bond, it obeys the order
Cr‐Cl > Fe‐Cl > Mn‐Cl. Due to the elongation in
the bonds, vibration frequency need smaller energy
and consequently appear at smaller frequency which
is confirmed from the practically IR values.
1. The optimized [C(10)‐N(37)]azomethan)1) and [C(9)‐
N(11)]azomethan(1) bond distances in the parent ligand
elongated due to its coordination in the isolated
complexes.
2. (C‐O)1 bond elongated only in [Cr2(BPCD)
Cl2(H2O)4].H2O due to coordination via O(38) and
O(17) of deprotonated OH groups.[59]
3. For (N‐N) bond, become slightly longer in both
[Mn2(H3BPCD)Cl3(H2O)3].3H2O and [Cr2(BPCD)
Cl2(H2O)4].H2O because of coordination via N(11),
N(37) and N(12), N(36) respectively. On contrast,
the bond become shorter in [Fe2(BPCD)
Cl2(H2O)4].5H2O. Moreover, (C=S) bond elongated
also in Mn (II) complex because of coordination takes
place from S(31).
3.5.3 | Chemical reactivity
Global reactivity descriptors
The highest occupied molecular orbital and the lowest‐
lying unoccupied molecular orbital (HOMO and LUMO
respectively) are also named as frontier molecular orbitals
(FMOs). The FMOs provide useful information about the
reactivity and kinetic stability of compounds.[61–63] Sur-
faces for the frontier orbital were drawn for more under-
standing of the bonding scheme of the investigated
compounds and it is shown in Figures 13 and 14 for
ligand keto/enol forms and the other compounds in sup-
plementary file (Figures S5‐S7).
4. C(15)‐O(19) and C(33)‐O(30) ketone‐type in
[Cr2(BPCD)Cl2(H2O)4].H2O
and
[Fe2(BPCD)
Cl2(H2O)4].5H2O, enolized resulting the disappear-
ance of the double bond character over C(15)‐O(19)
and C(33)‐O(30), and its appearance over N(14)‐
C(15) and N(34)‐C(33). Also, absence of double bond
character over both S(31)‐C(35) and C(13)‐S(18) and
its appearance over N(12)‐C(13) and C(35)‐N(36) in
Fe (III) complex.

EL‐MORSHEDY ET AL.
11 of 24
The HOMO represents the electron donor orbital (π
donor), while the LUMO represents the electron acceptor
orbital (π acceptor). The negative sign of HUMO and
LUMO energies and their neighboring orbitals indicate
the stability of prepared molecules.[64]
According to calculation results, it was found that
there is a rise in the value of EHOMO adhere by lengthen
(weakness) of the metal–ligand bonds leading to a short-
ness (strengthen) of the sites neighboring to the metal
ligand centers.[65] The HOMO level is mostly localized
on N(12),N(37), S(18), S(31),O(11), O(31), O(19) and
O(30) showing they are the favored sites for nucleophilic
attack at the central metal ion.
Moreover, the FMOs theory can anticipate coordina-
tion sites (or electrophilic attack) on aromatic com-
pounds. An initial presumption is that – in many
reactions – the reaction won't takes place until there is
a maximum overlap reached between HOMO on one
molecule, and the LUMO on the other. We can deduce
that, by determining the largest value of molecular orbital
coefficients from calculation which may be considered as
the sites of coordination. It was found that the nitrogen of
the (C=N1) group, the sulphur of (C=S) group and the
oxygen of (C=O2) group largest value of molecular orbital
coefficients. And this explains why metal atoms coordi-
nate mostly to the ligand from these sites.
In addition to determining how the interaction occurs
of the molecule with other species, the FMOs could also
predict the chemical reactivity and kinetic stability of
the molecule, optical polarizability and chemical
hardness–softness of a molecule through their energy
gap between HOMO and LUMO.[66,67]
Considering the chemical hardness, large ΔE means a
hard compound, and small ΔE means a soft compound.
Soft molecule favors easy polarization for both molecules,
so they are more reactive than hard molecules since they
could easily offer electrons to an acceptor.[68] This
explains why H4BPCD form (1) is the most reactive form
and why chelates in this form in all complexes.
