(2024) 18:150
Mansour et al. BMC Chemistry
https://doi.org/10.1186/s13065-024-01239-7

BMC Chemistry

RESEARCH

Open Access

Metal complexes featuring a quinazoline
schiff base ligand and glycine: synthesis,characterization, DFT and molecular docking
analyses revealing their potent antibacterial,anti‑helicobacter pylori, and Anti‑COVID‑19
activities
M. S. A. Mansour1, Abeer T. Abdelkarim1, Ahmed A. El‑Sherif1 and Walaa H. Mahmoud1*

Abstract
Mixed ligand complexes of manganese(II), cobalt(II), copper(II), and cadmium(II)with an innovative Schiffbase ligand denoted as (L1), 4-(2-((1E,2E)-1-(2-(p-tolyl)hydrazineylidene)propan-2-ylidene)hydrazineyl), served
as the principal ligand, while glycine (L2) was employed as secondary ligand were successfully effectively
characterized through a comprehensive set of analyses, including Elemental analysis, UV–Visible, FT-IR, Mass spectra,
and conductometric measurements. Density functional theory (DFT) computations were executed to discern
the enduring electronic arrangement, the energy gap, dipole moment and chemical hardness of the hybrid
ligand assemblies. The proposed geometry for the complexes is a distorted octahedral structure. The antimicrobial
efficacy of these compounds was assessed against a range of bacterial and fungal strains. Notably, these complexes
exhibited promising antimicrobial activities, with the cadmium (II) complex demonstrating superior efficacy
towards all tested organisms. These compounds were also examined for their antibiotic properties against H. pylori
to explore their broader medical potential. The Schiff base ligand and its corresponding metal complexes displayed
substantial potential as an antibiotic against H. pylori. Additionally, the antitumor potential of the synthesizedcomplexes was assessed against MCF-7 (Breast carcinoma) cells—the Cu (II) complex demonstrated superior
activity with the lowest ­IC50 value compared to cisplatin. Moreover, it exhibited reduced cytotoxicity towards normal
cells (VERO cells) compared to cisplatin, establishing it as the most potent compound in the study. Furthermore,
molecular docking was explored of the Schiff base ligand and its corresponding cadmium(II) complex. The analysisof the docking study yielded valuable structural insights that can be effectively utilized in conducting inhibition
studies for example against COVID-19. This comprehensive study highlights these synthesized compounds’
multifaceted applications and promising bioactive properties.
Keywords Schiff base complexes, Spectral studies, Molecular docking, DFT, Antimicrobial activity, H-Pylori, AntiCOVID-19*Correspondence:
Walaa H. Mahmoud
wmahmoud@sci.cu.edu.eg; dr.walaa@yahoo.com
Full list of author information is available at the end of the article© The Author(s) 2024. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which
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Mansour et al. BMC Chemistry(2024) 18:150

Introduction
Utilizing organic ligands with heteroatoms ascoordination sites has been a significant avenue incoordination chemistry, offering a diverse array of
exciting and practical complexes. Ligands containing
multiple donor heteroatoms have garnered global
attention due to their robust chelating capability,
enabling the formation of mono-, di-, or multinuclear
complexes [1, 2]. Moreover, the active electron pairon these heteroatoms significantly contributes to thebonding in metal–ligand interactions. Schiff bases,
distinguished by the existence of an azomethinemoiety, are known for their ability to form chelatingrings via coordination with transition metals. These
compounds are crucial in synthesizing promisingand potent anticancer drugs. Moreover, Schiff bases
manifest a broad spectrum of biological functionalities
encompassing
antibacterial,
antifungal,
antiinflammatory attributes, and antimalarial [2]. The
biological efficacy of Schiff bases may be heightened
through their complexation interaction with diverse
transition metal ions [3, 4]. Schiff bases are favored
ligands because they stabilize a broad spectrum of
metals across various oxidation states. This capability
enables precise control over the functionality ofmetals, contributing to a diverse array of valuableapplications in industrial sectors. Additionally, theirsignificant roles in organic synthesis further underscore
their importance in the field [5–8]. Mn(II), Co(II),Cu(II), and Cd(II) Schiff bases have been specificallychosen for their potential biological activity due
to their unique coordination chemistry and ability
to interact with biological molecules due to theirwide variety of donor atoms as N, O, and S [9–12].
Furthermore, Schiff bases and their complexes withtransition metals are essential in various fields dueto their unique structural properties and potential
applications. Combining Schiff bases and transition
metals offers potential applications in multiple fields,
including catalysis, medicine, materials science,
sensing, and environmental remediation [13, 14]. These
complexes’ unique structural features and versatility
drive research efforts to explore their properties anddevelop new applications. As highlighted in previous
studies, incorporating glycine as a secondary ligand
can potentially influence the synthesized complexes’
planarity, hydrophobicity, and coordination geometry[15]. Amino acids, characterized by the presenceof -NH2 and -COOH functional groups, are wellrecognized for their ability to form metal complexes,
holding significant importance in biological andpharmaceutical contexts [16, 17]. Recently, there

Page 2 of 31

has been an increasing scholarly focus on complexes
involving transition metals with amino acids dueto their demonstrated efficacy as antibacterial andantifungal agents. These complexes have shown
effectiveness against various Microorganisms like
Escherichia Coli and Staphylococcus aureus and havepotential applications in food and medical domains[18, 19]. Helicobacter pylori, a spiral-shaped Gramnegative microorganism, was first discovered in 1982
within the human gastric mucosa. Colonization by
H. pylori within the gastric environment can result invarious gastrointestinal issues, including persistentactive gastritis and the presence of duodenal andgastric ulcers, alongside indigestion. Furthermore, it
is associated with developing malignancies, including
gastric mucosa-associated lymphoid tissue (MALT)
B-cell lymphoma and gastric adenocarcinoma [20].
Apart from these gastric complications, H. pylori
infection has been linked to systemic disorders suchas idiopathic thrombocytopenic purpura, disruptionsin iron metabolism leading to anemia, deficiencies invitamin ­B12, coronary artery disease, neurodegenerative
disorders, and gall bladder issues like as cholecystitis
and the formation of gallstones [20]. By employing
DFT calculations, researchers can predict various
physicochemical properties and reactivity patterns,
offering valuable insights into the behavior of metal
complexes in different environments. Additionally,molecular docking studies play a crucial role inelucidating the interactions between metal complexes
and biological targets, facilitating the exploration of
their potential applications in medicinal chemistry,
catalysis, and other fields [21, 22]. Integrating DFT andmolecular docking approaches enables a comprehensive
understanding of the structure–function relationshipsof metal complexes, thus paving the way for therational design and optimization of novel materials
and compounds with tailored properties and activities[21–25]. The objective of this research is to synthesizea Schiff base ligand ­(L1) via the condensation processof(E)-1-(2-(p-tolyl)hydrazineylidene)propan-2-one
with 4-hydrazineylquinazoline and subsequently
developits
corresponding
complexeswithmanganese[II], cobalt[II], copper[II], and cadmium[II].
A comprehensive analysis utilizing various physicochemical techniques was employed for characterization
purposes. The study further examines the biological
functionalities, encompassing antimicrobial, antifungal,
and anticancer attributes of the Schiff base (L1) and
its associated metal complexes [26]. Additionally, theinvestigation aims to assess the suppressive impactsof the Schiff base ligand (L1) and its corresponding
metal complexes on H. pylori infection. Furthermore,Mansour et al. BMC Chemistry(2024) 18:150

computational molecular docking investigations wereconducted to elucidate the potential interaction modesof the ligand and its Cd (II) complex with the active
sites of various receptors (3AHU, 1GHP, 2ZIC, 1NEK,
5JPE, 7DAE, and 6W41) [27, 28].

