Synthesis, Characterization, Theoretical Studies, and Antimicrobial/Antitumor Potencies of Salen and Salen/Imidazole Complexes of Co (II), Ni (II), Cu (II), Cd (II), Al (III) and La (III)

Article abstract of DOI:10.1002/aoc.5912

Although salens and imidazoles are well-studied motifs among bioactive and therapeutic agents, their properties when combined in transition metal complexes are not well developed. To explore the structure/reactivity of this class of compounds, a salen-based ligand, namely (2,2′-{1,2-ethanediylbis[nitrilo(E)methylylidene]}diphenol, S), and its binary (MS) and ternary (MSI) complexes (I = imidazole; M = Co (II), Ni (II), Cu (II), Cd (II), Al (III), and La (III)) have been synthesized and fully characterized by standard physicochemical and theoretical methods. Evidence from structural analysis tools along with DFT modeling revealed an unusual monobasic tridentate salen binding mode, involving the phenolic oxygen, the nitrogen of the azomethine group, and NH group formed via phenol-to-cyclohexadienone tautomerization, giving rise to a general molecular formula of MSI complexes as [M(S)(I)₂(Cl)] for M (II) = Co, Ni, Cu and Cd or [M(S)(I)(Cl)₂] for M (III) = Al and La, respectively. The antimicrobial activities of S, MS, and MSI were screened against several bacterial and fungal strains. Of all tested complexes, CdS and CuSI were the most effective antimicrobials, giving larger inhibition zones than the reference antibiotics. The antimicrobial efficacy for the MS complexes follows the order: CdS > gentamicin > CuS > NiS > CoS > LaS > AlS > S, whereas MSI complex, potencies are ordered as CuSI > gentamicin > CdSI >NiSI > CoSI > LaSI > AlSI > S. In vitro cytotoxicity screening of MSI complexes disclosed that both CuSI and CdSI exhibited higher activity against human liver (Hep-G2) and breast (MDA-MB231) carcinoma cell lines than the reference (cisplatin) drug. The satisfactory bioactivities observed for several of these compounds supports the underlying design idea for combining important bioactive motifs for possible therapeutic benefit.

Full text of DOI:10.1002/aoc.5912

Received: 15 April 2020
DOI: 10.1002/aoc.5912
Revised: 4 June 2020
Accepted: 11 June 2020
F U L L P A P E R
Synthesis, Characterization, Theoretical Studies, and
Antimicrobial/Antitumor Potencies of Salen and
Salen/Imidazole Complexes of Co (II), Ni (II), Cu (II),
Cd (II), Al (III) and La (III)
Ehab M. Abdalla1 | Laila H. Abdel Rahman2
Mohamed R. Shehata4 | Asma A. Alothman5
| Antar A. Abdelhamid2,3
| Ayman Nafady5
|
1Chemistry Department, Faculty of
Although salens and imidazoles are well-studied motifs among bioactive and
therapeutic agents, their properties when combined in transition metal com-
plexes are not well developed. To explore the structure/reactivity of this class
of compounds, a salen-based ligand, namely (2,20-{1,2-ethanediylbis[nitrilo(E)
methylylidene]}diphenol, S), and its binary (MS) and ternary (MSI) complexes
(I = imidazole; M = Co (II), Ni (II), Cu (II), Cd (II), Al (III), and La (III)) have
been synthesized and fully characterized by standard physicochemical and
theoretical methods. Evidence from structural analysis tools along with DFT
modeling revealed an unusual monobasic tridentate salen binding mode,
involving the phenolic oxygen, the nitrogen of the azomethine group, and NH
group formed via phenol-to-cyclohexadienone tautomerization, giving rise to a
general molecular formula of MSI complexes as [M(S)(I)2(Cl)] for M (II) = Co,
Ni, Cu and Cd or [M(S)(I)(Cl)2] for M (III) = Al and La, respectively. The
antimicrobial activities of S, MS, and MSI were screened against several bacte-
rial and fungal strains. Of all tested complexes, CdS and CuSI were the most
effective antimicrobials, giving larger inhibition zones than the reference
antibiotics. The antimicrobial efficacy for the MS complexes follows the order:
CdS > gentamicin > CuS > NiS > CoS > LaS > AlS > S, whereas MSI
complex, potencies are ordered as CuSI > gentamicin > CdSI >NiSI > CoSI >
LaSI > AlSI > S. In vitro cytotoxicity screening of MSI complexes disclosed that
both CuSI and CdSI exhibited higher activity against human liver (Hep-G2)
and breast (MDA-MB231) carcinoma cell lines than the reference (cisplatin)
drug. The satisfactory bioactivities observed for several of these compounds
supports the underlying design idea for combining important bioactive motifs
for possible therapeutic benefit.
Science, New Valley University, Alkharga,
Egypt
2Chemistry Department, Faculty of
Science, Sohag University, Sohag, 82534,
Egypt
3Chemistry Department, Faculty of
Science, Albaha University, P.O. Box
1988, Albaha, Saudi Arabia
4Chemistry Department, Faculty of
Science, Cairo University, Giza, Egypt
5Department of Chemistry, College of
Science, King Saud University, Riyadh,
11451, Saudi Arabia
Correspondence
Laila H. Abdel Rahman, Chemistry
Department, Faculty of Science, Sohag
University, 82534, Sohag, Egypt.
Email: lailakenawy@hotmail.com
Ayman Nafady, Department of Chemistry,
College of Science, King Saud University,
Riyadh-11451, Saudi Arabia.
Email: anafady@ksu.edu.sa
Funding information
the Deanship of Scientific Research at
King Saud University, Grant/Award
Number: GR-1441-236
K E Y W O R D S
antimicrobial, cytotoxicity, DFT calculations, imidazole, Salen
Appl Organomet Chem. 2020;e5912.
wileyonlinelibrary.com/journal/aoc
© 2020 John Wiley & Sons, Ltd.
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https://doi.org/10.1002/aoc.5912

2 of 22
ABDALLA ET AL.
1 | INTRODUCTION
applications of both binary and ternary transition metal/-
lanthanides complexes.33,34 The present work offers
rationale for the design and synthesis of novel binary and
ternary complexes of di- and trivalent transition
metal ions with either salen-type ligand such as (2,20-
{1,2-ethanediylbis[nitrilo(E)methylylidene]}diphenol, S)
or in combination with imidazole (I) ligand. The
prepared salen and mixed salen/imidazole metal com-
plexes are referred to as MS and MSI, respectively, where
M = Co (II), Ni (II), Cu (II), Cd (II), Al (III), and La (III).
After full experimental and theoretical structural analy-
sis, which revealed a mono basic tridentate coordination
mode of the salen ligand, the antimicrobial/anticancer
activities of the new MS and MSI complexes have been
explored against several bacterial and fungal strains as
well as liver (Hep-G2) and breast (MDA-MB231)
carcinoma cell lines.35–37
Metallosalens are highly versatile coordination com-
pounds with a wide range of applications including
homogenous and heterogeneous catalysis, herbicidal and
fluorogenic agents, pesticides, as well as magnetic and
optical devices.1–10 As their ligating groups resemble
those in metalloproteins and enzymes, they are popular
bioinorganic model compounds and functional enzyme
mimics.11–13 Their biological activities and rich photo-
physical properties have led to numerous studies on
their potential usage as therapeutics and biosensors.14–17
Moreover, owing to their freedom of conformation, flexi-
ble salen-type ligands played important role in the con-
struction of infinite 1-D and 2-D coordination polymers
and supramolecular frameworks having different coordi-
nation modes with metal ions.18–20 Significantly, these
studies established that the structure of salen-based
complexes are highly dependent upon the identity of
metal ions, the ionic radius, the nature of counter ions,
and the pH of the medium.20–23
2 | EXPERIMENTAL
2.1 | Reagents
The imidazole nucleus is an important synthetic motif
in drug discovery, and many imidazoles have been
prepared as pharmacological agents, including azomycine,
clotrimazole, miconazole, ergothioneine, clonidine,
and oxendine. Imidazoles have become important
subunits of numerous pharmaceuticals, being found in
many vantifungal, antibacterial,24–27 anti-inflammatory,28
analgesic,29 antidepressant, and antihypertensive medica-
tions.30 Thus, different types of metal complexes compris-
ing imidazole derivatives were synthesized in order to
investigate their abilities to inhibit the growth of bacteria
and fungi as well as to fight against cancer cells. Among
these endeavors, mixed-ligand complexes are particularly
attractive candidates owing to their combined pharmaco-
logical activities such as the antimicrobial efficiency and
DNA cleavage. Recently, there have been many studies of
mixed-ligand complexes with nitrogen containing hetero-
cyclic amines and Schiff base ligands. The presence of
hetero-aromatic groups in the structure of nitrogen donors
such as 2,20-bipyridine, 1,10-phenanthroline and imidazole
gives these ligands additional structural properties as well
as therapeutic and pharmacological activity.31,32
The demand for new antimicrobial drugs is chronic
because of the increased clinical and microbiological
resistance of microbes. Accordingly, novel drugs that can
disrupt the action of microbes while remaining safe for
the host are urgently needed. A further pressing need for
cancer therapeutic agents also necessitates the develop-
ment of new molecular entities.32
Our ongoing interest in Schiff base ligands and their
metal complexes has focused on probing structure-
biological activity relationship and other related
All chemicals {ethylene diamine, salicylaldehyde, imidaz-
ole, sodium hydroxide, lanthanum (III) chloride
(LaCl3ꢀ7H2O), aluminum (III) chloride (AlCl3ꢀ6H2O),
cadmium (II) chloride (CdCl2ꢀH2O), cobalt (II) chloride
(CoCl2.6H2O), nickel (II) chloride (NiCl2ꢀ6H2O) and cop-
per (II) chloride (CuCl2ꢀ2H2O)} were purchased from
Sigma-Aldrich Chemie (Germany). Organic solvents such
as absolute ethanol and dimethyl sulfoxide (DMSO)
were commercially available reagent grade and used
without purification.
2.2 | Physical measurement methods
Melting and decomposition points for salen and its binary
(MS) and ternary (MSI) complexes were measured on a
Gallenkamp apparatus. FTIR spectra of the materials in
the region from 400 to 4,000 cm−1 were recorded using
the KBr pellet method with the aid of a Shimadzu FTIR
spectrophotometer (model 8,101). A Jenway conductivity
meter (model 4,320) was used to measure the molar
conductance of the binary and mixed complexes. UV–Vis
spectra were recorded in DMSO using a Jasco P-530 spec-
trophotometer. A Bruker 400 MHz spectrometer was
1
used to record H and 13C NMR spectra in DMSO-d6,
utilizing tetramethylsilane (TMS) as an internal standard.
Mass spectra were acquired using the electron impact
(EI) ionization technique at 70 eV on a Hewlett–Packard
MS-5988 GC–MS instrument at the Microanalytical Cen-
ter, National Center for Research, Egypt. Elemental