In the meantime the decrease of energy gap means
that the final charge transfer takes place within the com-
pound, which influences its biological activity. This con-
clusion proved by the comparison of biological study
data with ΔE gap, the order of the compounds according
to their ΔE gap calculations found to be as follow
H4BPCD > [Fe2(BPCD)Cl2(H2O)4].5H2O > [Cr2(BPCD)
Cl2(H2O)4].H2O
>
[Mn2(H3BPCD)Cl3(H2O)3].3H2O
which is the same order of biological reactivity in all
tested bio‐activities. That means that we can predict the
most reactive biological compounds with ΔE gap calcula-
tions before carrying out real tests.
According to the MOT, the electron affinity and ioni-
zation energy can be indicated by HOMO and LUMO

12 of 24
EL‐MORSHEDY ET AL.
FIGURE 13 3D plots frontier orbital
energies using DFT method for H4BPCD
(enol form)
energies as A = ‐ELUMO and I = ‐EHUMO, respectively. The
electronegativity, χ = −1/2 (ELUMO + EHOMO), global
hardness, η = 1/2 (ELUMO ‐ EHOMO). χ and η can also
expressed in terms of A and I as:
acids.[74] In between the molecules the transfer of elec-
trons occurs from molecule with low χ to that with high
χ. This fact agree well with results that parent molecule
H4BPCD have lowest value of χ so it could be considered
as Lewis base (soft base). Thus Lewis base ligands are
most efficacy for complex formation.[75] Thereby, it is
deduced that the ligand with a proper softness (σ) value
has a good propensity to coordinate metal ions effectively
ðI þ AÞ
ðI − AÞ
χ ¼
and η ¼
2
2
.
[76] Moreover, according to electrophilicity index (ω) def-
The chemical potential,
μ
=
−
χ
=
1/2
inition,[77] the ω measures the tendency of compound to
(ELUMO + EHOMO), global softness, S = 1/2 η, the softness,
σ =1/η and global electrophilicity index, ω = μ2/2 η .[69,70]
These parameters have been evaluated and tabulated
Table 6.
gain electrons.
Local reactivity descriptors
Fukui function f (r) one of the most useful parameter in
the identification of privileged sites of reactivity (active
sites) in a molecule.[78–80] It is defined as:
The atomic parameter linked with the energetics of
removal of an electron is the ionization potential (I),[71]
whereas that for the addition of an electron is electron
affinity (A). Therefore, these two parameters deciding,
somehow, the charge distribution and/or redistribution
in molecular systems during molecular formation and
hence chemical bonding as well as reactivity. The transfer
of partial charge takes place in many bonds such as cova-
lent and hydrogen bonds.[72]
The usefulness of electronegativity (χ) and absolute
hardness (η) includes their ability to predict chemical
activity.[73] For a given molecule it can be determined as
Lewis acid or Lewis base according to its χ value. For
bases, the χ values are small and large values characterize
ꢀ
ꢁ
∂ð∂E=δυextÞN
∂N
f ðr; NÞ ¼
υext
Where E is the energy, N the number of electrons, and
υ
ext is the external potential. The local (condensed) Fukui
functions ( f +, f ‐, fko) are calculated using conven-
k
k
tional method.[70]
The results for H4BPCD in enol form predict the
+
highest f
value for N(37) indicates that it is the most
k
probable site for nucleophilic attack. From the values

EL‐MORSHEDY ET AL.
13 of 24
While the results for the ligand in Keto form (Table 3S,
–
supplementary materials). predict the highest fk+ and fk
for S(31) followed by O(30) in case of nucleophilic attack
while C(35) in case of electrophilic attack. The radical
attack was predicted as C(33) > C(35) > S(18) > C(10).
In [Fe2(BPCD)Cl2(H2O)4].5H2O complex (Table S4, sup-
+
plementary materials) Fe(40) has the highest fk value.
The reactivity order for the nucleophilic case is
−
Fe(40) > Cl(41) > O(19) > C(13). The calculated fk
value predicts that the possible sites for electrophilic
attack is S(31) > O(30) > Cl(42) site and the radical attack
was predicted at Cl(42) site.