Experimental section
Materials and procedures

In this research, chemicals of high purity were utilized,
including 4-hydrazineylquinazoline 98% and (E)-1-(2(p-tolyl)hydrazineylidene)propan-2-one 99% (sourced
from Merck), glycine ≥ 99% and Manganese(II)chloride tetrahydrate ≥ 99% ­(MnCl2.4H2O) (obtained
from Sigma-Aldrich), Cobalt(II) chloride hexahydrate
98%(CoCl2.6H2O),
Copperchloride
dehydrate
99% ­(CuCl2.2H2O) and Cadmium chloride hydrate
99.99%(CdCl2.2H2O), (procured from BDH). Absolute
Ethanol (Ethyl alcohol 99,9%), an organic solvent ofspectroscopic purity, was sourced from BDH. For all
preparations, bidistilled water obtained from glass
equipment was consistently used. The human tumor cellline, MCF-7, stored in liquid nitrogen at −180 °C, wasobtained from the American Type Culture Collection.
Cultivation and maintenance of the MCF-7 tumor cellline were conducted at the National Cancer Institute in
Cairo, Egypt, through serial sub-culturing.
Solutions

Reservoir solutions containing the Schiff base ligand (L1),glycine and their corresponding metal complexes, each
formulated at a specific concentration of 1 X ­10−3 M,were created by precisely dissolving the appropriate
weight in N, N‐dimethylformamide for Cu(II) complex
and in ethanol for Schiff base ligand (L1), glycine (L2),
Mn(II), Co(II), and Cd(II) complexes. The conductivityof the 1 X 1­0−3 M metal complex solution was thenmeasured. Subsequently, solutions of the Schiff baseligand and its ternary metal complexes were diluted toa concentration of 1 X ­10−4 M, utilizing precise dilution
techniques from the initially prepared reservoir solutions
for UV–Vis spectra measurement.
Solution of anti‑H. Pylori study

Preparation of microbial suspensions An initial cultureof each microbial strain employed in susceptibility assessments was generated by transferring recent colonies ofthe microorganisms into tubes filled with sterile physiological sodium chloride solution. The turbidity of the
inoculum was then adjusted to the 2.0 McFarland standard. This specific turbidity level produces a suspension
density equivalent to (1.0 × ­108) CFU/mL of H. pylori [29].

Page 3 of 31

Assessment of inhibitory effects against H. pylori The
well agar diffusion method assessed the in vitro anti-Helicobacter pylori (H. pylori) activities. In brief, a 100 μL volume of an H. pylori suspension ((1.0 × ­108) colony-forming units (CFUs)/mL) was evenly spread onto Mueller
Hinton agar plates (BBL) supplemented with 10% sheep
blood. Subsequently, a well with a diameter ranging from
6 to 8 mm was created using a sterile cork borer or tip.
A 100 μL volume of the antimicrobial agent at the specified concentration was introduced into the well. Dimethyl
sulfoxide (DMSO) served as the (−ve) control, while theantibiotics amoxicillin (AMX, (0.05) mg/mL), clarithromycin (CLR, (0.05) mg/mL), and metronidazole (MTZ,(0.8) mg/mL) were employed as (+ ve) controls. Following
72 h of incubation at 37 °C in a microaerophilic environment with humidity, the diameter of the inhibition zone
was measured [30].
Solution for anticancer investigation

A freshly prepared reservoir solution (1 × ­10−3 M) of thetested compounds using ethanol (90%) in an appropriate
volume. For cell cryopreservation, DMSO was employed,
while the RPMI‐1640 medium, formulated for thecultivation and sustenance of a human tumor cell line,
was synthesized from its powdered state. The procedureentailed the amalgamation of 10.40 g of a specified
medium with 2 g of sodium bicarbonate, finalizing thecomposition to a volume of 1 L by incorporating distilledwater and promoting dissolution through meticulous
agitation. Following this, the medium underwent
sterilization through filtration using a Millipore bacterial
filter with a pore size of 0.22 µm, after which it wasstored at a temperature of 4 degrees Celsius. Regularassessments were conducted to monitor and detect
any signs of contamination. The RPMI-1640 medium
was preconditioned to 37 °C in a water bath before
application, and it underwent supplementation withpenicillin–streptomycin and fetal bovine serum (FBS).
The inclusion of sodium bicarbonate was imperativein the formulation of the RPMI-1640 medium. A 0.05%
isotonic trypan blue solution was prepared using normal
saline for assessing cell viability. Before use, the RPMI1640 medium was fortified with 10% heat-inactivated FBS(at 56 °C for 30 min), 100 units/ml of penicillin, and 2 mg/
mL of streptomycin. Cell harvesting employed trypsin(0.25 X 1
­ 0−1% w/v), while unbound sulforhodamine B(SRB) dye was dissolved using acetic acid (1% v/v). The
protein–dye SRB (0.40%) was dissolved in 1% acetic
acid for its intended application. A stock solution
containing trichloroacetic acid (TCA) at a concentrationof 50% was prepared and stored for subsequent use.
The experimental protocol involved adding 50 μL of the
prepared stock solution to 200 μL of RPMI-1640 medium

Mansour et al. BMC Chemistry(2024) 18:150

per well, resulting in a final concentration of 10% TCA
for protein precipitation. Additionally, 100% isopropanoland 70% ethanol were employed in the experimental
procedures. For the solubilization of sulforhodamine B(SRB) dye, Tris base at a concentration of 10 mM anda pH of 10.50 was utilized. Specifically, 121.10 g of Tris
base was dissolved in 1000 mL of distilled water, and the
pH was adjusted to the desired level using hydrochloric
acid with a concentration of 2 M.
Instrumentation

The elemental composition analysis of carbon, hydrogen,and nitrogen was executed at Cairo University’s
Microanalytical Center in Egypt, utilizing a CHNS932 (LECO) Vario elemental analyzer. Melting point
determinations were conducted with the triforce XMTD3000 instrument. Metal content analyses were performedat the Egyptian Petroleum Research Institute utilizing
inductively coupled plasma spectrometry (ICP). Fouriertransform infrared spectroscopy (FT-IR) analyses,
spanning from 4000 to 400 ­cm−1, were recorded using
KBr disks and a Perkin-Elmer 1650 spectrometer. The
molar conductivities of 1
­0–3 M solutions of the solid
complexes in DMF were determined using a Jenway
4010 conductivity meter. For solutions in DMSO-d6, 1H
NMR spectra were obtained with tetramethylsilane as
an internal standard, utilizing a 300 MHz Varian-Oxford
Mercury instrument at room temperature. Mass spectra
were acquired through the electron ionization technique
at 70 eV employing an MS-5988 GS-MS HewlettPackard instrument at Cairo University’s MicroanalyticalCenter. Thermal analyses, including thermogravimetric(TG) and differential thermogravimetric (DTG)
measurements of the Schiff base ligand and its ternary
metal complexes, were conducted using a Shimadzu
TG-50H thermal analyzer, spanning the temperature
range from room temperature to 1000 °C. Solutionbased spectrophotometric measurements were carriedout using an automated UV–Vis spectrophotometer,
PerkinElmer Model Lambda 20, covering the wavelength
range from 200 to 700 nm. Anticancer activity
experiments were executed at the National Cancer
Institute, specifically within the Cancer Biology andPharmacology Departments at Cairo University, Egypt.
Antimicrobial assessments were performed at Cairo
University’s Microanalytical Center. Anti-H. Pylori
activity assessments were conducted at the Microbiology
Center at Alazhar University.
Preparation of Schiff base ligand

Continuing our previous work synthesizing new Schiffbase Complexes [13, 31, 32], the recently developed Schiffbase ligand ­(L1) was synthesized using a standard method.

Page 4 of 31

The process involved the condensation of 4-hydrazineylquinazoline (4.370 mmol, 0.7 g) and (E)-1-(2-(p-tolyl)
hydrazineylidene)propan-2-one (4.370 mmol, 0.770 g) in
hot 100% ethanol at 60 °C in a round-bottom flask. The
reaction mixture underwent reflux for 4 h in an open
system under controlled laboratory conditions to ensure
thorough mixing. During reflux, the reaction progressed,
leading to the formation of the desired Schiff base ligand.
After the reflux time, the reaction mixture was allowed tocool to room temperature. The resulting pure Schiff base
was obtained with a yield of 96%, filtering and recrystallizing the resultant orange solid. Scheme 1 illustrates
the configuration of the Schiff base ligand (L1) and theformation reaction involved in its creation. Yield 96%;orange solid, m.p 210 °C. The theoretical compositionfor ­C19H19N5 is anticipated to be as follows: Carbon (C)71.90%, Hydrogen (H) 6.03%, and Nitrogen (N) 22.07%.
The experimental findings yield the following actual composition: Carbon (C) 71.53%, Hydrogen (H) 5.88%, andNitrogen (N) 21.82%. IR (ν, c­ m−1): 3437sh (NH), 1605 sh(C = N), 1545sh (υ(C = N) Pyridine. In the ultraviolet–visible (UV–Vis) spectroscopic analysis, distinct absorption
peaks were observed at wavelengths of 314 (attributed
to π–π* transitions), 334 (indicative of n–π* transitions),
and 388(associated with charge transfer).
Preparation of ternary complexes