ABDALLA ET AL.
3 of 22
analyses of all new compounds were performed at Cairo
University with a Perkin-Elmer elemental analyzer
(model 240c). Magnetic measurements were performed
with the aid of a Gouy's balance. Additionally, a
Shimadzu DTG-60H differential thermal gravimetric
analyzer was utilized to record the thermograms of
the complexes in air at a heatingꢁ rate of 10 ꢁCꢀmin−1
from ambient temperature to 800 C. A Hanna 211 pH
meter was used to measure the pH values using
the Britton universal buffers series. Finally, to evaluate
anticancer activity, a Metertech Σ 960 ELISA microplate
reader was used to measure the absorbance for each well
at 564 nm.
CH2-N), 6.69–7.37 (m, 8H, Ar-H), 8.54 (s, 2H, 2 N=CH),
13.3 (br s, 2H, 2 ArOH). 13C NMR (100 MHz, DMSO-d6, δ):
58.68, 116.99, 119.00, 132.22, 132.94, 161.19, 167.28.
2.4 | Synthesis of binary metal complexes
(MS)
Binary salen complexes of Co (II), Ni (II), Cu (II), Cd (II),
Al (III), and La (III) were obtained according to the
following general procedure. The salen ligand (0.268 g,
1 mmol) was dissolved in ethanol (10 ml) and added to
the metal salt (1 mmol; = 0.238 g Co (II); 0.236 g Ni (II);
0.249 g Cu (II); 0.201 g Cd (II); 0.241 g Al (III); or 0.372 g
La (III)) in aqueous ethanol (10 mL). The reaction mix-
ture was refluxed for 2 hr at 70 ꢁC with constant stirring.
The resultant solution was let cool with solvent evapora-
tion; the solid precipitate was filtered from the reaction
mixture, thoroughly washed with ethanol to remove any
traces of starting materials, and dried under vacuum. The
purity of the complexes was checked by TLC.39
2.3 | Synthesis of salen
In a round-bottomed flask, ethylenediamine (0.601 g,
0.01 mol) and salicylaldehyde (2.44 g, 0.02 mol) were
mixed in absolute ethanol (50 ml) and refluxed for
60 min. The reaction mixture was concentrated to half of
its volume, whereupon a yellow precipitate was formed.
This was collected by filtration, washed with ethanol,
and dried at laboratory temperature.38
2.5 | Synthesis of ternary salen/imidazole
complexes (MSI)
2,20-{1,2-Ethanediylbis[nitrilo(E)methylylidene]}
ꢁ
diphenol (salen): Yield 96%; mp 127 C, yellow solid.
Anal. Calc. for C16H16N2O2 (%): C, 71.59; H,
5.96; N, 10.44, Found (%): C, 71.52; H, 5.88; N, 10.36.
Mixed salen/imidazole complexes of Co (II), Ni (II),
Cu (II), Cd (II), Al (III), and La (III) were obtained
according to a general procedure (Scheme 1). The salen
ligand (0.268 g, 1 mmol) was dissolved in ethanol (10 ml)
and the metal salt (1 mmol = 0.238 g Co (II); 0.236 g
FTIR (KBr, cm−1): 3292 (OH), 3,049–3,007 (CH)arom
,
2,899–2,867 (CH)aliph, 1,608 (C=N), 1,217 (C–C). 1H
NMR (DMSO-d6/D2O, 400 MHz, δ): 3.87 (t, 4H, N-CH2-
SCHEME 1 Synthesis pathway for Co (II),
Ni (II), Cu (II), Cd (II), Al (III) and La (III)
mixed ligand of Salen and imidazole complexes