In [Mn2(H3BPCD)Cl3(H2O)3].3H2O the most favored
site (Table S5, supplementary materials). for the nucleo-
philic, electrophilic and radical attack is C(9), Cl(35)
and S(18) respectively. Moreover, the most favored site
for the nucleophilic and attack In [Cr2(BPCD)
Cl2(H2O)4].H2O complex (Table 6S, supplementary mate-
rials) is S(31) and for radical attack is O(49). The ability of
attack sites in H4BPCD and its complexes are listed in
Table 7.
Mulliken population analysis We use the formalism
due to Mulliken in order to perform the population anal-
ysis.[81] Mulliken Population Method can be used for
explaining and predicting the reactive behavior of a wide
set of chemical systems and the nature of the chemical
bond.[82,83] Mulliken atomic charges calculated by DFT
method is collected and shown by the corresponding
Mulliken's plots (Figure 15). It is worthy to mention that
C(15), C(13), N(12), N(11), O(19) and S(18) atoms of
H4BPCD (enol form) exhibit positive value, while C(23),
C(29), N(34), C(11), O(38), S(31), N(36) and N(37) exhibit
negative charge. N(37) of azomethane1 group has a max-
imum negative charge value. On the other hand, the max-
imum positive atomic charge is obtained for S(18) of
(C=S) group. For the keto form C(21), C(9), O(19),
C(10), S(18) and C(33) atoms exhibit positive charge,
while C(29), N(11), C(13), C(16), O(30), O(38) and S(31)
atoms exhibit negative charges. S(31) of (C=S) group
FIGURE 14 3D plots frontier orbital energies using DFT method
for H4BPCD (keto form)
reported in (Table S2, supplementary materials). The
reactivity order for the nucleophilic case as N(37)
> > N(36) > C(35) > S(31). The calculated fk− value pre-
dicts that the possible sites for electrophilic attack is
S(18) > O(19) > N(11) > N(12) site and the radical attack
was predicted as S(18) and O(19) site.
TABLE 6 Calculated EHOMO, ELUMO, energy band gap (EH – EL), chemical potential (μ), electronegativity (χ), global hardness (η), global
softness (S), global electrophilicity index (ω) and softness (б), ionization potential (I) and electron affinity (A) for H4BPCD and its metal
complexes
EHUMO ELUMO ΔE
χ
μ
(eV)
η
(eV)
S
ω
(eV)
б
A
(eV)
I
Compound
(eV)
(eV)
(eV)
(eV)
(eV−1
)
(eV−1
)
(eV)
H4BPCD (enol form)
−4.897
−5.136
−5.662
−4.000
−3.979
−4.593
−4.087
−3.899
0.897 4.448 −4.448 0.448 1.115
1.157 4.558 −4.558 0.578 0.865
1.070 5.128 −5.128 0.535 0.935
1.475 4.825 −4.825 0.737 0.678
2.037 4.917 −4.917 1.018 0.491
22.064 2.230
17.960 1.729
24.579 1.870
15.783 1.356
11.872 0.982
4.000 4.897
3.979 5.136
4.593 5.662
4.087 5.562
3.899 5.936
H4BPCD (keto form)
[Fe2(BPCD)Cl2(H2O)4].5H2O
[Mn2(H3BPCD)Cl3(H2O)3].3H2O −5.562
[Cr2(BPCD)Cl2(H2O)4].H2O −5.936

14 of 24
EL‐MORSHEDY ET AL.