For synthesizing the mixed ligand complexes, the synthesized Schiff base ligand serves as the principal ligand
denoted as (L1). The Schiff base ligand (L1) was formulated by dissolving (0.314 mmol, 0.10 g) in 40 ml ofheated absolute ethanol. The secondary ligand (L2),the amino acid Glycine (0.314 mmol, 0.02 g), was solubilized in a 10-ml volume of heated distilled water. The
chelates were formed by combining a hot solution of the
primary Schiff base ligand (­L1) in absolute ethanol withthe secondary ligand glycine in distilled water. To thismixture, a hot ethanoic solution (20 ml) of the relevant
metal chloride salt (such as M
­ nCl2.4H2O, ­CoCl2 0.6H2O,­CuCl2.2H2O, and C­ dCl2.2H2O,) (0.314 mmol) was gradually added dropwise. The resultant solution underwent
reflux for three hours, leading to the formation of precipitates representing the complexes. These precipitates
were collected via filtration and further purified throughmultiple washes using a combination of ethanol andwater. Subsequently, they underwent desiccation withina vacuum environment employing anhydrous ­CaCl2.
Scheme 2 illustrates the structure configuration of themixed ligands complexes and their formation reaction.
[Mn(L1)(L2)(H2O)].Cl.H2O

Yield 96%; m.p. = 274 °C; Brown solid. Anal. Calc. for (C2
0H26ClMnN7O4) (%): C, 46.25; H, 5.01; N, 18.90; Cl 6.83;

Mansour et al. BMC Chemistry(2024) 18:150

Page 5 of 31

NH

H

CH3

N

O

H 2N

NH

N

H3C

N

4-hydrazineylquinazoline(E)-1-(2-(p-tolyl)hydrazineylidene)propan-2-one

Reflux/ethanol
4hrs

CH3

HN

CH3

N
N

NH

N
N

"
"Ligand L1
Scheme 1 Synthetic route for Schiff Base ligand (L1)

Mn, 10.58 Found (%): C, 46.08; H, 4.88; N, 18.77; Cl 6.72;
Mn, 10.46. Λm (Ω−1 ­mol−1 ­cm2) = 86; FT‐IR (ν, c­ m−1):
Azomethine (C = N) 1610, azomethine (C = N)Pyridine
1560 m, ν (COO)asy 1421 m, ν (COO)sym 1336 s,(M─O) 506w, (M─N) 460w. UV–Vis (λmax, nm): 307(π–π*), 310 (π–π*) conjugated, 369(n- π*).

[Co(L1)(L2)(H2O)].Cl.H2O

Yield 97%; m.p. = 285 °C; dark brown solid. Anal.
Calc. for (C20H26ClCoN7O4) (%): C, 45.94; H, 4.97; N,
18.75; Cl 6.78; Co, 11.27 Found (%): C, 45.87; H, 4.88;
N, 18.51; Cl 6.62; Co, 11.17. Λm (Ω−1 ­mol−1 ­cm2) = 79;
FT‐IR (ν, c­m−1): Azomethine (C = N) 1619, azomethine (C = N)Pyridine 1563 m, ν (COO)asy 1410 m, νMansour et al. BMC Chemistry(2024) 18:150

Page 6 of 31

CH3

HN

N

CH3
N

+

NH

N

MnCl2.4H2O
CoCl2.6H2O
CdCl2.2H2O
CuCl2.2H2O

O

+

H2N

OH

glycineN

4-(2-((1E,2E)-1-(2-(ptolyl)hydrazineylidene)propan-2ylidene)hydrazineyl)quinazoline

4h

Refluxing
+

H3C
CH3
N
H

N

N

M
R
H2N O

H 2C

C

NH

. nCl . xH2O

NON

M= Mn, Co, Cu or Cd
R=Cl or H2O
n= Number of Cl
x= Number of water molecules
Scheme 2 Structure of the mixed ligands complexes and their formation reaction(COO)sym 1324 s, (M─O) 547w, (M─N) 458w. UV–Vis(λmax, nm): 316 (π–π*), 347(n- π*).
[Cu(L1)(L2)(H2O)].Cl.2H2O

Yield 96%; m.p. = 292 °C; Reddish brown solid. Anal.
Calc. for (C20H28ClCuN7O5) (%): C, 44.03; H, 5.13; N,
17.97; Cl 6.49; Cu, 11.65 Found (%): C, 43.95; H, 5.03;
N, 17.85; Cl 6.38; Cu, 11.51. Λm (Ω−1 ­mol−1 ­cm2) = 82;
FT‐IR (ν, ­cm−1): Azomethine (C = N) 1628, azomethine(C = N)Pyridine 1559 m, ν (COO)asy 1413 m, ν (COO)
sym 1327 s, (M─O) 560w, (M─N) 436w. UV–Vis (λmax,nm): 292 (π–π*), 362(n- π*), 360 (Charge transfer).
[Cd(L1)(L2)Cl]Yield 97%; m.p. = 261 °C; yellow solid. Anal. Calc. for(C20H22CdClN7O2) (%): C, 44.45; H, 4.07; N, 18.51; O,
5.92; Cl 6.56; Cd, 20.80 Found (%): C, 44.21; H, 4.00;

N, 18.06; O, 5.85; Cl 5.42; Cd, 20.66. Λm (Ω−1 ­mol−1­cm2) = 16; FT‐IR (ν, ­cm−1): Azomethine (C = N) 1620,
azomethine (C = N)Pyridine 1573 m, ν (COO)asy 1422 m,
ν (COO)sym 1336 s, (M─O) 586w, (M─N) 469w. UV–
Vis (λmax, nm): 280 (π–π*), 315 (π–π*) conjugated,
360(n- π*).
Exploring spectrophotometry

Absorption spectra were recorded for solutions
containing the free Schiff base ligand and its ternarycorresponding metal complexes at a concentration of(1 × ­10−4 M). The spectra were systematically scannedover the wavelength range from 200 to 700 nm.
Computational methodology

Theoretical calculations were conducted on the free
Schiff base ligand (L1) and its corresponding metal

Mansour et al. BMC Chemistry(2024) 18:150

Page 7 of 31

Fig. 1 Infrared spectroscopy analysis of Schiff Base ligand (L1): A theoretical spectrum and B experimental spectrum

complexes utilizing the software package (Gaussian 09w).
Density functional theory (DFT) served as the chosenlevel of theory for these calculations. The structural configuration geometry of the ligand was extensively optimized through the utilization of the B3LYP method in
combination with (LANL2DZ) basis set for Schiff baseligand (L1) and its corresponding metal complexes [33].

Fig. 2 The optimized configuration structure of Schiff base ligand (L1)

The Chemcraft version 1.8 software suite and Gaussian View version 6.0.1 package were employed to visualize the optimized structure of the ternary complex. Key
chemical quantum parameters, including (­EHOMO) and­(ELUMO), as well as the HOMO–LUMO energy gap (ΔE),
were computed for the studied molecule. These parameters offer crucial information regarding the electronic
configuration and reactivity of the ligand.

Mansour et al. BMC Chemistry(2024) 18:150

Page 8 of 31

The B3LYP method, in combination with the
LANL2DZ basis set, is commonly used in computational
chemistry calculations for several reasons [34, 35]:
Accuracy and reliability: The B3LYP functional,
which is a hybrid functional that incorporates a mixtureof Hartree–Fock exchange and density functional
exchange–correlation, has been extensively tested andproven to provide accurate results for a wide range ofsystems, especially for molecular geometries, vibrationalfrequencies, and thermochemical properties [36, 37].
Balanced performance: The B3LYP functional balancescomputational cost and accuracy, making it a popular
choice for moderately sized systems and transition metal
complexes, where more computationally demanding
methods may not be feasible. Transition metal complexes:
The LANL2DZ basis set is handy for transition metal
systems. It is an effective core potential (ECP) basis set,
which incorporates relativistic effects and treats the coreelectrons implicitly, reducing the computational cost
while providing reasonable accuracy for transition metal
complexes [38, 39].
Benchmark studies: Numerous benchmark studies
have been conducted on the performance of the B3LYP/LANL2DZ combination for various properties oftransition metal complexes, providing a reference point
and validation for its use in specific applications [40, 41].
Antimicrobial activity

The investigation into the antimicrobial efficacy of theexamined compounds utilized the agar well diffusion
method. In vitro assays were performed to evaluate antibacterial properties against Gram (+ ve) bacteria, specifically Staphylococcus aureus and Streptococcus mutans,as well as Gram (-ve) bacteria, including Escherichia
coli, Pseudomonas aeruginosa, and Klebsiella pneumonia. These assessments were conducted on a nutrient
agar medium. Antifungal activity was appraised towards

Candida albicans and Aspergillus niger using Sabouraud
dextrose agar medium. Standard drugs, including (Gentamicin and Ampicillin) for Gram (−ve) and Gram (+ ve)
bacteria, respectively, and Nystatin for fungal strains,
were employed as reference points. Dimethyl sulfoxide(DMSO) served as the control (negative) solvent. The
compound concentration tested against bacterial andfungal strains was 15 mg/mL.
Testing method