4 of 22
ABDALLA ET AL.
Ni (II); 0.249 g Cu (II); 0.201 g Cd (II); 0.241 g Al (III);
or 0.372 g La (III)) was dissolved in 10 ml aqueous etha-
nol (1:1 H2O/EtOH). The two solutions were mixed
dropwise with constant stirring and refluxed for 1 hr at
70 ꢁC. Then, imidazole (0.136 g, 2 mmol) in ethanol
(10 ml) was added dropwise to the previous mixture and
reflux was continued for 1 hr. The reaction mixture was
left to cool and evaporate overnight. The colored solid
products (light brown CoSI, brownish red NiSI, dark
green CuSI, pale yellow CdSI, dark yellow AlSI, and
yellow LaSI) were filtered off, thoroughly washed with
ethanol to remove any traces of unreacted starting mate-
rials, and dried under vacuum. The purity of the com-
plexes was checked by TLC.40
(br s, 2H, 2OH for 2H2O), 3.87 (t, 4H, Ph-CH=N-CH2-
CH2-N), 6.72–6.88 (m, 4H, Ar-H), 7.36–7.43 (m, 5H, 4H
cyclic hexadaine + 1H for NH), 8.53 (s, 2H, Ph-CH=N-
CH2-CH2-NH-CH=C), 13.34 (br s, 1H, ArOH). 13C NMR
(100 MHz, DMSO-d6, δ): 53.51, 116.34, 120.03, 121.64,
134.58, 135,47, 164.96, 167.59.
AlSI: Yield 76%; mp 285 ꢁC dec.; dark yellow solid. Anal.
Calc. for [C19H21AlClN4O3]+ClꢀH2O (%): C, 48.63; H,
4.94; N, 11.94; M, 5.75. Found (%): C, 48.56; H, 4.87; N,
11.90; M, 5.67. Am (Ω−1mol−1cm−2) 76.20. μeff, diamag-
netic. FTIR (KBr, cm−1): 3121 (NH), 3,010 (CH)arom
,
2,914–2,787 (CH)aliph, 1740 (C=O), 1,630 (C=N), 1,202
1
(C-O), 977 (H2O coordinated), 528 (M-O), 482 (M-N). H
NMR (DMSO-d6/D2O, 400 MHz, δ): 3.30 (s, 2H, H2O for
complex), 3.33–3.86 (t, 4H, Ph-CH=N-CH2-CH2-N),
6.61–6.92 (m, 4H, Ar-H), 7.10 (m, 5H, 4H cyclic
hexadiene + 1H for NH), 7.30–7.63 (m, 3H, imidazole
ring), 8.60 (s, 2H, Ph-CH=N-CH2-CH2-N=CH), 12.04
(br s, 1H, 1NH imidazole ring). 13C NMR (100 MHz,
DMSO-d6, δ): 53.51, 79.68, 116.34, 120.03, 121.64, 134.58,
135.47, 164.96, 167.59, 174.65.
The yields and characterization details for the MS and
MSI complexes follow:
ꢁ
CdS: Yield 75%; mp 265 C dec; yellow solid. Anal. Calc.
for C16H15CdClN2O2 (%): C, 46.29; H, 3.64; N, 6.75; M,
27.08. Found (%): C, 46.14; H, 3.60; N, 6.68; M, 26.95.
Am (Ω−1mol−1cm−2
)
41.5. μeff, diamagnetic. FTIR
(KBr, cm−1): 3292 (OH), 3,260 (NH), 3,067 (CH)arom
,
LaS: Yield 79%; mp 250 C dec.; brown solid. Anal. Calc.
ꢁ
2,956 (CH)aliph, 1739 (C=O), 1,640 (C=N), 1,202 (C-O),
536 (M-O), 449 (M-N). 1H NMR (DMSO-d6/D2O,
400 MHz, δ): 2.61–3.00 (t, 2H, Ph-CH=N-CH2-CH2-N),
3.93 (t, 2H, Ph-CH=N-CH2-CH2-N), 6.67–6.86 (m, 4H,
Ar-H), 7.23–7.41 (m, 5H, 4H cyclic hexadione + 1H ole-
fin), 8.59 (s, 1H, Ph-CH=N-CH2-CH2-N), 13.34 (br s, 1H,
ArOH). 13C NMR (100 MHz, DMSO-d6, δ): 59.21, 116.94,
119.10, 132.13, 132.80, 161.09, 167.37, 168.86.
for [C16H17Cl2LaN2O3].2H2O (%): C, 36.18; H, 3.98; N,
5.27; M, 26.15. Found (%): C, 36.04; H, 3.53; N, 5.19; M,
26.01. Am (Ω−1mol−1cm−2) 30.80. μeff, diamagnetic. FTIR
(KBr, cm−1): 3555 (OH), 3,209 (NH), 3,086 (CH)arom
,
2,971–2,805 (CH)aliph, 1740 (C=O), 1,623 (C=N), 1,215
(C-O), 979 (H2O coordinated), 536 (M-O), 420 (M-N).
LaSI: Yield 80%; mp 270 ꢁC dec.; yellow solid. Anal.
Calc. for [C19H19Cl2LaN4O2].1.5H2O (%): C, 39.85;
H, 3.84; N, 9.79; M, 24.28. Found (%): C, 39.77; H,
3.79; N, 9.70; M, 24.21. Am (Ω−1mol−1cm−2) 33.10. μeff,
diamagnetic. FTIR (KBr, cm−1): 3555 (OH), 3,115
(NH), 3,065 (CH)arom, 2,971–2,839 (CH)aliph, 1740 (C=O),
1,629 (C=N), 1,217 (C-O), 534 (M-O), 420 (M-N). 1H
NMR (DMSO-d6/D2O, 400 MHz, δ): 3.11–3.15 (s, 2H,
H2O for complex), 3.84–3.93 (t, 4H, Ph-CH=N-CH2-CH2-
N), 6.85–6.95 (m, 4H, Ar-H), 7.30–7.38 (m, 6H, 4H
for cyclohexadiene + 2H (NH for NH-CH=C + NH for
imidazole ring)),7.41–7.49 (s, 1H, 1H of imidazole ring),
8.35 (s, 2H, 2H of imidazole ring), 8.60 (s, 2H, Ph-CH=N-
CH2CH2NH-CH=C). 13C NMR (100 MHz, DMSO-d6, δ):
56.37, 59.18, 116.87, 119.20, 121.42, 132.10, 132.92,
133.02, 135.30, 160.51, 167.36, 168.37.
CdSI: Yield 78%; pale yellow solid. Anal. Calc. for
[C22H23CdClN6O2]0.5H2O (%): C, 49.41; H, 4.49; N,
15.72; M, 21.04. Found (%): C, 49.21; H, 4.42; N, 15.63; M,
20.96. Am (Ω−1mol−1cm−2) 33.10. μeff, diamagnetic. FTIR
(KBr, cm−1): 3337 (OH), 3,129 (NH), 3,050–3,009
(CH)arom, 2,928–2,849 (CH)aliph, 1739 (C=O), 1,630
1
(C=N), 1,217 (C–O), 558 (M–O), 472 (M–N). H NMR
(DMSO-d6/D2O, 400 MHz, δ): 3.03 (br s, 1H, OH for 0.5
H2O), 3.68–3.93 (t, 4H, Ph-CH=N-CH2-CH2-N), 6.85–6.87
(m, 4H, Ar-H), 7.10 (m, 4H, 4H for cyclic hexadiane),
7.30–7.79 (m, 6H, 2 imidazole rings), 8.59 (s, 2H, Ph-
CH=N-), 11.71 (br s, 1H, NH for NH-Cd), 13.32 (br s, 2H,
2NH imidazole). 13C NMR (100 MHz, DMSO-d6, δ):
59.21, 116.95, 118.57, 119.10, 122.24, 132.11, 132.79,
136.55, 161.08, 167.36.
CoS: Yield 86%; mp 260 ꢁC dec.; brown solid. Anal. Calc.
for [C16H17CoN2O3]+Cl−ꢀH2O (%): C, 48.32; H, 4.81; N,
7.04; M, 14.82. Found (%): C, 48.12; H, 4.42; N, 6.96; M,
13.62. Am (Ω−1mol−1cm−2) 75.40. μeff (B.M.) 1.8. FTIR
ꢁ
AlS: Yield 74%; mp 260 C dec.; yellow. Anal. Calc. for
[C16H19AlClN2O4]+Cl− (%): C, 47.90; H, 4.77; N, 6.98; M,
6.72. Found (%): C, 47.85; H, 4.69; N, 6.95; M, 6.65.
Am (Ω−1mol−1cm−2) 131.50. μeff, diamagnetic. FTIR
(KBr, cm−1): 3431 (OH), 3,212 (NH), 3,049–3,010
(CH)arom, 2,973–2,867 (CH)aliph, 1740 (C=O), 1,636
(C=N), 1,209 (C-O), 903 (H2O coordinated), 548 (M-O),
(KBr, cm−1): 3362 (OH), 3,205 (NH), 3,050 (CH)arom
,
2,970 (CH)aliph, 1740 (C=O), 1,626 (C=N), 1,223 (C-O),
964 (H2O) coordinated, 527 (M-O), 438 (M-N).
CoSI: Yield 88%; mp 273 ꢁC dec.; light brown solid. Anal.
Calc. for [C22H23ClCoN6O2]0.5 H2O (%): C, 52.09; H,
1
483 (M-N). H NMR (DMSO-d6/D2O, 400 MHz, δ): 3.30

ABDALLA ET AL.
5 of 22
4.73; N, 16.75; M, 11.62. Found (%): C, 51.65; H, 4.43; N,
16.25; M, 11.32. Am (Ω−1mol−1cm−2) 39.80. μeff (B.M.)
2.41. FTIR (KBr, cm−1): 3389 (OH), 3,134 (NH),
3,052–3,023 (CH)arom, 2,969 (CH)aliph, 1740 (C=O), 1,632
(C=N), 1,203 (C-O), 516 (M-O), 446 (M-N).
NiS: Yield 83%; mp 265 ꢁC dec.; red solid. Anal. Calc. for
[C16H15ClN2NiO2] 0.5H2O (%): C, 51.82; H, 4.32; N,
7.56; M, 15.84. Found (%): C, 51.42; H, 4.27; N, 7.36; M,
15.64. Am (Ω−1mol−1cm−2) 29.60. μeff (B.M.) 1.99. FTIR
(KBr, cm−1): 3432 (OH), 3,397 (NH), 3,054–3,026
(CH)arom, 2,963–2,794 (CH)aliph, 1739 (C=O), 1,627
(C=N), 1,212 (C-O), 538 (M-O), 442 (M-N).
The average crystallite size (ξ) can be calculated from
the XRD pattern according to the Debye–Scherrer
equation17,42:.
Kλ
ξ =
β½ Cosθ
The equation uses the reference peak width at angle θ,
where λ is the wavelength of the X-rays (1.542475 Å), K is
a constant taken as 0.95 for organic compounds,17 and
β½ is the width at half maximum of the reference diffrac-
tion peak measured in radians.
NiSI: Yield 79%; mp 291 ꢁC dec.; brownish red solid. Anal.
Calc. for [C22H23ClN6NiO2]ꢀ0.5H2O (%): C, 52.11; H,
4.74; N, 16.58; M, 11.58. Found (%): C, 52.08; H, 4.67; N,
16.43; M, 11.52. Am (Ω−1mol−1cm−2) 37.50. μeff (B.M.) 2.40.
FTIR (KBr, cm−1): 3240 (OH), 3,118 (NH), 3,080–3,018
(CH)arom, 2,942–2,845 (CH)aliph, 1740 (C=O), 1,618 (C=N),
1,224 (C-O), 553 (M-O), 429 (M-N).
2.8 | Antimicrobial potency
The biological potencies of the MS and MSI complexes
were evaluated against two Gram-positive bacteria
(Bacillus subtilis (+ve) and Staphylococcus aureus (+ve)),
two Gram-negative bacteria (Escherichia coli (−ve) and
Proteus vulgaris (−ve)), and two fungi (Candida albicans
and Aspergillus flavus) using the agar diffusion test. DMSO
was used to dissolve the compounds43 and paper discs
were impregnated with the various MS and MSI complex
solutions. After drying, the discs were placed in plates
inoculated with the microorganismsꢁ. The plates were then
ꢁ
CuS: Yield 78%; mp 271 C dec.; dark green solid. Anal.
Calc. for [C16H15ClCuN2O2]ꢀ2H2O (%): C, 47.67; H,
4.76; N, 6.96; M, 15.79. Found (%): C, 47.37; H, 4.56; N,
6.76; M, 15.69. Am (Ω−1mol−1cm−2) 72.10. μeff (B.M.) 1.73.
FTIR (KBr, cm−1): 3283 (OH), 3,210 (NH), 3,042–3,011
(CH)arom, 2,951–2,860 (CH)aliph, 1740 (C=O), 1,646
(C=N), 1,210 (C-O), 572 (M-O), 438 (M-N).
ꢁ
CuSI: Yield 75%; mp 278 C dec.; dark green solid. Anal.
incubated for 25–33 hr at 24
2 C and the inhibition
Calc. for [C22H23ClCuN6O2]ꢀ½H2O (%): C, 51.62; H,
4.69; N, 16.42; M, 12.42. Found (%): C, 51.42; H, 4.56; N,
16.22; M, 12.12. Am (Ω−1mol−1cm−2) 32.10. μeff (B.M.)
2.33. FTIR (KBr, cm−1): 3223 (OH), 3,100 (NH),
3,045–3,011 (CH)arom, 2,919–2,854 (CH)aliph, 1739 (C=O),
1,646 (C=N), 1,213 (C-O), 572 (M-O), 440 (M-N).
zones were accurately evaluated. As the microorganisms
developed, except in the zone where the concentration of
salen and its metal complexes was over the minimum
inhibitory concentration (MIC), inhibition areas were
observed. The obtained results were compared against two
standards, gentamicin as the antibacterial agent, and keto-
conazole as the antifungal agent.
2.6 | Computational study
2.9 | MTT assay for anticancer activity
The lowest energy geometries were calculated using
density functional theory (DFT) via the Gaussian09
program. The DFT/B3LYP/LANL2DZ level of theory
was utilized for the geometry optimization to obtain the
lowest energy structures for salen and its complexes.
The cytotoxicity of the synthesized ligand and
complexes against breast cancer cell line was examined by
MTT assay [MTT: 3(4,5-dimethylthiazol-2-yl)-2,5-diphenyl
tetrazolium bromide]. The cell suspension was diluted
with complete medium to a concentration of 5 × 104
cellꢀml−1. Using a micropipette, the cell suspension
(100 μL) was pipetted into each well of a 96-well plate
(abꢁout 5,000 cells per well). The plate was incubated at
37 C for 24 hr to allow cell attachment. After 24 hr, the
cells were treated with growth medium (100 μL)
containing the newly synthesized compounds (0, 0.001,
0.01, 0.1, 1, 10 and 100 μL) in triplicate. Cells were washed
with phosphate buffered saline (PBS) and fresh relevant
medium containing a solution of MTT in PBS (20 μL,
0.5 mgꢀmL−1) was added to the test wells. The plate was
2.7 | PXRD analysis
Powder diffraction is a technique that uses X-ray, neutron,
or electron diffraction from powder or microcrystalline
samples for structural characterization of the materials. It
can only reveal that each solid represents a definite com-
pound with a defined structure which is not contaminated
with starting materials. The identification of the complexes
was performed using a known standard method.41