TABLE 7 Ordering the nucleophilic, electrophilic and radical attack sites for H4BPCD and its metal complexes
Nucleophilic
attack
Electrophilic
attack
Radical
attack
Compound
H4BPCDenol
N(37) > > N(36) > C(35) > S(31) S(18) > O(19) > N(11) > N(12) S(18)> > O(19) > N(11) > N(12)
S(31) > O(30) > C(13) > O(38) C(35) > C(10) > C(33) > S(18) C(33) > C(35) > S(18) > C(10)
H4BPCDketo
[Fe2(BPCD)Cl2(H2O)4].5H2O
Fe(40) > Cl(41) > O(19) > C(13) S(31) > O(30) > Cl(42)
Cl(42) > Cl(41) > S(31) > S(18)
Cl(51) > S(31) > S(18) > N(34) S(18) > S(31) > Cl(51) > C(13)
S(31) > S(18) > O(17) > O(44) O(49) > C(13) > N(36) = N(37)
[Mn2(H3BPCD)Cl3(H2O)3].3H2O C(9) > C(15) = Mn(47) > C(13)
[Cr2(BPCD)Cl2(H2O)4].H2O S(31) > Cr(39) > Cl(43) > S(18)
FIGURE 15 The Mulliken diagram distribution of a) H4BPCDketo, b) H4BPCDenol
has the greatest values of negative charge, while the
highest positive atomic charge is obtained for C(33) of
(C=O)2 group.
For the keto form C(21), C(9), O(19), C(10), S(18) and
C(33) atoms exhibit positive charge, while C(29), N(11),
C(13), C(16), O(30), O(38) and S(31) atoms exhibit nega-
tive charges. S(31) of (C=S) group has a maximum nega-
tive charge values, while the maximum positive atomic
charge is obtained for C(33) of (C=O)2 group.
3.5.4 | Molecular electrostatic potential
(MEP)
MEP correlates with electronegativity, partial charges and
chemical reactivity of the molecules.[84–87] MEP maps of
H4BPCD in enol and keto form have been observed in
FIGURE 16 Molecular electrostatic potential map for
H4BPCDenol
two different planes (Figures 16 and 17, respectively) for
each molecule. The different values of the electrostatic
potential at the surface are represented by different
colors: red color symbolize to regions of most negative
electrostatic potential which preferred site for electro-
philic attack and blue color symbolize to regions of most
positive electrostatic potential which preferred site for
nucleophilic attack. An increase in potential has the
order: red< orange < yellow < green < blue. The color
scale of the map ranges from −0.12278 to 0.14147 kcal/
mol in enol form, while in keto form −0.0018995 to
0.79213 kcal/mol.

EL‐MORSHEDY ET AL.
15 of 24
I. Removal of the hydrated water from about 22 to
108 °C, and resumes from about 108 to 244 °C for
coordinated water.
II. Depending on the nature of each complex, the deg-
radation process of the ligand part starts mostly
from about 243 °C. The weight loss at this step
may attribute to the evolution of gases such as
CO2, H2S, N2, SO2, NO2 or HCl.
III. The last step of decomposition process belongs to
the strongly bound fragment of the remaining
organic molecule, which includes the removal of
the metal sulfide or metal oxide. Finally, the
thermogram shows stability until 800 °C
(Figures 18–20).
FIGURE 17 Molecular electrostatic potential map for
H4BPCDketo
3.7 | Kinetic data
The thermal stability of the chelated have been analyzed
in terms of decomposition kinetic parameters derived
from Broido (B),[88] the integral method using the
Coats‐Redfern (CR) equation[89] and the approximation
method using the Horowitz‐ Metzger (HM) equation[90]
(Table 8). The 1st decomposition step of Fe (III)‐complex
which calculated by three methods was graphed in
Figure 21 as representative example. The next steps of
this complex in addition to the whole decomposition pro-
cess of other complexes were represented in Figures S8‐
S16, supplementary materials. Generally, all methods
used to measure the change in physical properties of
compounds such as weight variation as a function of tem-
perature or time. According to the output data the follow-
ing observations can be illustrated:
3.6 | Thermogravimetric studies
All synthesized complexes are subjected to the (TG) and
the 1st derivative (DTG) analysis within temperature rang
22–800 °C in nitrogen flow to understanding their ther-
mal stability, hydrated and coordinated water molecules
as well as a general pattern for their thermal decomposi-
tion steps. Moreover, TGA data provides remarkable
information about the water molecules within the com-
plexes complementary to the elemental analyses. Gener-
ally, thermal degradation of the complexes takes place
in three major steps:
FIGURE 18 Thermal analysis curves of [Cr2(BPCD)Cl2(H2O)4].H2O complex

16 of 24
EL‐MORSHEDY ET AL.