The aseptic culture medium was dispensed into
Petri dishes, each receiving an approximate volumeof 20–25 mL, and subsequently allowed to solidify
at ambient temperature. A microbial suspension,
mirroring the McFarland 0.5 standard solution(1.5 × 105 CFU ­mL−1), was meticulously prepared insterilized saline. The suspension’s turbidity was precisely
adjusted to an optical density (OD) of 0.13 using aspectrophotometer set at 625 nm [30]. Within a timeframe of approximately 15 min post-turbidity adjustment,a sterile cotton swab was immersed in the preparedmicrobial suspension and uniformly streaked onto thedesiccated agar surface. The swab-laden dish was left
undisturbed for 15 min with the lid securely in place.
Subsequently, employing a sterile borer, wells measuring
6 mm in diameter were generated in the solidified culture
medium [30]. Then, 100 μL of the test compound solution
was carefully added to each well using a micropipette.
The specimens were subsequently incubated at 37
degrees Celsius for 24 h to observe antibacterial activity.
This experimental process was conducted in triplicate,
and the diameters of the inhibition zones were assessedin millimeters, as reported in a prior study [30].
Anti‑H. Pylori activity

The assessment of Schiff base (L1) and its metal
complexes’ efficacy against H. pylori ATCC 43504

Table 1 Displays the physical and analytical data concerning the Schiff base ligand (L1) and its associated ternary metal complexes
Compound"chemical formula"

Color(%)(Yield)

M.p. (°C)

Schiff base ligand (L1)
C19H19N5

Orange(96)[Mn(L1)(L2)(H2O)].Cl.H2O(C20H26MnClN7O4)Found (Calcd)
Cl (%)M (%)

Am(Ω−1 ­mol−1­cm2)

18.51 (18.75)

6.62 (6.78)

11.17 (11.27)

86

4.00 (4.07)

18.06 (18.51)

5.42 (6.56)

20.66 (20.80)

79

46.08 (46.25)

4.88 (5.01)

18.77 (18.90)

6.72 (6.83)

10.46 (10.58)

82

43.95 (44.03)

5.03 (5.13)

17.85 (17.97)

6.38 (6.49)

11.51 (11.65)

16

C (%)

H (%)

N (%)

210

71.53 (71.90)

5.88 (6.03)

21.82 (22.07)

Dark brown
(97)

285

45.87 (45.94)

4.88 (4.97)[Co(L1)(L2)(H2O)].Cl.H2O(C20 H26CoClN7O4)

yellow(97)261

44.21 (44.45)[Cu(L1)(L2)(H2O)].Cl.2H2O(C20 H28CuClN7O5)

Brown
(96)

274

[Cd(L1)(L2)Cl](C20H22CdClN7O2)

Reddish brown
(96)

292

Mansour et al. BMC Chemistry(2024) 18:150

Page 9 of 31

Fig. 3 Morphological analysis of Schiff Base metal complexes via SEM [A Mn(II), B Co(II), C Cu(II), D Cd(II)]involved the application of the micro-dilution brothmethod. The determination of minimal inhibitory
concentration (MIC) and minimal bactericidal
concentration (MBC) for the tested compounds was
carried out using Mueller–Hinton broth supplemented
with lysed horse blood [42].
Minimal inhibitory concentration (MIC)

The micro-dilution broth method determined thetest compounds’ minimal inhibitory concentration(MIC). This method involved the use of Mueller–Hinton broth supplemented with lysed horse blood. Serial
two-fold dilutions were systematically performed toestablish a concentration range from 0.98 to 1000 μg/
mL for the tested extracts. Sterile 96-well polystyrene
microtitrate plates were employed, and each well was
loaded with 200 μL of the respective extract dilution in
the broth medium. Inocula were prepared by cultivating fresh microbial cultures in sterile 0.85% NaCl, withadjustments made to achieve turbidity matching the 1.0
McFarland standard. Subsequently, 2 µL of the prepared

Table 2 EI- mass data of Schiff base ligand (L1) metal complexes
Compoundm/z valueInterpretation

Calculated

Found

Schiff base ligand (L1)

318.38318.78[M]+[Mn (L1)(L2)(H2O)].Cl.H2O

464.39465[M + ­1]+[Co(L1)( L2)(H2O)].Cl.H2O

468.38468[M]+[Cu(L1) (L2)(H2O)].Cl .2H2O

473

472.8

[M]+

[Cd (L1) (L2)Cl]

539.30540[M + ­1]+

inoculum was added to each well, resulting in a final
density of 3.0 × 106 CFU (colony-forming units)/mL.
Following an incubation period of 72 h at 35 °C under
microaerophilic conditions (15% ­CO2), the MICs were
determined by visually identifying the lowest extract concentration that completely inhibited the growth of thereference strain. Every microplate comprised a positive
control, wherein inoculum was present without the test
extracts, and a negative control, wherein the test extracts
were present without inoculum [42].

Mansour et al. BMC Chemistry(2024) 18:150

Minimal bactericidal concentration (MBC)The Minimum Bactericidal Concentration (MBC) was
ascertained by inoculating 100 mL of the microbial
culture derived from wells displaying complete growth
inhibition, observed in both the last (+ ve) and growth
control wells, onto Mueller–Hinton agar plates
supplemented with 5% horse blood. Subsequently, theplates underwent incubation at 35 °C for 72 h under amicroaerophilic environment. The MBC was definedas the lowest concentration of the extracts where
no microbial growth was observed. To ascertain thebactericidal or bacteriostatic effects of the tested extracts,
MBC/MIC ratios were calculated. Notably, in this study,
antibacterial agents were considered bactericidal if the
MBC/MIC ratio did not exceed four times the MIC [43].
Each trial was executed in triplicate, and the presented
data represent the findings.

Page 10 of 31

Table 3 presents the 1H NMR spectral data for the Schiff baseligand (L1) and its ternary Cd(II) complex
CompoundChemical shift,(δ) ppm

Assignment

Schiff base ligand (­ L1)

11.13(s, H, ph-NH)

9.68(s, H, NH-Pyridine)

8.49(s, H, N–CH = N)

8.04

(s, H, pyridine)

7.45–8.22(m, 8H, aromatic)

2.07(s, 3H, N = C-CH3)[Cd(L1)(L2)Cl]

Anticancer activity

To evaluate the cytotoxic effects of both the Schiff baseligand (L1) and its associated metal complexes, thestudy followed a methodology developed by Skehan andStoreng [44]. This method involved utilizing a 96-wellplate with 104 cells per well, allowing 24 h to facilitate
cell adhesion to the well’s surface. The compounds underinvestigation, including the Schiff base ligand and its
metal complexes, underwent examination across diverse
concentrations (100, 50, 25, and 12.5 μg ­mL−1). with eachconcentration assessed in triplicate. After introducing
the test compounds, the cellular monolayer underwent
a 48-h incubation period at 37 °C within an atmosphere
containing 5% C
­ O2. After this incubation, the cells were
subjected to fixation, thorough washing, and SRB stain
staining. Surplus stain was eliminated through treatment
with acetic acid, and the residual staining was extractedusing a tris–EDTA buffer solution. The optical density(O.D.) of individual well samples was assessed at awavelength of 564 nm employing a spectrophotometer,with automatic subtraction of the mean backgroundabsorbance. Mean values for each concentration of thetested compounds were subsequently calculated. To
assess the impact of the compounds on cell survival, arelation was established between the surviving fraction
and the drug concentration, generating a survival curvefor the specific breast tumor cell line being studied. The
percentage of cell survival was determined using thefollowing formula:
Survival fraction = O.D. of treated cells/O.D. of control cells.