6 of 22
ABDALLA ET AL.
further incubated in a CO2 incubator at 37 ꢁC for 4 hr, and
after which the MTT assay was performed. The assay is
based on reducing the tetrazolium salt MTT to insoluble
purple formazan by metabolically active cells that are
quantifiable by spectrophotometry. For this purpose, the
formed formazan crystals were dissolved in DMSO
(120 μL) for each well. The cell viability was determined
by measuring the absorbance of each well at 570 nm and a
reference wavelength of 630 nm using an ELISA spectro-
photometer. Results were expressed in terms of the con-
centration required to inhibit cell growth by 50% relative
to untreated cells (IC50). IC50 values were calculated using
Graph Pad Prism version 6.01, 2012 (Graph Pad software,
San Diego, CA, USA). Dose response curves were
generated by plotting the log concentration versus
corresponding viability %.
the different metal ions.44 The multiplet signals in the
3.87 ppm region in the salen spectrum may be assigned to
the four protons of the ethane bridge (CH2CH2); these
signals appear at 3.68–3.93, 3.30–3.86, and 3.84–3.93 ppm in
the [Cd(S)(I)2Cl]ꢀ0.5H2O, [Al(S)(I)(H2O)Cl]ClꢀH2O, and [La
(S)(I)Cl2]ꢀ1.5H2O complexes, respectively.
The multiplet signals in the 6.69–7.37 ppm region in
the salen spectrum are assigned to aromatic protons;45,46
these signals are found at 6.85–6.87, 6.61–6.92, and
6.85–6.95 ppm in the [Cd(S)(I)2Cl]ꢀ0.5H2O, [Al(S)(I)(H2O)
Cl]ClꢀH2O, and [La(S)(I)Cl2]ꢀ1.5H2O complexes, respec-
tively. Moreover, other signals appear at 7.10, 7.10, and
7.30–7.38 ppm due to (4H, 4H for cyclic hexadiane), (5H,
4H cyclic hexadiene + 1H for NH) and (6H, 4H for cyclo-
hexadaine + 2H (NH for NH-CH=C + NH for imidazole
ring) in the [Cd(S)(I)2Cl]ꢀ0.5H2O, [Al(S)(I)(H2O)Cl]
ClꢀH2O, and [La(S)(I)Cl2]ꢀ1.5H2O complexes, respectively
are due to the formation of the carbonyl group in the com-
plexes via tautomerization in salen upon complexation.
The singlet signal observed at 8.54 ppm in the salen
spectrum is assigned to the two imino protons; this signal
shifts slightly to 8.59, 8.60, and 8.60 ppm in the [Cd(S)
(I)2Cl]ꢀ0.5H2O, [Al(S)(I)(H2O)Cl]ClꢀH2O, and [La(S)(I)
Cl2]ꢀ1.5H2O complexes, respectively, and can be attributed
to coordination of the different metal ions to the
azomethine group. The singlet signal observed at 13.3 ppm
3 | RESULTS AND DISCUSSION
3.1 | Characterization of salen and its
complexes
3.1.1 | Physicochemical properties
All the prepared binary and ternary salen-based metal
chelates are colored and air stable.. The analytical results
for the complexes are consistent with the proposed
molecular formula and confirm the formation of 1:1 (M:
S) binary complexes and 1:1:2 mixed salen/imidazole (M:
S: I) complexes of Co (II), Ni (II), Cu (II), and Cd (II). For
Al (III) and La (III), the molar ratios for the mixed
salen/imidazole complexes are 1:1:1. The molar conduc-
tance values for the complexes in 10−3 M DMF solution
are in the range 29.6–41.5 Ω−1cm2mol−1 for the binary
complexes, except for AlS, which has a value of
131.5 Ω−1cm2mol−1. The range for the MSI complexes
(32.9–76.2 Ω−1cm2mol−1) reveals their non-electrolytic
nature, except for the AlS binary complex, which is ionic.
1
in the H NMR spectrum of salen, which corresponds
to the phenolic proton, disappears in the [Cd(S)(I)2Cl]ꢀ
0.5H2O, [Al(S)(I)(H2O)Cl]ClꢀH2O, and [La(S)(I)Cl2]ꢀ
1.5H2O complexes. Other signals appear for the imidazole
and NH groups of the metal complexes; the signals
observed at 11.71, 7.10, and 7.30–7.38 ppm may be
assigned to for NH-groups in the Cd, Al, and La
complexes. For [Cd(S)(I)2Cl]ꢀ0.5H2O, the signals observed
at 7.30–7.79 and 13.32 ppm may be assigned to protons on
the imidazole rings as well as the NH–imidazole group,
respectively. Similar resonances at 7.30–7.63 and 12.04
may be assigned for [Al(S)(I)(H2O)Cl]ClꢀH2O, respectively,
whereas the imidazole ring protons are separated into two
groups at 7.41–7.49 and 8.35 ppm and the NH–imidazole
peak shifts to 7.30–7.38 ppm for [La(S)(I)Cl2]ꢀ1.5H2O.
1
3.1.2 | H and 13C NMR spectra of salen
The H NMR data clearly show that the complexes
1
and its complexes
contain water molecules, with signals observed at 3.03,
3.30, and 3.11–3.15 ppm integrating to one-half, one, or
one-and-a-half mol H2O in [Cd(S)(I)2Cl]ꢀ0.5H2O, [Al(S)(I)
(H2O)Cl]ClꢀH2O and [La(S)(I)Cl2]ꢀ1.5H2O, respectively.
Moreover, 13CNMR spectrum of salen ligand
(Figure S2A) showed that presence of 2CH2 equivalents
at 58.96, aromatic signals 116.99 to 161.19 and 167.28
signal significant to the azomethine group of CH=N.
Upon complexation with Cd to form CdS complex, the
obtained 13C NMR spectrum (Figure S2B) revealed the
disappearance of the azomethine group of CH=N and
To help assign the structures of the new complexes, they
1
were subjected to H and 13C NMR spectroscopy. Repre-
1
sentative H and 13C NMR spectra for salen, CdS, and
AlS,as well as CdSI, AlSI, and LaSI are presented in
Figure 1, and Figure S1 and S2.
In comparing the positions of the proton signals in the
MSI complexes of Cd, Al, and La with those of salen itself, it
can be concluded that all signals are in the expected region
and shift only slightly due to the coordination of salen with

ABDALLA ET AL.
7 of 22
FIGURE 1 1H NMR spectrum of Salen(a), CdS(b) and CdSI(c) complex in DMSO d6