FIGURE 19 Thermal analysis curves of [Fe2(BPCD)Cl2(H2O)4].5H2O complex
FIGURE 20 Thermal analysis curves of [Mn2(H3BPCD)Cl3(H2O)3].3H2O complex
i. It was inferred that all the thermal decomposition
reaction of complexes have the first order, these
complexes show similar type of thermal behavior
as it shown by Ea and A values of these reactions.
The kinetic parameters of different decomposition
steps are impacted by type and nature of central
metal atoms.
ii. The output Ea values using three variable methods
gives different data although difference was found
in a narrow range. Over all, the calculation of Ea
using Briodo's method gives higher values than the
two other methods.[91]
iii. Moreover, the high values of Ea, in complexes,
reflects the high stability of the complexes due to
their covalent bond character.[92] The Ea values obey
the order: Mn (II) > Fe (III) > Cr (III) complex. Con-
sequently, the thermal stability increases in this
sequence.
iv. The positive values of ΔG* of the degradation pro-
cesses indicate their non‐spontaneously nature and
for the concerning complexes the value increases
from one step to another so that the values of TΔS
overweight the values of ΔH*.[93–95]
The negative value of ΔS* (entropy of activation) in
all complexes due to the lower rate and slow of
decomposition reactions than the natural ones. The
high degree of ordered is controlled by the polarization
of bonds in the activated state which occur by elec-
tronic transition and charge migrations.[96] The positive
sign in few decomposition steps may attributed to that
the reaction produces more gas molecules than it
consumes.
v. Comparison of the three sets of kinetic parameters
show no significant difference between them.[91]

EL‐MORSHEDY ET AL.
17 of 24
TABLE 8 Kinetic Parameters evaluated by Horowitz‐ Metzger, Coats‐Redfern and Broido equations for Fe (III), Mn (II) and Cr (III)
complexes of H4BPCD
Ea
A
ΔH*
ΔS*
ΔG*
Mid
Temp.(K)
Compound
step
Method
KJ\mol
(S−1
)
KJ\mol
KJ\mol. K
KJ\mol
[Cr2(BPCD)Cl2(H2O)4].H2O
1st
299.66
346.67
660.41
774.33
HM
CR
B
HM
CR
B
HM
CR
B
HM
CR
B
244.29
247.79
258.4
59.73
55.25
2.41 × 1040
1.00 × 1041
5.8 × 1043
4.81 × 106
1.09 × 106
2.56 × 106
5.08 × 107
1.26 × 107
3.29 × 107
1.49 × 1041
4.51 × 1039
1.87 × 1040
241.79
245.31
255.91
56.85
52.37
59.52
124.28
116.27
130.28
626.77
604.34
630.76
−0.528
−0.539
−0.593
−0.118
−0.131
−0.104
−0.104
−0.116
−0.088
0.535
83.54
83.50
78.26
97.84
97.62
2nd
3rd
4th
62.41
95.69
129.77
121.76
135.77
633.21
610.78
637.19
192.96
192.59
188.70
212.23
212.30
214.74
0.506
0.537
[Fe2(BPCD)Cl2(H2O)4].5H2O
1st
316.95
553.62
758.7
HM
CR
B
HM
CR
B
HM
CR
B
HM
CR
B
88.52
84.17
89.45
92.72
88.43
5.3 × 1012
1.06 × 1012
9.31 × 1012
1.77 × 106
7.66 × 105
9.50 × 106
5.66 × 1018
6.53 × 1019
5.1 × 1020
2.59 × 1026
3.67 × 1025
2.63 × 1026
85.88
81.53
86.82
88.12
83.83
−0.002
−0.015
−0.002
−0.130
−0.137
−0.116
0.106
0.127
0.163
−0.252
−0.236
−0.252
86.46
86.34
85.91
2nd
3rd
4th
160.33
159.88
157.23
228.21
228.15
213.81
233.85
233.73
233.93
97.35
92.75
315.19
330.56
343.71
450.09
436.49
450.28
308.88
324.25
337.40
443.19
429.59
443.38
829.97
[Mn2(H3BPCD)Cl3(H2O)3].3H2O
1st
312.16
348.4
HM
CR
B
HM
CR
B
HM
CR