The primary goal of this study was to calculate the I­ C50
values, which represent the concentrations of the free
Schiff base ligand (L1) or its associated metal complexes
needed to inhibit cell growth by 50%. The entire

2.32(s, 3H, ph-CH3)

11.27(s, H, ph-NH)

10.03(s, H, NH-Pyridine)

8.36(s, H, N–CH = N)

7.90(s, H, N = CH)

7.45–8.49(m, 8H, aromatic)

3.54(s, 2H, C­ H2-C = O)glycine

2.07(s, 3H, N = C-CH3)

2.32(s, 3H, ph-CH3)

1.35(s, 2H, N­ H2)glycine

experiment was meticulously repeated three times for the
MCF7 cell line to ensure the reliability and consistency of
the results.
Molecular docking

Molecular docking analyses were conducted utilizing
the MOE 2014 software, which is recognized for its
rigid molecular docking capabilities. These analyses
were pivotal in predicting potential binding modes ofboth the Schiff base ligand (L1) and its Cadmium [II]complex with significant receptors. Specifically, thestudy targeted crystal structures of essential receptors
for bacterial and fungal strains, including (PDB ID:
3AHU, 1GHP, 2ZIC, 1NEK, 5JPE), in addition to
microtubules, crucial elements of the cytoskeleton
associated with cancer treatment (PDB ID: 7DAE), and(PDB ID: 6W41) the crystal structure of the SARS-CoV-2
receptor binding domain bound to the human antibody(CR3022). It can compute and present likely docking
configurations of the receptors with the Schiff base ligand
and its complex molecules. The software necessitates
input in PDB format, comprising the Schiff base ligand,the ternary cadmium [II] complex, and the receptors.
While preparing the input files, extraneous components
such as aqueous entities, co-crystallized ligands, andunaccompanied elements such as sodium, potassium,
mercury, etc., should be excluded. However, the aminoacid chains were retained for further analysis [45]. The
Schiff base ligand and its ternary Cadmium [II] complex

Mansour et al. BMC Chemistry(2024) 18:150

Page 11 of 31

were generated in PDB file format using Gaussian
software. The structural configurations of each receptor
were acquired from the Protein Data Bank (PDB),
accessible at http://​www.​rcsb.​org/​pdb. This methodology
allows for investigating potential binding interactions
and evaluating the interplay of the Schiff base ligand (L1)and its Cadmium [II] complex with these vital receptors.
This analysis provides valuable insights into possible
therapeutic applications.

Results and discussion
Characterization of the Schiff base (­ L1)

The elemental analysis of the tridentate Schiff baseligand (L1) revealed experimental data consistent withthe calculated values, affirming its molecular formula
as C18H18N6. This compound exhibited favorable physical properties: it had a melting point of approximately
210 °C and demonstrated solubility in various solvents
such as DMF and DMSO, displaying an orange coloration. The proton of the NH group was detected in
the Schiff base ligand’s 1H NMR spectrum at 9.68 and11.13 ppm, along with azomethine protons at 8.49 ppm
and aromatic protons between 7.45 and 8.22 ppm (seeTable 3). The lack of observable indications of any evidence for the NH2 group confirms the synthesis of the
Schiff base ligand (L1). Further structural insights into
Schiff base ligand (L1) were obtained through its mass
spectrum analysis. The recorded spectrum depicted
a molecular ion peak at m/z = 318.78 a.u, consistent
with the ligand’s formula weight of C18H18N, having
a molecular weight of 318.38 g/mol. In the UV–Vis
absorption spectrum of the Schiff base ligand (L1),three discernible bands manifested at 314 nm, indicative of π‐π* transitions, at 334 nm, associated withn‐π* transitions, and at 388 nm, correlated with chargetransfer phenomena. Significant bands corresponding to the ligand’s structure were observed in the prepared Schiff base ligand’s infrared spectrum. Notably,
a notable band at 1605 ­cm−1 signified the existence of
two azomethine groups, while the band spectral feature at 1545 ­cm−1 corresponded to (C = N) Pyridine, as
listed in Table 5. A broad vibration band attributed to ν(NH) was also detected at 3437 ­cm−1 [46]. These bands
were recorded by DFT at 3580, 1655, and 1590 ­cm−1,
respectively. The concurrence of the theoretical andexperimental frequencies was perfect and indicatedthe successful preparation of the Schiff base ligand
and supported the chemical structure of the ligand, as
illustrated in Fig. 1. The differences between theoreticaland experimental frequencies may result from systematic errors (derived from harmonicity) or the use of gas
phase molecules in the DFT calculations. So, the correlation coefficient was used as 0.9648 for LAN2DZ toovercome these errors [33, 47]. In these investigations,Fig. 2 elucidates the molecular configuration of the
Schiff base ligand denoted as L1.
Characterization of Schiff base ternary metal complexes
Elemental analysis

Four metal complexes were synthesized via the combination of equimolar quantities of a Schiff base (L1) and glycine ligand (L2) with manganese(II), cobalt(II), copper(II),and cadmium(II) metal salts in suitable solvents. Detailed
elemental analyses and an exploration of these compounds’ molecular formulae, melting points, and various
physical properties were conducted. These complexes
demonstrated stability at room temperature and exhibited high sharp melting points. They were determined
to exhibit limited solubility in water and high solubility
in DMF and DMSO solvents. The estimated values andTable 4 Thermal Analysis Findings for Schiff Base Ligand (L1) and Its Metal Complexes via TG and DTG
Complex

TG-range (oC)

[Mn(L1)(L2)(H2O)].Cl.H2O(C20H26MnClN7O4)(35–105)85

1(105–295)

244

2[Co(L1)(L2)(H2O)].Cl.H2O(C20 H26CoClN7O4)[Cu(L1) (L2)(H2O)].Cl.2H2O(C20H28CuClN7O5)[Cd(L1) (L2) Cl](C20H22CdClN7O2)

DTG maxn*

Mass loss Estim (calcd)%

Assignment

Residues

3.05 (3.46)-Loss of ­H2O

MnO

29.99 (30.76)-Loss of ­C7H10ClNO(295–446)310

310.49 (11.19)-Loss of ­C2H4NO(445–800)

560

440.53 (40.90)-Loss of ­C11H10N5(45–105)75

13.61 (3.70)-Loss of ­H2O

(105–505)315

243.94 (44.55)-Loss of ­C10H17Cl ­N2O2-Loss of ­C10H7N5(505–800)565

337.31 (37.71)(35–125)70

1

6.007 (6.59)-Loss of ­2H2O(125–345)

225

239.398 (39.70)-Loss of ­C9H14ClN2O2(345–800)505

338.16 (38.90)-Loss of ­C11H10N5(45–355)275

135.51 (36.02)-Loss of ­C9H9ClN3(355–800)615

240.11 (40.20)-Loss of ­C11H13N4O

CoO

CuO

CdO

Mansour et al. BMC Chemistry(2024) 18:150

Page 12 of 31

the experimental elemental analysis of the complexes
demonstrated a remarkable level of agreement. As indicated in Table 1, the complexes prominently manifest a
1:1:1 ratio, wherein a single metal ion forms a bond with
one Schiff base (L1) ligand and one glycine ligand. Consequently, this outcome gives rise to a complex with stoichiometry denoted as M: L1: L2.
EDX‑SEM analysis

SEM and EDX analyses were performed to investigate Schiff base complexes’ morphology and elemental composition [48]. the Mn(II) complex exhibiteda morphology in the SEM image Characterized byirregular, elongated structures. The individual structures have varying lengths and diameters, suggesting a
non-uniform growth process (Fig. 3A). The EDX analysis (Table S4) revealed manganese complex at 11.17%(calculated 11.27%), matching well with the elemental
analysis of manganese at 11.17% (calculated 11.27%),
indicating successful formation of the expected
C20H26MnClN7O4 composition. For the Co(II) complex, the SEM image characterized by overlapping
sheet-like structures. These sheet-like structures appear
to be stacked and intertwined, creating a layered

arrangement. The sheets seem to have smooth surfaces
with well-defined edges, indicating a more ordered
growth process compared to the Mn(II) complex(Fig. 3B). The EDX data (Table S2) aligned with the elemental composition analysis (Table 1), detecting cobalt(20.66% found vs 20.80% calculated) and other elements
consistent with the C20H26CoClN7O4 composition. The
Cu(II) complex displayed a different morphological pattern in the SEM micrograph reveals a different morphological pattern from the Mn(II) and Co(II) complexes.
The Cu(II) complex exhibits a structure composed ofirregularly shaped particles or agglomerates. These
particles appear to be randomly oriented and loosely
packed, with a rough surface texture. The lack of awell-defined shape or ordered arrangement suggests
a more disordered growth process (Fig. 3C). The EDX
data (Table S3) Correlated with the elemental composition analysis of copper at 10.46% (calculated 10.58%)(Table 1) showed copper along with C, N, O indicating
successful formation of the C20H28CuClN7O5 complex.
Finally, The Cd(II) Schiff base complex exhibited exhibits a well-defined crystalline structure, as evident fromthe SEM image. The crystals appear to be cubic or rectangular in shape, with distinct edges and smooth faces.