8 of 22
ABDALLA ET AL.
the appearance of cyclic C=O at 167.37. Similarly, in the
case of AlS complex, a rearrangement of the phenolic
group gave rise to the disappearance of the CH=N signal
and the detection of a cyclic C=O signature at 167.59 as
illustrated in Figure S2C. However, in case of ternary
salen/imidazole Cd complex (CdSI) the obtained 13C
NMR spectrum (Figure S2D) showed sharp and strong
signals in the aromatic region, consistent with the pres-
ence of two imidazole moieties coordinated to Cd ion. In
a masked contrast, both ternary AlSI and LaSI complexes
gave the signature for only one imidazole moiety as
shown in Figure S2E and S2F.
form in both binary and ternary complexes. The appear-
ance of a new band at 3134, 3118, 3,100, 3,129, 3,121, and
3,115 cm−1 in the ternary complexes is due to the NH of
the imidazole ligand. In addition, all the prepared metal
chelates displayed broad bands at 3389, 3223, 3,337,
3,121, and 3,568 cm−1, which are interpreted as the υ(OH)
stretching vibrations of hydrated water molecules, and in
agreement with the elemental analysis and 1H NMR
results. Indeed, the FTIR spectra of the prepared Al and
La complexes show bands at 977 and 976 cm−1, respec-
tively, which are assigned to the rocking mode of the
coordinated water in the metal complexes.
Based on the foregoing results, it can be concluded
that the metal ions coordinate to the salen ligand through
azomethine nitrogen and phenolic oxygen from one side,
and NH group from the second side. The NH group
coordinates to the metal ion and salen behaves as
monobasic tridentate ligand. The results also confirm the
presence of two imidazole molecules in the coordination
sphere in the case of the Cd complex and only one
imidazole in the cases of Al and La complexes.
3.1.4 | Electronic spectra
The UV–Vis spectra of salen and its metal complexes
were measured at room temperature in the region of
200–700 nm in DMSO, as shown in Figure 2. The absorp-
tion spectrum of salen shows three absorption bands. The
3.1.3 | IR spectra of salen and its
complexes
FTIR spectra of salen and its binary and ternary salen/
imidazole metal complexes are depicted in Figure S3
(A–M). The salen spectrum shows a band at 1608 cm−1
which corresponds to the −C=N stretching vibration. On
complexation, this band is shifted to a higher frequency
for the binary (1,626, 1,627, 1,624, 1,613, 1,636, and
1,623 cm−1) and mixed-imidazole (1,632, 1,618, 1,646,
1,630, 1,630, and 1,629 cm−1) salen complexes of Co, Ni,
Cu, Cd, Al, and La, respectively. The red-shifts are
evidence of the participation of the azomethine nitrogen
atoms in complex formation.39,41,47 Salen also displays a
band at 1279 cm−1, which is assigned to the ν(C-O)
stretching vibration. The coordination of the phenolic
oxygen atom can be confirmed by the red-shift of this
vibration to 1,231–1,213 cm−1 upon complex formation.
This is supported by appearance of a band at 446, 426,
440, 431, 482, and 420 cm−1 and another at 516, 553,
572, 558, and 534 cm−1, which correspond to the
stretching vibrations of the M–N and M–O bonds in the
Co, Ni, Cu, Cd, Al, and La complexes, respectively.
Importantly,
a distinct IR band appearing at
1740 cm−1 for all complexes is attributed to the
C=O stretching vibration, whereas the band at
3205–3260 cm−1 for MS complexes and 3,223–3,389 cm−1
for MSI complexes can be referred to the NH group of the
salen ligand. These data confirm that salen prefers to
coordinate to the metal ion using the more stable keto
FIGURE 2 Electronic spectra of the synthesized Co (II), Ni
(II), Cu (II), Cd (II), Al (III) and La (III) complexes of Salen(a) and
Mixed Salen imidazole(b) in DMSO with concentration 10−3 M at
298 K

ABDALLA ET AL.
9 of 22
first high intensity band at λmax = 280 nm may be attrib-
uted to the π ! π* transition of the aromatic rings. The
second and third absorption bands (at 320 and 409 nm)
are attributed to the n ! π* transition of the azomethine
group (C=N) and charge transfer, respectively.48,49 In the
electronic spectra of the complexes, these bands are
shifted from those of the free ligand, to 274–291 and
304–363 nm for the π ! π* transitions of the aromatic
rings and n ! π* transitions of the azomethine groups,
respectively, confirming the coordination of the
azomethine nitrogen to the metal ions. Also, a band
appears at 421 nm in the Cd complex, corresponding to
charge transfer. Furthermore, absorption bands in the
visible region – at 422 nm for the Co complex and at
430 nm for the Ni complex – are observed; these bands
are considered to arise from d–d transitions.50
peaks at m/z 269.07 amu for salen and m/z 508.53,
498.08, 512.63, 558.09, 469.00, and 572.32 amu for the
respective metal complexes. These data are in good agree-
ment with the proposed molecular formulas for salen
and its complexes.
3.1.6 | PXRD of salen and its binary and
ternary salen/imidazole complexes
Since the growth of single crystals of the synthesized com-
plexes failed, PXRD was performed. The powder diffrac-
tion patterns of salen and its binary and mixed-imidazole
complexes of Cd and La were recorded over 2θ = 5–70ꢁ
Table 1 and Figure 4. The position of the highest intensity
peak was determined, along with the width of this peak at
half-maximum and the d spacing. The diffractogram of
salen displays a reflection with a maximum at 2θ = 13.14ꢁ,
corresponding to a d value of 6.7318.
3.1.5 | ESI-MS spectra
The powder XRD patterns of the complexes are
completely different from that of salen, demonstrating
the formation of the coordination compounds. The pat-
terns reveal well-defined crystalline peaks indicating the
crystalline nature of salen and its binary and mixed-
imidazole Cd and La complexes.
MS has been increasingly used for the elucidation of
ligand and metal–ligand complex molecular structure.
The ESI-MS spectra of the complexes are depicted in
Figure 3 and S5, and the proposed fragmentation pattern
for salen and the NiSI complex are shown in Scheme 2.
The mass spectra of salen and the MSI complexes of Co,
Ni, Cu, Cd, Al, and La (Figure S4) display molecular ion
The average particle sizes of the salen ligand and its
Cd and La binary and mixed-imidazole complexes,
FIGURE 3 The mass spectrum of Salen Schiff base ligand(S) and its binary (LaS), mixed ligand (LaSI) complexes

10 of 22
ABDALLA ET AL.
SCHEME 2 Mass fragmentation of
Salen ligand and its NiSI complex
TABLE 1 PXRD results for salen and its Cd and La binary and mixed-imidazole complexes
Crystallographic parameters
Crystal system
Monoclinic
Monoclinic
Monoclinic
Monoclinic
Monoclinic
D (nm)
49.93
32.99
77.08
55.67
95.98
a (nm)
6.98
b (nm)
14.90
11.30
25.72
7.69
c (nm)
10.41
11.05
8.17
CdS
CdSI
LaS
9.17
7.56
LaSI
Salen
6.65
19.61
17.24
9.80
8.78
calculated using the Scherrer equation, are 0.554 (S), 1.01
(CdS), 0.388 (CdSI), 0.343 (LaS), and 0.531 (LaSI) nm.
compounds, as well as to collect information about the
water content within the lattice structure. Thus, TG
and differential thermogravimetric (DTG) analyses for
salen ligand and all the prepared metal complexes over
ꢁ
3.1.7 | Thermogravimetric analysis
the 30–800 C temperature range are shown in Table 2,
Figure 5, Figure S5, Scheme 3 and Scheme S1. The TG
curves for the [M(S)(I)2Cl]ꢀ0.5H2O complexes (M = Co,
Ni, Cu, Cd) show six weight-loss events. The first
Thermogravimetric analysis (TGA) was carried out to
probe the thermodynamic stability of the obtained

ABDALLA ET AL.
11 of 22
FIGURE 4 XRD powder pattern of
Salen ligand(a) and its complexes where
CdS(b), CdSI(c), LaS(d) and LaSI(e)
ꢁ
decomposition step takes place between 40 and 150 C
and is accompanied by a weight loss of 1.50–1.90%,
which is interpreted as the loss of the half molecule of
lattice water from the complexes. The second step
10.25–30.90% (calc. Mass loss = 10.26–39.96%) occurs at
375–720 ꢁC and corresponds to the loss of HCl + O,
C2H6NO + HCl, C2H4N + HCl, and C7H7NO2 + HCl
from the mixed imidazole complexes of Co, Ni, Cu, and
Cd, respectively. The final products are the Co, Ni, Cu,
and Cd metals.
ꢁ
occurs in the range 140–250 C and corresponds to the
losses of C6H5CN, C6H5CN, C3H4N2, and C6H4 moieties
with an estimated weight loss range of 12.9–18.20%
(calc. Mass loss = 13.29–18.15) from the MSI com-
plexes. The third step occurs between 210 and 345 ꢁC
and is considered the loss of C7H5O, C3H4N2, C3H4N2,
and C6H8N4 moieties with an estimated mass reduction
of 13.4–24.25% (calc. Mass loss = 13.29–24.30%). The
The thermal degradation curves for the [Al(S)(I)Cl
(OH2)]ClꢀH2O and [La(S)(I)Cl2]ꢀ1.5H2O complexes reveal
ꢁ
five weight loss stages. The first loss at 25–95 C corre-
sponds to the loss of one or one-and-a-half water mole-
cules of hydration (estimated mass loss = 3.90–4.95%;
calc. Mass loss = 3.84–4.72%). The second step occurs
in the range 80–170 ꢁC and corresponds to the loss
of C3H4N2 + HCl + H2O and C3H4N2 + HCl, with
an estimated loss of 18.00–25.75% (calc. Mass
loss = 18.09–25.89%) from the Al and La complexes,
respectively. The third step occurs within the range of
ꢁ
fourth step takes place at 275–505 C and can be attrib-
uted to the loss of C2H6N, C6H5CN, C7H5NO, and
CH2N fragments, with an estimated mass loss of
4.95–23.25% (calc. Mass loss = 5.00–23.27%). The fifth
degradation step takes place at 325–670 ꢁC and is
attributed to the loss of C6H8N4, C7H5O, C7H5NO, and
C2H5 with an estimated weight loss of 4.90–26.55%
(calc. Mass loss = 5.18–26.86%). The final loss of
ꢁ
160–286 C and is attributed to the loss of the C6H4O
moiety (est. mass loss = 16.10–19.50%; calc. Mass
loss = 16.08–19.60%). The fourth weight loss takes place