B
HM
CR
B
67.05
64.51
69.78
1.24 × 109
5.02 × 108
6.5 × 109
64.45
61.91
67.19
−0.071
−0.079
−0.057
−0.276
−0.284
−0.313
−0.040
−0.034
−0.005
0.145
86.68
86.49
85.10
97.24
97.16
2nd
3rd
4th
196.27
198.96
204.87
144.68
147.78
157.39
352.61
334.12
347.52
1.88 × 1027
4.89 × 1027
1.61 × 1028
9.17 × 1010
1.91 × 1011
6.14 × 1012
6.7 × 1020
4.37 × 1019
2.11 × 1020
193.37
196.06
201.97
140.07
143.17
152.78
345.85
327.37
340.52
92.94
555.35
812.8
162.39
162.12
155.69
227.63
227.59
230.37
0.123
0.136
FIGURE 21 1st degradation step for [Fe2(BPCD)Cl2(H2O)4].5H2O complex by a) Coats‐Redfern method. b) Horowitz‐Metzger method. c)
Broido method

18 of 24
EL‐MORSHEDY ET AL.
i. H4BPCD and [Fe2(BPCD)Cl2(H2O)4].5H2O were
effective against all organisms, but the parent ligand
was the most effective.
3.8 | Biological studies and molecular
docking
ii. [Cr2(BPCD)Cl2(H2O)4].H2O exhibited both antibac-
terial and antifungal activities towards S. aureus
and C. Albicans respectively.
3.8.1 | Determination of minimum inhib-
itory concentration (MIC)
Importance of MIC arises clearly in symptomatic research
centers to confirm resistance of microorganisms to anti-
microbial agents, in addition, to control the activity of
new antimicrobial agents. The isolated compounds were
initially evaluated for in vitro antibacterial activity against
G + ve and G‐ve bacteria and fungal using Broth
method.[97] Standard antibiotic namely Ampicillin and
standard antifungal drug Clotrimazole were applied as
reference drugs. On the basis of the data obtained and
listed in Table 9 (Figure 22). A glance of data indicates
that:
iii. [Mn2(H3BPCD)Cl3(H2O)3].3H2O show moderate
activity against C. Albicans only.
iv. Finally, the negative results can be explained either
to the disability of the compounds to diffuse through
the cell wall of the bacterium and/or fungi organ-
isms, and hence couldn't interfere with its biological
activity or they can diffuse and inactivated by
unknown cellular mechanism.
3.8.2 | Antioxidant activity (determina-
tion of SOD‐like activity)
TABLE 9 Minimal inhibitory concentration (MIC, μg/ml) of the
newly synthesized compounds
Within a cell, the superoxide dismutases (SODs) consti-
tute the first line of defense against ROS.[98] Therefore,
SOD mimics have these great attention potential pharma-
ceutical agents for treating such diseases. A significant
SOD‐like activity was observed for H4BPCD as repre-
sented in Table 10, with inhibition percent 77.3%. Since
iron is a most relevant metal for the design of synthetic
SOD catalysts,[99] [Fe2(BPCD)Cl2(H2O)4].5H2O shows
high SOD‐like activity as inhibition percent 70.1%
followed by [Cr2(BPCD)Cl2(H2O)4].H2O with 63.5% per-
cent. [Mn2(H3BPCD)Cl3(H2O)3].3H2O exhibited lowest
SOD‐like activity (33.1%). Therefore, H4BPCD and
Compound
E. coli S. aureus C. Albicans
Ampicillin
125
‐‐‐‐
93.7
‐‐‐‐
‐‐‐‐
5.8
23.4
750
Clotrimazole
H4BPCD
187.5
750
125
750
NA
750
[Fe2(BPCD)Cl2(H2O)4].5H2O
[Mn2(H3BPCD)Cl3(H2O)3].3H2O NA
750
375
[Cr2(BPCD)Cl2(H2O)4].H2O
NA = no activity
NA
FIGURE 22 Comparison of MIC (mg/ml) of prepared compounds with standard antibiotics and antifungal drug: Amp. (Ampicillin);
Clotri. (Clotrimazole)

EL‐MORSHEDY ET AL.