Table 5 The most significant infrared (IR) spectral bands of the isolated Schiff base ligand (L1) ternary Complexes are as follows
Compoundυ(C = N)υ(C = N) pyridineringυ(COO)Asymmetricglycineυ(COO)symmetricglycineυ(M–O)

υ(M–N)

Schiff base ligand ­(L1)

1605 sh1545 sh

–

–

–

–

[Mn(L1)(L2)(H2O)].Cl.H2O

1610 m1560 sh1421 sh1336 sh

506 m

460 w

[Co(L1)( ­L2)(H2O)].Cl.H2O

1619 m1563 m1410 m1324 m

547 m

458 w

[Cu(L1)(L2)(H2O)].Cl.2H2O

1628 sh1559 m1413 sh1327 m

560 m

436 w

[Cd(L1)(L2)Cl]

1620 sh1573 s1422 m1336 sh

586 m

469 m

Fig. 4 Comparison of a Experimental and bTheoretical IR Spectra for [Cd(L1)(L2)Cl]Mansour et al. BMC Chemistry(2024) 18:150

These crystals are agglomerated, forming larger clusters
or crystalline assemblies. The regular shape and welldefined facets of the crystals indicate a highly ordered
growth process for the Cd(II) complex (Fig. 3D). Thismorphology correlated well with the elemental composition data which showed the presence of cadmium(11.51% found vs 11.65% calculated) along with carbon, nitrogen, oxygen (Table 1) in agreement with datafrom EDX analysis (Table S1), confirming the formationof the expected C20H22CdClN7O2 complex. The close
agreement between observed and calculated elemental compositions from EDX, coupled with the distinct
complex morphologies from SEM, provides strong evidence for the successful synthesis of the desired Schiffbase metal complexes [49, 50]. These analyses provide
valuable insights into the successful formation of thedesired Schiff base complexes and their structural characteristics, which can be further correlated with theirpotential applications in various fields, such as catalysis, materials science, or biological systems.
Molar conductivity measurements

Conductivity assessments serve as a means to evaluate thelevel of ionization in metal complexes. The investigation
into the molar conductivity of metal complexes derived
from Schiff bases was systematically examined acrossvarious solvents, each chosen based on the solubilityof the compounds, utilizing a concentration of(1.0 × ­10−3 M), conducted at a standardized temperatureof 25 °C. The findings distinctly demonstrated that theFig. 5 The optimized structure of [Cd(L1)(L2)Cl] complex

Page 13 of 31

Cd [II] complexes exhibited characteristics indicativeof non-electrolytic behavior [46]. In contrast, the metal
complexes involving Co(II), Mn(II), and Cu(II) exhibited
electrolytic characteristics, as delineated in Table 1 [51].
Mass spectral studies

The mass spectra of the Schiff base (L1) and its ternary
metal complexes exhibited distinct molecular ion peaks,
as outlined in Table 2. Examination of the mass spectral
data verified the stoichiometric composition of the metal
complex as ML1L2. Furthermore, the results obtained
from these investigations were in complete concordancewith the predicted molecular formulas, which were also
substantiated by elemental analysis data. A consistentand noteworthy observation in all complex spectra was
the presence of the Schiff base ligand (L1) at 318.78 m/z
and the glycine (L2) moiety at about 74 m/z. This finding
serves as a robust indicator of the complexation process.
UV–visible absorption spectra for the Schiff Base Ligand ­(L1)
and its metal complexes

The electronic spectra of the tridentate Schiff base ligand(L1) and its metal complexes were examined within the
200–700 nm spectral range in a suitable solvent. The
UV–Vis spectrum of the standalone Schiff base ligand(L1) displayed three distinct absorption bands at 314,
334, and 388 nm. These absorptions were attributed todifferent transitions: the first at 314 nm was linked toπ-π* transitions, the second at 334 nm signified n-π*transitions within the -C = N- group, while the higherenergy band at 388 nm was associated with charge

Mansour et al. BMC Chemistry(2024) 18:150

Page 14 of 31

Table 6 Optimization and Quantum Chemical Characteristics of Schiff Base Ligand (L1) and its Cadmium (II) Complex
The calculated quantum chemical parameters

Schiff base ligand (­ L1)[Cd(L1)(L2)Cl] complex

E (a.u)−1018.80−1371.310

Dipole moment (Debye)

3.9111

15.1873

EHOMO (eV)−7.4355−5.863786

ELUMO (eV)1.4609−2.766583

ΔE (eV)8.8964

3.097203

χ(eV)2.98734.3151845

η(eV)

4.4482

1.5486015

σ(eV)−10.224810.645743918

Pi (eV)−2.9873−4.3151845

S (eV)−1

0.112405

0.322871959

ω(eV)

1.003098

6.01213975

ΔNmax

0.671575

2.786504146

Bond lengths (Å)

Schiff base ligand (­ L1)[Cd(L1)(L2)Cl] complex

N(8)-N(9)

1.337

1.353

N(12)-N(13)

1.351

1.394

N(15)-C(16)

1.344

1.387

N(9)-Cd(25)3.386

N(12)-Cd(25)2.531

N(15)-Cd(25)2.372

Cd(25)-Cl(31)2.510

Bond angles (o)Schiff base ligand (­ L1)[(L1)(L2)Cd(Cl)]complex

Cl(31)-Cd(25)-O(27)–115.32

Cl(31)-Cd(25)-N(26)–116.939

Cl(31)-Cd(25)-N(15)–124.104

Cl(31)-Cd(25)-N(12)–90.783Cl(31)-Cd(25)-N(9)–72.177

O(27)-Cd(25)-N(26)–73.444O(27)-Cd(25)-N(15)–83.746

O(27)-Cd(25)-N(12)–149.146

O(27)-Cd(25)-N(9)–146.129

N(26)-Cd(25)-N(15)–118.863
110.445

N(26)-Cd(25)-N(12)–N(26)-Cd(25)-N(9)–74.062

N(15)-Cd(25)-N(12)–67.386

N(15)-Cd(25)-N(9)–120.784

N(12)-Cd(25)-N(9)

–

55.01

transfer [52, 53]. Upon complexation with diverse metal
cations, the bands observed at 314 nm in the Schiff baseligand (L1) spectrum exhibited shifts to higher or lower
wavelengths within the range of 292–316 nm, denoting
alterations in the π-π* transitions in all complexes. Furthermore, the band attributed to the azomethine group,
observed initially at 334 nm in the ligand spectrum, experienced a shift to the range of 347–369 nm, indicative ofn-π* transitions [54]. This spectral data strongly suggests
a pronounced implication of the nitrogen azomethine(C = N-) in coordination interaction with the metal ions.
1

H‐NMR spectral studies

The suggested bonding pattern in the synthesizedcomplexes finds support through 1H-NMR spectral
analysis. The 1H-NMR spectra of the prepared SchiffMansour et al. BMC Chemistry(2024) 18:150

base ligand (L1) and its Cd (II) complex were recordedin DMSO-d6, and their respective chemical shift
values (ppm) were measured. Multiplet signals at 7.45–
8.22 ppm within the ligand spectrum were observed,
corresponding to the aromatic group. In comparison,
the signal at 8.04 ppm was attributed to the proton of
the pyridine ring, as delineated in Table 3. These signals
were also evident in the Cd (II) complex, appearing at
7.45–8.49 ppm and 8.36 ppm, respectively. Furthermore,
the proton signals from the NH group appeared as
singlets at 11.13 and 9.68 ppm in the Schiff base ligand(L1). These signals persisted in the Cd (II) complex but
experienced a shift to higher values, registering at 11.27
and 10.031 ppm, respectively. The proton signals fromthe N–CH = N in pyridine also presented as singlets
at 8.49 ppm in the Schiff base ligand (L1). In the Cd(II)complex, these signals remained detectable but shifted toa lower value at 8.36 ppm, indicating the chelation effect(see Table 3). The protons from the methylene and aminogroups of the amino acid glycine were observed at 3.54
and 1.35 ppm, respectively. This observation suggests
chelation occurred in the Cd(II) complex through Cd
binding to the glycine amino group. No signal appeared
corresponding to the carboxylic proton of the glycine
amino acid, which proves that the depression of the
carboxylic proton accompanies the chelation of theglycine amino acid to the metal ions [55, 56].
13

C NMR

A direct comparison of the 13C NMR spectra of free L1
and its cadmium complex would reveal differences inpeak positions and intensities, indicating changes incarbon chemical environments upon metal coordination.
This spectral change supports the conclusion that L1 isbound to cadmium in the complex. While simulation of
the actual spectra would require unambiguous structural
information, the general trends discussed here could beobserved experimentally to confirm complex formation.
The formation of the cadmium complex with the Schiffbase ligand (L1) involves coordination and chelation,evidenced by the shifts observed in the 13C NMR
spectra. In the cadmium complex [Cd(L1)(L2)Cl], theazomethine carbon (-CH = N-) shifts from 140.0 ppm
in the free ligand to 138.8 ppm (1.2 ppm shift) in thecomplex, suggesting coordination of the azomethine
nitrogen to the cadmium center [57]. The appearance ofa new peak at 138.8 ppm is attributed to the methylene
carbon (-CH2-) bridging the Schiff base and the cadmium
center, which is absent in the free ligand spectrum. The
peak at 169.9 ppm is assigned to the carbon atom of the
deprotonated carboxylate group (-COO-) coordinatedto the cadmium center [58], not present in the freePage 15 of 31

ligand, indicating deprotonation and coordination. The
carbon of the carbonyl group (-C = O) in the glycinate
exhibits a significant downfield shift from 178.8 ppm
in the free ligand to 169.9 ppm (8.9 ppm shift) in thecomplex, suggesting the carbonyl oxygen’s involvementin cadmium coordination [58]. No shift is observed formethyl, phenyl, and pyridine carbons. The new peaks andshifts provide evidence for chelation of L1 to cadmium,forming a stable five-membered chelate ring involving
the azomethine nitrogen and deprotonated glycinate
carboxylate.
Thermal analysis of ternary Schiff base ­(L1) metal complexes