12 of 22
ABDALLA ET AL.
TABLE 2 TGA results for thermal degradation of Salen ligand and its mixed imidazole complexes
Compound
Salen
Temp. range ꢁC
150–330
>330
Weight lost % calc (found)
79.5 (79.76)
19.50 (20.12)
1.77 (1.75)
Assignments
C12H10N2O2
C4H6
CoSI
25–90
0.5H2O
C6H5CN
C7H5O
C2H6N
HCl + O
C6H8N4
Co
[Co(S)(I)2Cl]ꢀ0.5H2O
90–225
225–345
345–505
505–670
670–720
>720
20.32 (20.29)
20.72 (20.65)
8.68 (8.71)
10.36 (10.29)
26.83 (26.78)
58.93
Residue
NiSI
90–110
110–205
205–248
248–288
288–335
335–405
405–555
>555
1.78 (1.75)
0.5H2O
Cl
[Ni(S)(I)2Cl]ꢀ0.5H2O
7.01 (6.88)
20.33 (20.31)
20.73 (20.83)
11.84 (11.81)
13.42 (13.39)
13.42 (13.44)
58.69
C6H5CN
C7H5O
C2H6NO
C3H4N2
C3H4N2
Ni
Residue
CuSI
100–205
205–250
250–275
275–340
340–375
375–515
>515
1.76 (1.79)
0.5H2O
C3H4N2
C3H4N2
C7H5NO
C7H5O
C2H4N + HCl
Cu
[Cu(S)(I)2Cl]ꢀ0.5H2O
13.29 (13.41)
13.29 (13.35)
23.27 (23.22)
20.53 (20.49)
15.39 (15.28)
63.54
Residue
CdSI
110–160
160–210
210–240
240–335
335–380
380–640
>640
1.61 (1.55)
0.5 H2O
C6H4
[Cd(S)(I)2Cl]ꢀ0.5H2O
13.56 (13.49)
24.27 (24.21)
4.99 (4.93)
2C3H4N2
CH2N
5.18 (5.13)
C2H5
Residue
30.96 (30.65)
112.41
C7H7O2N + HCl
Cd
AlSI
25–95
3.83 (3.79)
H2O
[Al(S)(H2O)(I)Cl]Cl.H2O
95–160
160–286
286–375
375–575
>575
25.89 (25.78)
19.60 (19.63)
22.37 (22.40)
22.69 (22.64)
26.98
C3H6N2OCl
C6H4O
C7H5O
C3H7N2Cl
Al
Residue
LaSI
30–80
4.72 (4.74)
1.5 H2O
C3H4N2Cl
C6H4O
C7H5O
C3H7N2Cl
La
[La(S)(I)Cl2]ꢀ1.5H2O
80–170
170–240
240–340
340–470
>470
18.09 (17.98)
16.08 (16.01)
18.35 (18.31)
18.61 (18.59)
138.90
Residue

ABDALLA ET AL.
13 of 22
FIGURE 5 TGA curves for
thermal degradation of Salen ligand and
its Co (II), Ni (II), Cu (II), Cd (II), Al
(III), La (III) binary(a) and mixed
imidazole(b) complexes from ambient
temperature to 800 ꢁCat heating rate of
10 ꢁC/min
SCHEME 3 Thermal degradation
of CuSI and LaSI mixed imidazole
complexes from ambient temperature to
800 ꢁC with heating rate of 10 ꢁC/min
at 240–375 ꢁC and refers to the loss of the C7H5O
fragment, with an estimated mass loss of 18.25–22.25%
(calc. Mass loss 18.35–22.37%). The last step, occurring
at 340–575 ꢁC with a weight loss of 18.20–22.60%
(calc. Mass loss = 18.16–22.69%), corresponds to the loss
of the C3H7N2Cl fragment, leaving Al and La metals as
the final products of decomposition.
applications of the synthesized MIS chelates is from
pH 5 to 11.
3.2 | Theoretical and DFT computations
To support the proposed structures of the prepared
complexes and gain more insights about the favored and
most stable forms, types of bonding and coordination
sites offered by the salen ligand, DFT calculations were
conducted for the ligand and corresponding metal
complexes as described below.
3.1.8 | pH profile
The pH profiles (absorbance vs. pH) presented in
Figure S6 exhibit typical dissociation curves and high
stability of binary MS and ternary mixed ligand MIS
complexes, where in the pH ranges of 5–9, 6–9, 6–10,
5–10, 6–10, and 7–11 for the tested MIS chelates
(M = Co, Ni, Cu, Cd, Al, and La). Thus, metal chelate
formation greatly stabilizes the mixed ligands. Conse-
quently, a suitable pH range for potential biological
3.2.1 | Salen
It is generally established that salen ligand can adopt two
isomeric structures, namely keto-enol and enol-enol
forms. DFT calculations (Figure 6) showed that the

14 of 22
ABDALLA ET AL.
FIGURE 6 The optimized structure of the
Keto-Enol (a) and the Enol-Enol (b) by density
function B3LYP/LANL2DZ
TABLE 3 Total energies of isomeric keto-enol (S) and enol-enol (S0) forms of salen
Hartree
−879.716
−879.131
−0.585
eV
kcalꢀmol−1
−552030.147
−551663.054
−367.093
kJꢀmol−1
−2309694.136
−2308158.219
−1535.917
S
−23938.48
−23922.561
−15.919
S0
Difference
former is more stable than the latter by −0.585 Hartree,
−15.919 eV, −367.093 kcal/mol, or −1535.917 kJ/mol, as
evident by the optimized ligand structure with the lowest
energy configuration as shown in Table 3 and Figure 6.
The natural charges obtained from natural bond orbital
(NBO) analysis showed that the more negative active
sites are ordered as, O2 (−0.728) > O1 (−0.720) > N1
(−0.488) > N2 (+0.583). This finding clearly established
that the salen ligand offers a tridentate coordination to
the metal using O2, N1, and N2 sites to form stable 5-
and 6-membered rings.
To lend further support for this conclusion, total ener-
gies calculations have been performed for the CoSI com-
plex as a model example, and taking into consideration
the two possible forms of salen ligand during complex
formation. DFT results (Figure S7) revealed that the
energy of the complex CoSI, with coordinated Cl− ion as
[Co(L)(imidazole)2Cl] is more negative, and therefore
more stable than that of the other possible structure with-
out coordinated chloride ion, [Co(L)(imidazole)2], and
the salen ligand has two OH groups and two -C=N
groups (Table S1). This result supports the experimental
findings in which the salen ligand acts as a mono basic
tridentate ligand rather than the dibasic tetradentate. The
former configuration is most likely stabilized by the facile
resonance-assisted hydrogen bonding induced by the
coordination of Cl− ion to the metal center in the inner
sphere of the complex.
3.2.2 | DFT calculations for ternary
salen/imidazole (MSI) complexes
Figure 7 shows the optimized structures of the mixed
salen/imidazole complexes {[Co(S)(I)2Cl], [Ni(S)(I)2Cl],
[Cu(S)(I)2Cl], [Cd(S)(I)2Cl], [Al(S)(H2O)(I)Cl]+, and [La
(S)(I)Cl2]} in their lowest energy configurations, and
Tables 4 and 5 and S2–5 present the related important
optimized bond lengths and bond angles. In all the com-
plexes, the six-coordinate metal atom adopts an octahe-
dral geometry with the N1, N2, Cl, and O2 atoms lying
nearly in one plane, which deviates by 0.204ꢁ to −3.477ꢁ.
The distances between N1•••N2, N1•••O2, and N2•••O2
in the ligand (3.756, 4.288, and 7.414 Å, respectively) are
longer than those in the complexes due to complex for-
mation through the N1, N2, and O2 atoms. The natural
charges computed by NBO analysis on the coordinated
atoms are summarized in Table 6.
3.2.3 | MEP surfaces and HOMO-LUMO
energies
Figure 8 displays the molecular electrostatic potential
(MEP) surfaces for these complexes, which map the posi-
tively (blue) and negatively (red, i.e., representing loosely
bound or excess electrons) charged electrostatic potentials
in the molecule. The computed total energies, highest