19 of 24
TABLE 10 Superoxide (SOD)‐like activity of the metal complex
for very short distances. The activity of the compounds
as antioxidative enzyme
follow
the
order
H4BPCD
>
[Fe2(H2BPCD)
Cl4(H2O)2].5H2O
>
[Cr2(BPCD)Cl2(H2O)4].
Δ through
%
H2O > [Mn2(H3BPCD)Cl3(H2O)3].3H2O. The active com-
pounds were subjected to MG‐DNA displacement assay
and the results are shown in Table 11. These results are
in accordance with the antimicrobial screening data and
explain them, suggesting that binding with DNA may
contribute to the activity of these compounds against bac-
terial infections.
The molecular interactions of compounds for inhibi-
tion against E. coli are represented in Table 12 and Fig-
ures 23–26. According to this interaction, H4BPCD
shows interactions with the active site residues and it
has the highest glide E‐model with −186.345 for E. coli
Compound
5 min
inhibition
Control
0.468
0.101
0.106
0.140
0.313
0.171
0%
L‐Ascorbic acid
78.4%
77.3%
70.1%
33.1%
63.5%
H4BPCD
[Fe2(BPCD)Cl2(H2O)4].5H2O
[Mn2(H3BPCD)Cl3(H2O)3].3H2O
[Cr2(BPCD)Cl2(H2O)4].H2O
% inhibition = (ΔControl‐ ΔTest/ΔControl) × 100
[Fe2(BPCD)Cl2(H2O)4].5H2O complex can be used as
antioxidants.
compared
with
reference
drug,
ampicillin
(E‐model = −65,69) (Figures 23 and 24) which similar
to experimental DNA‐binding affinity. The high affinity
3.8.3 | DNA‐binding affinity and docking
studies
The displacement was determined by a spectrophotomet-
ric assay as a decrease in the absorbance at 630 nm.
Mostly all compounds under investigation showed high
affinity to DNA which was confirmed by retaining the
DNA‐compound complex at the origin or by migrating
TABLE 11 DNA/methyl green colorimetric assay of the DNA‐
binding and E‐model of ligands (H4BPCD) and its metal complexes
DNA/methyl green E‐model
compound
(IC50, μg/ml)
(towards E.coli)
H4BPCD
29.5 1.7
65.6 3.5
−186.345
−47.976
[Cr2(BPCD)
Cl2(H2O)4].H2O
[Mn2(H3BPCD)
Cl3(H2O)3].3H2O
70.5 3.7
40.2 2.5
−44.994
[Fe2(H2BPCD)
‐‐
Cl4(H2O)2].5H2O
IC50 values represent the concentration (mean SD, n = 3–5 separate deter-
minations) required for a 50% decrease in the initial absorbance of the DNA/
methyl green solution.
FIGURE 23 2D molecular interaction of H4BPCD for inhibitor to
E. Coli
TABLE 12 Molecular interactions predicted for inhibitor binding to E.Coli
Hydrogen bonds
Compound
Donor Acceptor
Salt bridge
π‐cation
π‐ π Stacking edge to face
H4BPCD
ILE20 ➔ (C=O)
SER91 ➔ (N−)
H2O ➔ (C=O)
LYS163‐‐(C‐O−)
‐‐‐‐
TYR146
PHE94
[Cr2(BPCD)Cl2(H2O)4].H2O
H2O ➔ (C=O)
LYS43‐‐‐(C‐O−)
LYS43‐(Ar ring)
PHE94
[Mn2(H3BPCD)Cl3(H2O)3].3H2O
(NH) ➔ SER198
‐‐‐‐
‐‐‐‐
‐‐‐‐

20 of 24
EL‐MORSHEDY ET AL.