The study utilized Thermal Gravimetric Analysis (TGA)
to assess the synthesized metal complexes’ thermal
resilience and distinguish between water molecules
existing as hydrated or coordinated within theirstructures [59–64]. Analysis through TG and DTG wasconducted on the Schiff base ligand metal complexes,
examining their behavior across a temperature spectrum
from ambient conditions to 1000 °C. The outcomes
encompassed the temperature ranges, decomposition
stages, product loss during decomposition, calculated
versus observed weight loss percentages, and residuesof all compounds, as detailed in Table 4. The thermal
analysis of the [Mn(L1)(L2)(H2O)].Cl.H2O complex
exhibited four decomposition steps. The initial step,
between 35 and 105 °C with a peak at 85 °C, led to theloss of hydrated water molecules, estimating a massloss of 3.05% (calculated = 3.46%). The subsequent step,
between 105 and 295 °C with a peak at 245 °C, involved
the loss of C7H10NOCl with an estimated mass loss of
29.99% (calculated = 30.76%). The third step, between
295 and 445 °C with a peak at 310 °C, indicated theloss of C2H4NO with an estimated mass loss of 10.49%(calculated = 11.19%). The final step, between 445
and 800 °C with a peak at 560 °C, related to the lossof C11H10N5 with an estimated mass loss of 40.53%(calculated = 40.90%). After complete decomposition,
magnesium oxide (MnO) remained as residues. For
the [Co(L1)(L2)(H2O)].Cl.H2O complex, the firstdecomposition step occurred between 43 and 103 °C,
with a peak at 74 °C, indicating the loss of hydrated
water molecules, estimating a mass loss of 3.61%(calculated = 3.70%). The second step occurred from
105 to 505 °C with a peak at 315 °C, involving the lossof C10H17N2O2Cl with an estimated mass loss of 43.94%(calculated = 44.55%). The final step, from 505 to 800 °C
with a peak at 565 °C, showed the loss of C10H7N5 withan estimated mass loss of 37.31% (calculated = 37.71%),
leaving behind cobalt oxide (CoO) as the decomposition
product. Regarding the [Cu(L1)(L2)(H2O)].Cl.2H2Ocomplex, the decomposition occurred in three steps. The

Mansour et al. BMC Chemistry(2024) 18:150

Page 16 of 31

Fig. 6 Molecular electrostatic mapping potential of A Schiff Base Ligand (L1) and B [Cd(L1)(L2)Cl] Complex. The Isosurface Represents an electron
density of 0.004 Atomic Units

first step, between 35 and 125 °C with a peak at 68 °C,
accounted for a mass loss of 6.007% (calculated = 6.59%),
attributed to the loss of two water molecules. The
subsequent step, between 125 and 345 °C with a peakat 225 °C, involved the loss of C9H14ClN2O2 with anestimated mass loss of 39.398% (calculated = 39.70%).
The final step, between 345 and 800 °C with a peak at
505 °C, related to the loss of C11H10N5 with an estimatedmass loss of 38.16% (calculated = 38.90%). After complete
decomposition, copper oxide (CuO) remained as
residues. In the case of the [Cd(L1)(L2)Cl] complex, thefirst decomposition occurred between 45 and 355 °C,
peaking at 275 °C, resulting in the loss of C9H9ClN3 withan estimated mass loss of 35.51% (calculated = 36.02%).
The second step occurred between 355–800 °C with apeak at 615 °C, indicating the loss of C11H13N4O with anestimated mass loss of 40.11% (calculated = 40.20%), andleaving behind Cadmium oxide (CdO) as the product ofdecomposition.

IR spectra

To estimate the chelation mode of different ligands tometal (II) ions, the IR spectra of the free primary Schiffbase ligand (L1) and secondary ligand glycine (L2) werecompared with the IR spectra of the resulting metal complexes [65]. The IR spectrum of the Schiff base ligand displayed three critical characteristic peaks, with the mostsignificant peak appearing at 1605 and 1545 ­cm−1, corresponding to two (C = N) azomethine and (C = N) pyridine, respectively. In the metal complexes, these bands
shifted to higher wavenumbers [66]: 1610, 1560 ­cm−1 forMn(II), 1619, 1545 ­cm−1 for Co (II),1628, 1559 ­cm−1 forCu(II) and 1620, 1573 ­cm−1 for Cd (II), This shift strongly
suggests the involvement of (C = N) groups in coordination [67]. Two other characteristic bands observed in the
prepared complex spectra at 1421, 1336 ­cm−1 for Mn(II),1410, 1324 ­cm−1 for Co(II),1413, 1327 ­cm−1 for Cu(II)and 1422, 1336 ­cm−1 for Cd(II) were associated with−­(COO ) asy and ­(COO−) sym, indicating the participation of the carboxylic group of the glycine ligand in coordination with the metal ions [68, 69]. Additionally, two
new distinct bands emerged in all metal complex spectraMansour et al. BMC Chemistry(2024) 18:150

Page 17 of 31

Table 7 Bioactivity Evaluation of Schiff Base Ligand (L1) and Its Corresponding Metal(II) Complexes
SampleMicroorganism

L1(1)[Mn(L1)(L2)H2O].
Cl.H2O(2)[Co(L1)(L2)H2O].
Cl.H2O(3)[Cu(L1)(L2)H2O].
Cl.2H2O(4)[Cd(L1) ­(L2)Cl]

Standard drug

Escherichia coli
(ATCC: 10536)

13.9 ± 1.0

19.8 ± 0.5

NA12.0 ± 1.0

28.7 ± 0.5

27 ± 0.5

Klebsiella Pneumonia(ATCC: 10031)

NA24.0 ± 1.0

10 ± 0.5

12.6 ± 0.5

25.3 ± 0.5

25 ± 0.5

Staphylococcus Aureus(ATCC: 13565)

NA

14.3 ± 0.5

19 ± 0.6

23.3 ± 0.6

29.3 ± 0.6

20 ± 0.1

Streptococcus mutans(ATCC: 25175)

10.9 ± 0.5

17.4 ± 1.0

NANA21.0 ± 1.0

28 ± 0.5

Gram-negative bacterial

Gentamicin

Gram-positive bacteria

Ampicillin

Fungi

Nystatin

Candida Albicans(ATCC: 10231)

15.3 ± 0.5

12.3 ± 0.5

15.3 ± 0.5

18.6 ± 0.6

31.0 ± 1.0

21 ± 0.5

Aspergillus Nigar(ATCC: 16404)

14.6 ± 0.5

16 ± 0.5NANA

35.6 ± 0.5

29 ± 0.5

40
35
30
25
20
15
10
5
0

Escherichia coli

Klebsiella
Pneumonia

Staphylococcus
AureusStreptococcus
mutansCandidaAlbicans

L1

Co(II) complex

Cd(II) complex

Mn(II) complex

Cu(II) complex

Gentamicin

Ampicillin

Nystatin

Aspergillus
Nigar

Fig. 7 Antimicrobial activity of Schiff base ligand (L1) and its associated ternary complexes

within the range of 547–560 ­cm−1 and 436–458 ­cm−1,
representing the formation of M‐O and M‐N bonds,
respectively (Table 5) [70]. The spectra of the Cd (II)complex exhibit distinctive bands at 1550 and 1590 ­cm−1,
corresponding to the (C = N) azomethine and (C = N)
pyridine moieties, respectively. Also, 1460 and 1340 ­cm−1
peaks indicate (COO −) asymmetric and (COO −) symmetric vibrations, respectively. Furthermore, characteristic signals at 550 ­cm−1 for M–O and 450 ­cm−1 for
M–N provide insights into the metal–ligand interactions. Additionally, a broad vibration band attributed toν (NH) was detected at the range 3430–3437 ­cm−1 dueto the coordination of the water molecule OH band and
NH stretching vibrations [46]. These spectral features areillustrative examples in theoretical studies, specificallyfocusing on utilizing Density Functional Theory (DFT),
as depicted in Fig. 4. These recorded frequencies alignwith the theoretical predictions, affirming the successful
synthesis of mixed ligand complexes involving a Schiffbase ligand (L1). This unity between experimental andtheoretical frequencies lends support to the proposed
chemical structure of the mixed ligand complex. Discrepancies observed between theoretical and experimental frequencies may be attributed to systematic errors,