ABDALLA ET AL.
15 of 22
FIGURE 7 The optimized structure of [Co(S)(I)2Cl](a), [Ni(S)(I)2Cl](b), [Cu(S)(I)2Cl](c), [Cd(S)(I)2Cl](d), [Al(S)(H2O)(I)Cl]+(e) and [La
(S)(I)Cl2](f) using B3LYP/LANL2DZ, H atoms on carbon atoms are omitted for clarity
TABLE 4 Important optimized bond lengths (Å) and bond
angles (ꢁ) for [Co(S)(I)2Cl]
TABLE 5 Important optimized bond lengths (Å) and bond
angles (ꢁ) of [La(S)(I)Cl2]
Bond length (Å)
Bond length (Å)
Type of Bond length
Type of
bond
Type of
bond
Bond length
(Å) Complex
Type of
bond
bond
(Å) Complex
L
Complex
L
Complex
Co-N1
Co-N2
Co-O2
Co-Cl
Co-N4
1.938
Co-N5
-
1.993
La-N1
La-N2
La-O2
La-Cl1
La-Cl2
2.736
2.842
2.278
2.329
2.773
La-N4
-
2.704
2.054
1.894
N1•••N2
3.756 2.723
N1•••N2
N1•••O2
N2•••O2
3.756 2.916
4.288 2. 892
7.414 4. 653
2.278
N1•••-O2 4.288 2.708
1.978
N2•••O2
7.414 3.944
Type of
Angle
Angle (ꢁ)
Complex
Type of
Angle
Angle (ꢁ)
Complex
Type of
Angle
Angle (ꢁ)
Complex
Type of
Angle
Angle (ꢁ)
Complex
N1-Co-N2
N1-Co-O2
O2-Co-Cl
N2-Co-Cl
N4-Co-N1
N4-Co-N2
N4-Co-Cl
N4-Co-O2
85.95
89.93
93.11
90.98
89.43
88.57
89.33
90.50
N5-Co-N1
N5-Co-N2
N5-Co-Cl
N5-Co-O2
N1-Co-Cl
N2-Co-O2
N4-Co-N5
N1-N2-Cl-O2
91.37
92.96
89.95
88.03
176.7
175.8
178.3
0.204*
N1-La-N2
N1-La-O2
O2-La-Cl2
N2-La-Cl2
N4-La-N1
N4-La-N2
N4-La-Cl2
N4-La-O2
63.00
69.77
117.5
100.9
77.89
70.43
80.02
85.91
Cl1-La-N1
Cl1-La-N2
Cl1-La-Cl2
Cl1-La-O2
N1-La-Cl2
N2-La-O2
N4-La-Cl1
85.60
85.18
111.7
106.2
156.1
130.3
154.8
N1-N2-Cl2-O2
−0.340*
*dihedral angle.
*dihedral angle.
occupied molecular orbital (HOMO) energies, lowest
unoccupied molecular orbital (LUMO) energies, and
dipole moments for salen and the salen/imidazole
complexes were calculated (Table 7). The more-negative
total energy values for the complexes relative to that of free
salen indicate that the complexes are more stable than the

16 of 22
ABDALLA ET AL.
TABLE 6 The natural charges computed by NBO analysis for
active atoms of the ligand and its complexes
compared to that of the ligand explains the charge-transfer
interactions upon complex formation.
The natural charges, computed by NBO
compound
analysis
3.3 | Biological activity
S (keto-enol)
O2 (−0.728) > O1 (−0.720) > N1 (−0.488) > N2
(−0.583).
3.3.1 | Antimicrobial bioassay
[Co(S)(I)2Cl]
[Ni(S)(I)2Cl]
[Cu(S)(I)2Cl]
[Cd(S)(I)2Cl]
Co (+0.409), O2 (−0.650), N1 (−0.487), N2
(−0.653), N4 (−0.498), N5 (−0.490) and Cl
(−0.433
Practically, a number of designed pharmaceutical drugs
have been found to be active against Gram-positive than
Gram-negative bacteria.51 The prepared compounds, in
this work, were found to be active against both types of
bacteria, which may indicate broad-spectrum properties.
Salen and its binary (MS) and ternary (MSI) complexes
were screened for their antibacterial activity against
E. coli and P. vulgaris (Gram −ve bacteria) and S. aureus
and B. subtilis (Gram +ve bacteria), as well as their anti-
fungal activity against C. albicans and A. flavus, using the
agar diffusion technique; these activities were compared
with those of the standard drugs, gentamicin (antibiotic)
and ketoconazole (antifungal).
Ni (+0.594), O2 (−0.662), N1 (−0.525), N2
(−0.680), N4 (−0.542), N6 (−0.554) and Cl
(−0.439)
Cu (+0.803), O2(−0.695), N1(−0.584),
N2(−0.686), N4(−0.577), N5(−0.571) and
Cl(−0.513)
Cd (+1.354), O2 (−0.783), N1 (−0.677), N2
(−0.741), N4 (−0.617), N6 (−0.626), and Cl
(−0.719)
[Al(S)(H2O)
(I)Cl]+
Al (+1.959), O2 (−0.897), N1 (−0.758), N2
(−0.803), N4 (−0.748), O3 (−1.021) and Cl
(−0.597)
The measured antibacterial and antifungal activities
of salen and its complexes are listed in Tables S6 and S7
and presented in Figure 10 (a-c). From these results, it
is clearly established that the activities of the MS
complexes follow the order: CdS > gentamicin >
CuS > NiS > CoS > LaS > S > AlS, with CdS binary com-
plex being more powerful antimicrobial than that of
gentamicin for all bacterial strains except E. coli (−ve).
[La(S)(I)Cl2]
La (+1.156), O2 (−0.600), N1 (−0.216), N2
(−0.473), N4 (−0.276), Cl1 (−0.465), and Cl2
(−0.462)
free ligand. Also, the energy gaps (Eg = ELUMO − EHOMO
)
are smaller in the cases of the complexes compared to that
of salen due to chelation of the ligand to the metal ions
(Table 7, Figure 9). The lowering of Eg in the complexes
FIGURE 8 Molecular electrostatic potential (MEP) surface of ligand, L (Keto-Enol) and complexes ([Co(S)(I)2Cl], [Ni(S)(I)2Cl], [Cu(S)
(I)2Cl], [Cd(S)(I)2 Cl] and [La(S)(I)Cl2]) using B3LYP/LANL2DZ

ABDALLA ET AL.
17 of 22
TABLE 7 DFT calculated energies of salen and its complexes at the B3LYP/LANL2DZ level
d
E a
−879.716
HOMO b
−5.5120
−3.6649
−4.2989
−5.0012
−4.9931
−8.5940
−5.8238
LUMO c
−2.0202
−1.9029
−2.3046
−2.3298
−2.6050
−5.3373
−2.5745
E g
Dipole moment (μ) e
S (keto-enol)
[Co(S)(I)2Cl]
[Ni(S)(I)2Cl]
[Cu(S)(I)2Cl]
[Cd(S)(I)2Cl]
[Al(S)(H2O)(I)Cl]+
[La(S)(I)Cl2]
3.4918
1.7620
1.9943
2.6714
2.3881
3.2567
3.2493
4.1271
12.416
11.053
11.674
10.974
11.950
18.978
−1491.00
−1515.21
−1542.06
−1394.00
−1198.10
−1166.16
aE: total energy (a.u.).
bHOMO: highest occupied molecular orbital (eV).
cLUMO: lowest unoccupied molecular orbital (eV).
dEg = ELUMO − EHOMO (eV).
edipole moment (Debye).
FIGURE 9 HOMO and LUMO charge density maps of ligand and complexes ([Co(S)(I)2Cl], [Ni(S)(I)2Cl], [Cu(S)(I)2Cl], [Cd(S)(I)2Cl],
[Al(S)(H2O)(I)2Cl]+ and [La(S)(I)Cl2]) using B3LYP/LANL2DZ
We also found that the inhibition zone of CuS is slightly
larger than that of gentamicin in the case of S. aureus
(+ve), whereas for P. vulgaris (−ve), the zone is nearly
equal to the standard (26 vs. 25 mm for gentamicin,
respectively). Thus, the obtained results clearly show that
the antibacterial potency of salen ligand has dramatically
increased upon complexation for all tested bacterial spe-
cies. This enhancement in the antibacterial activity of
metal-salen (MS) complexes can be explained in terms of
the partial sharing of the positive charge of the metal ion
with the donor (N and O) atoms of salen, leading to
electron delocalization over the whole chelate ring
system. Given that the biological activity of the metal
compounds depends on the chelate effect of the ligands,
the total charge on the complex ion, the nature of the
donor atoms and the metal ion, and the geometrical
structure of the complex.52 Therefore, for the studied
divalent ions, which have different electronic configura-
tion Co (II) d7, Ni (II) d8, Cu (II) d9 and Cd (II) d10, it was
found that the ionic radius decreases on going from Co
(II) to Cd (II). This means that the charge density is
increasing in the same direction, giving rise to an