FIGURE 24 3D molecular interaction of H4BPCD for inhibitor to E. Coli
FIGURE 25 3D molecular interaction
of [Cr2(BPCD)Cl2(H2O)4].H2O for
inhibitor to E. Coli
of H4BPCD against E.coli is resulting from interaction via
hydrogen bonds [ILE20 ➔ (C=O), SER91 ➔ negative (N
−) and H2O ➔ (C=O)], Salt bridge between LYS163 and
negative oxygen of (C‐O−) as well as π‐ π stacking edge
to face of aromatic rings with TYR146 and PHE94. While,
the interaction of [Cr2(BPCD)Cl2(H2O)4].H2O (glide E‐
model = −47.98) with E. coli (Figure 25) through
hydrogen bonds H2O ➔ (C=O), Salt bridge between
LYS43 and negative oxygen of (C‐O−), π‐cation between
LYS43‐(aromatic ring) and π‐ π stacking edge to face of
aromatic
ring
with
PHE94.
Furthermore,
[Mn2(H3BPCD)Cl3(H2O)3].3H2O
shows glide
E‐model = −44.99 with interaction only through hydro-
gen bond donor (NH) ➔ SER198 (Figure 26).[43] While,

EL‐MORSHEDY ET AL.
21 of 24
FIGURE 26 3D molecular interaction
of [Mn2(H3BPCD)Cl3(H2O)3].3H2O for
inhibitor to E. Coli
while [Fe2(H2BPCD)Cl4(H2O)2].5H2O hasn't any interac-
tion with E.coli.
I. In general, compounds were active against G + ve
more than G‐ve bacteria. The higher resistance can
be attributed to the different composition of cell‐
wall membrane.[100]
II. It was observed that Fe (III) complex exhibited
moderate activity against tested organisms, followed
by Cr (III) complex. This activity might be due to
the presence of free C=N groups which is electron
donating group. Antimicrobial activity was consid-
erably enhanced by presence of electron donating
groups.[101]
3.8.4 | Structure activity relationships
(SAR's)
From the results of antimicrobial activity of the newly
investigated compounds and on correlating by their struc-
tures it has been observed that:
FIGURE 27 MTT‐cytotoxicity assay of H4BPCD and its Cr (III) and Mn (II) complexes

22 of 24
EL‐MORSHEDY ET AL.
III. The presence of free OH groups in most of the pre-
pared compounds may confer the turbulence of
membranous permeability of the bacterial cell‐wall
through their lateral interactions mediated by H‐
bonds with it.[102] So it could be an important factor
to inhibit the bacterial growth. This may explain
why Mn (II) complex have no activity against tested
bacteria cause there in no free OH groups in it.
H4BPCD show greater response than Cr (III) and Mn (II)
complexes with human tumor cells of hepatocellular car-
cinoma (HePG‐2). Since of the compounds are good can-
didate for future pharmacological studies the obtained
results will be useful in their use in these areas.
ORCID
Mohammed M. El‐Gamil
https://orcid.org/0000-0001-
5605-2844
Gaber M. Abu El‐Reash https://orcid.org/0000-0002-0456-
7325
3.8.5 | MTT‐cytotoxicity assay
In our experiments, IC50 values (compound concentra-
tion that produces 50% of cell death) in micro molar units
were calculated. For comparison purposes, the cytotoxic-
ity of Fluorouracil (5‐FU) and the free ligand as well as
its complexes has been evaluated under the same experi-
mental conditions (Figure 27). It is clearly observed that
chelation with metal has no synergistic effect on the cyto-
toxicity. Importantly, it should be emphasized that the
ligand shows good activity with IC50 = 37.01 μmol/l rela-
tive to that of Fluorouracil (2.95 μmol/l) for HePG2.
These gratifying results are encouraging its further
screening in vitro. Later on, upon further analysis, the
ligand also exhibits considerable cell growth inhibition
activity against human liver hepatocellular carcinoma
HePG‐2 cells. Therefore, its further biological evaluation
in vivo as well as studies of mechanism of action is neces-
sary. But the two complexes of Cr (III) and Mn (II) show
results of IC50 (μmol/l) = 79.12 and 49.46 against (HePG‐
2), respectively.
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