18 of 22
ABDALLA ET AL.
FIGURE 10 (a, b): Graph showing a) antibacterial activity of binary Salen complexes and b) antibacterial activity of mixed imidazole-
Salen complexes at concentration of 10 mg ml −1against Gentamycin as reference drug. c) The inhibition zone of the new compounds binary
salen and mixed salen/imidazole complexes against (A) Gram-positive B. subtilis and (B) Gram-negative P. vulgaris bacteria for a) LaS, b)
AlS, c) NiS, d) CdS, e) LaSI, f) AlSI, g) NiSI, and h) CdSI at 10 mgꢀml−1
increase the antimicrobial activity as noted in our results.
The fact that the antibacterial potency of the trivalent
ions, La (III) 5d0 and Al (III) 2s22p6 is less than that
of the divalent metal ions could be referred to their
electronic configuration.
Among all MSI complexes, CuSI displays a larger
inhibition zone (30 mm) than that of gentamicin
(26 mm) in the case of S. aureus, while the inhibition
potency of CdSI against the B. subtilis bacterial strain is
greater than the standard (Figure 10). In the antifungal
activity tests against C. albicans and A. flavus (Figure S8),
none of the compounds demonstrate growth inhibition
of the target fungi except CuSI, which has antifungal
activity higher than that of the reference compound,
ketoconazole.
Variability in cell wall structure can produce differ-
ences in antibacterial susceptibility; some antibiotics can
kill only Gram-positive bacteria and are ineffectual
against Gram-negative pathogens.51 For example, the for-
mer bacteria possess thick cell walls containing many
layers of peptidoglycan and teichoic acids, while the lat-
ter have relatively thin cell walls consisting of a few
layers of peptidoglycan surrounded by a second lipid
membrane containing lipopolysaccharides and lipopro-
teins. Thus, the variation in the activity of the metal com-
plexes against the different organisms depends on the
impermeability of the microorganism's cells. Other differ-
ences, such as ribosomal structure, can also apply.53
Furthermore, the size of the inhibition zone depends
upon the concentration of the antibacterial agent where
other factors such as culture medium, incubation condi-
tions and rate of diffusion have been fixed.
In view of the aforementioned biological findings, the
efficient potencies of all prepared and tested complexes
could be explained in terms of chelation theory,49 in
which chelation is expected to increase the lipophilic
nature of the central atom, thus favors its permeation
through the lipid layer of cell membranes.54 The
established improvement in the activity of MSI compared
to MS is directly related to introducing of imidazole
moiety as a secondary ligand. Having structural similarity
with histidine, imidazole nucleus can easily bind to
protein molecules, giving rise to strong chelation around
metal ion and better pharmacodynamic characteristics.

ABDALLA ET AL.
19 of 22
Furthermore, the strong inhibitory effects of imidazole
derivatives on cell-membranes and their low toxicity
for hum an boosted utilization in various new drugs
developments.55
1, 10, and 100 μM are shown in Figure 11 and Figure S10.
Based on the surviving fraction results and IC50 values
for the different compounds, the activity of salen and its
complexes is further evaluated in Table S8.
Among the tested compounds, salen (IC50 = 1.1 μM)
and the CuSI complex (IC50 = 1.1 μM) exhibit the
greatest activity against the HepG-2 cancer cell line,
although their IC50 values are smaller than that of the
standard, cisplatin (1.55 μM). The IC50 values for CdSI,
AlSI, and LaSI are in the range 1.77, 2.28, and 3.22 μM,
respectively, and are comparable with that of cisplatin
(1.55 μM). For the MDA-MB231 breast cancer carcinoma
cell line, the IC50 values of complexes CuSI (7.49 μM)
and CdSI (4.38 μM) are lower than that of salen alone
(27.54 μM). Thus, the Cu (II) and Cd (II) complexes pos-
sess the highest activity against the tested cell line. The
IC50 values follow the order: cisplatin < CdSI < CuSI
< salen < LaSI < AlSI < NiSI < CoSI.
3.3.2 | Cytotoxicity
The in vitro cytotoxicity of the new MSI complexes
against human Hep-G2 liver and MDA-MB231 breast car-
cinoma cell lines was determined using the MTT assay,
in which the mitochondrial dehydrogenase activity is
measured as an indication of cell viability in terms of the
optical density. The absorbance values were evaluated by
non-linear regression methods to determine the IC50
values for the tested compounds in both cancer cell lines.
The cytotoxicity results for salen and its mixed imid-
azole complexes of divalent ions Co (II), Ni (II), Cu (II),
and Cd (II) and trivalent ions Al (III) and La (III) against
HepG-2 and MDA-MB231 at concentrations of 0, 0.1,
From the obtained results, it is obvious that the pre-
pared salen ligand and its ternary MSI complexes are
FIGURE 11 a: IC50 Values of Salen and its Cu (II), Cd (II), Al (III) and La (III) mixed Imidazole complexes against Hep-G2 carcinoma
cell lines compared to cisplatin. b: IC50 Values of Salen and its Cu (II), Cd (II), Al (III) and La (III) mixed Imidazole-Salen Complexes against
MDA-MB231 breast carcinoma cell lines compared to cisplatin
FIGURE 12 plot of the
interaction between Ligand (a), Cu
(II) complex (b) and Cd (II) complex
(c) with the active site of the
receptor of breast cancer
oxidoreductase (PDB ID: 3HB5).
Hydrophobic interactions with
amino acid residues are shown with
dotted curves

20 of 22
ABDALLA ET AL.
potent agents against the HepG-2 human liver and MDA-
MB231 breast cancer carcinoma cell lines. Importantly,
both CuSI and CdSI, in particular, are more potent than
the reference standard (cisplatin) and show concentration-
dependent effects, which could suggest their potential use
in cancer therapy. On the basis of molecular docking
results (see below), it is clearly demonstrated that the
hydrogen of the NH group of imidazole interacts
hydrophobically with the amino acids residues of the
breast cancer oxidoreductase (Figure 12) as well as the
stacking interaction between the two aromatic moieties.
This behavior is expected to increase the permeability of
the complex through the membrane of the cancer cells
and eventually behaves as carriers for anti-tumor agents.
TABLE 8 Docking interaction data for salen, [Cu(S)(I)2Cl], and [Cd(S)(I)2Cl] at the active site of the breast cancer oxidoreductase (PDB
ID: 3HB5) receptor
Receptor
Interaction
Distance (Å)*
E (kcalꢀmol−1
)
Salen
O 16
O 14
O 14
CuSI
N 51
C 21
N 20
N 51
C 16
CdSI
N 18
N 18
N 43
N 43
N 45
5-ring
OD1 ASP 153
NE ARG 214
NH2 ARG 214
H-donor
3.17 (2.21)
2.91 (2.00)
3.35 (2.60)
−3.2
−2.8
−0.8
H-acceptor
H-acceptor
OD1 ASP 153
OE2 GLU 100
OE2 GLU 100
OD1 ASP 153
6-ring PHE151
H-donor
H-donor
ionic
3.06 (2.24)
3.25 (2.34)
3.69
−9.2
−1.8
−1.3
−4.1
−1.1
ionic
3.06
H-pi
4.66
OD1 ASP 153
OD1 ASP 153
OD1 ASP 153
OD2 ASP 153
OD1 ASP 153
N LEU 99
H-donor
ionic
2.81 (1.83)
2.81
−18.6
−5.9
−2.4
−0.9
−3.4
−0.6
ionic
3.39
ionic
3.80
ionic
3.18
pi-H
4.22
*The lengths of H-bonds are in brackets.
FIGURE 13 Molecular
docking simulation studies of the
interaction between Ligand (a), Cu
(II) complex (b) and Cd (II) complex
(c) with the active site of the
receptor of breast cancer
oxidoreductase (PDB ID: 3HB5). The
docked conformation of the
compound is shown in ball and stick
representation

ABDALLA ET AL.
21 of 22
3.3.3 | Molecular docking studies
The antimicrobial efficacy for the binary salen-metal
complexes follows the order: CdS > gentamicin >
CuS > NiS > CoS > LaS > AlS > S.
To locate possible binding modes at the most active site
of the receptor of breast cancer oxidoreductase (PDB ID:
3HB5), molecular docking studies were performed using
MOA2014 software.56 The crystal structures of the 3HB5
breast cancer receptor were downloaded from the Protein
Data Bank, and the structures of salen and its complexes
were created in PDB file format using the Gaussian09
software package. Table 8 and Figures 12 and 13.
In the present study, the binding affinities of the
synthesized compounds against the receptor of protein
3HB5 (Figure 12) were performed using Hex 8.0 software,
which is an interactive molecular graphics program to
facilitate the understanding of drug-protein interac-
tions.57–59 The binding free energies of salen and its metal
complexes with the target protein receptor are deter-
mined as −250.27 (S) − 285.69 (CuSI), and −305.22
(CdSI) kJꢀmol−1. The more-negative binding energy indi-
cates the greater binding propensity of the compound
with the protein as illustrated in Figure 13. Thus, the
binding order (Table 8) is determined as CdSI > CuSI
> S, which agrees with the experimental results.
4- For the MSI complexes, CuSI demonstrates higher
antimicrobial potency compared to gentamicin. The
antimicrobial activity of these complexes follows the
order: CuSI > gentamicin > CdSI > NiSI > CoSI >
LaSI > AlSI > S.
5- Testing of in vitro cytotoxicity for salen and the MSI
complexes against the Hep-G2 liver carcinoma cell
line showed lower IC50 values for salen and CuSI than
that of the reference drug, cisplatin. Notably, CuSI
and CdSI showed concentration-dependent effects,
which could suggest a potential use for these com-
pounds as cancer therapeutics.
ACKNOWLEDGEMENTS
We extend our sincere appreciation to the Deanship of
Scientific Research at King Saud University for funding
this project through Research Group GR-1441-236 and
RSSU for their technical support.
ORCID
Laila H. Abdel Rahman https://orcid.org/0000-0001-
7375-2885
Asma A. Alothman https://orcid.org/0000-0002-4701-
5424
4 | MAJOR CONCLUSIONS
In the present study, new complexes of Co (II), Ni (II),
Cu (II), Cd (II), Al (III), and La (III) containing either
salen or mixed salen/imidazole ligands were synthesized
and fully characterized using a wide range of spectro-
scopic and structural tools. Their biological activities
against microbial pathogens and cancer cell lines were
evaluated. The results can be summarized as follows:
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SUPPORTING INFORMATION
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How to cite this article: Abdalla EM, Abdel
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Alothman AA, Nafady A. Synthesis,
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