Mansour et al. BMC Chemistry(2024) 18:150

potentially arising from harmonicity or the utilizationof gas-phase molecules in DFT calculations. To addressthese discrepancies, a correlation coefficient of 0.9648
was applied for LAN2DZ, offering a corrective measure
to enhance the accuracy of the theoretical predictions
and mitigate the influence of systematic errors [33, 47].
These observations suggest that the prepared Schiff baseligand (L1) acted as a neutral tridentate ligand, coordinating with metal ions via two N‐azomethine and (C = N)
pyridine, while the metal coordinated with the glycine
moiety through ­NH2 and C­ OO− groups, forming a uninegative bidentate ligand.
Geometry optimization

The geometry optimization was done at the DFT levelof theory, and the fully optimized geometry with atomic
numbering of the Cd (II) complex was depicted in Fig. 5[71]. The determined bond lengths and bond angles for
the Cadmium [II] complex indicate a distorted octahedral arrangement surrounding the Cd (II) ion, as outlined in Table 6 [72]. The molecular dimensions werecomputationally determined, precisely the interatomic
distances and bond angles of the Schiff base ligand (L1)and its Cadmium(II) complex. A slight elongation inbond lengths N(8)-N(9), N(12)-N(13), and N(15)-C(16)was noted in the Cd(II) complex as a ligand (L1)coordinated via two azomethine nitrogen and azomethinegroup of pyridine. The main orbital that take place inchemical stability are HOMO (highest occupied molecular orbital) and LUMO (lowest unoccupied molecularorbital). The HOMO represents the electron donor, while
LUMO is the electron acceptor. Various supplementaryparameters, including the HOMO–LUMO energy gap(ΔE), absolute electronegativities (χ), absolute hardness(η), absolute softness (σ), chemical potentials (Pi), global
softness (S), global electrophilicity (ω), and additional
electronic charge (ΔNmax), were computed for boththe Schiff base ligand (L1) and its Cd (II) complex. The
parameters ω + , ω−, and ω are related to the concept ofelectrophilicity index (ω), which provides a quantitative
measure of the electrophilic or nucleophilic behaviorof a compound [73, 74]. Where ω + is the electrophilicity index associated with the LUMO acting as an electron acceptor, ω- is the electrophilicity index related
to the HOMO acting as an electron donor, and ω is thenet electrophilicity index considering both ω + and ω−.
The importance of these parameters lies in their ability
to predict the reactive behavior of a molecule towards
nucleophilic or electrophilic reagents based on the relative stabilities of the compound’s LUMO and HOMO levels. ω +  = μ2/2η, where μ is the chemical potential and η
is the chemical hardness. A higher ω + value indicates a
better ability of the LUMO to accept electrons, making

Page 18 of 31

Table 8 Minimum inhibition and minimum bacteriostatic/
bactericidal concentration of Schiff base ligand (L1) and its
associated metal complexes against H. pylori
Compounds

MIC (µg/ml)

MBC (µg/ml)

MBC/
MIC
Index

Schiff base ligand (L1)

62.5

62.5

1

[Mn(L1)(L2)(H2O)].Cl.H2O

15.62

15.62

1

[Co(L1)( L2)(H2O)].Cl.H2O

15.62

15.62

1

[Cu(L1)(L2)(H2O)].Cl.2H2O

62.5

125

2

[Cd(L1)(L2)Cl]

31.25

62.5

2

the molecule more electrophilic. ω− = μ2/2(IP-μ), where
IP is the ionization potential. A higher ω- value suggests
the HOMO can more easily donate electrons, making themolecule more nucleophilic. The overall ω (ω = ω +  + ω−)
combines the electrophilic (LUMO) and nucleophilic(HOMO) characteristics into a single descriptor of total
electrophilicity. In the context of this study, calculating and analyzing ω + , ω−, and ω can provide valuable
insights:
1. Compare the electrophilicities of the ligand vsmetal complexes to understand how complexation
modulates reactivity.
2. Identify potential electrophilic/nucleophilic reaction
sites based on high ω + /ω− values on specific atoms/
regions.
3. Correlate electrophilicity differences with observed
reactivity trends like biomolecular interactions.
Guide further molecular design by tuning ω to achieve
desired nucleophilic/electrophilic characteristics.
So, in summary, these electrophilicity indices serve
as valuable quantum chemical reactivity descriptors
that can complement the other calculated parameters
in rationalizing structure–activity relationships anddirecting future compound optimization. The calculations employed specific Eqs. (1–9) outlined in the references [24, 25, 75, 76], and the obtained results havebeen systematically presented in Table 6:

I = − EHOMO(1)

A = − ELUMO(2)

E = ELUMO − EHOMOχ = −ELUMO + EHOMO
I +A
=
2
2

(3)

Mansour et al. BMC Chemistry(2024) 18:150

Page 19 of 31

140
120
100
80
60
40
20
0

inhibition zones in dimeter

MIC (µg/ml)

MBC (µg/ml)

MBC/MIC Index

Fig. 8 The inhibitory potential of Schiff base ligand (L1) and its metal complexes against H. pylori

Table 9 The diverse inhibitory capacities against H. pylori demonstrated by Schiff base ligand (L1) and its associated metal complexes
Compounds

Read1

Read2

Read3

Mean

SD

SE

Schiff base ligand (L1)

27.00

26.50

26.50

26.67

0.29

0.09

[Mn(L1)(L2)(H2O)].Cl.H2O

28.00

28.00

28.00

28.00

0.00

0.00

[Co(L1)(L2)(H2O)].Cl.H2O

28.00

28.00

28.00

28.00

0.00

0.00

[Cu(L1)(L2)(H2O)].Cl.2H2O

26.00

26.00

25.50

25.83

0.29

0.09

[Cd(L1) (L2)Cl]

26.00

26.00

26.00

26.00

0.00

0.00

Positive control

24.00

24.00

24.50

24.17

0.29

0.09

η =

ELUMO − EHOMO
I −A
=
2
2

(I + A)2w =4 (I − A)

(4)

(5)

w− =

(3I + A)2
16 (I − A)

(6)

w+ =

(I + 3A)2
16 (I − A)(7)

σ = 1/η

(8)

�Nmax = −I/η(9)

The gap energy (ΔE) is a crucial metric for assessing
stability, elucidating the structural intricacies
and conformational hindrances within numerous
molecular systems. This energy gap was 8.89 eV for
the Schiff base ligand (L1) and 3.097 eV for the Cd (II)complex. When this energy increases, the compound
becomes more stable. Moreover, the chemical
potential (Pi) exhibited a negative value, whereas theelectrophilicity index (χ) demonstrated a positiveMansour et al. BMC Chemistry(2024) 18:150

Page 20 of 31

50
45
40
35
30
25
20
15
10
5
0

Schiff baseligand (L1)

Mn(II) complex

Co(II) complex

12.5

25

50

Cu(II) complex
100

Cd(II) complex

IC50 (μg/mL)

Fig. 9 Anticancer activity against breast cancer of the Schiff bases ligand (L1) and its metal complexes

Table 10 Anticancer activity against breast cancer of Schiff baseligand (L1) and its metal complexes
Compounds

Conc. (μg/mL)
12.5

25

IC50 (μg/mL)
50

100

Surviving fraction (MCF7)
Schiff base ligand (L1)

92

72

44

39.5

44.5

[Mn(L1)(L2)(H2O)].Cl.H2O

48

42

23.5

16

12

[Co(L1)( L2)(H2O)].Cl.H2O

45

34.5

27

24.5

10.2

[Cu(L1)(L2)(H2O)].Cl.2H2O

32

28

26

18

9

[Cd(L1)(L2)Cl]

36

27

25

19

9.5

The ­IC50 value (µg/mL) signifies the concentration of a drug required to impede
the growth of cancer cells by 50%, denoting its cytotoxic dose
The ­IC50 range (µg/mL) categorizes potency levels as follows: 1–10 (very potent),
11–20 (potent), 21–50 (moderately potent), 51–100 (mildly potent), and above
100 (non-cytotoxic) [104]Specifically referencing MCF-7, a type of carcinoma breast cell line

numerical representation [22, 23]. These indicate that
the Schiff base ligand might donate electrons to metal
ions [77]. The higher HOMO energy of the complex
shows that it is easier to remove an electron from thecomplex compared to the ligand, suggesting increased
reactivity. The lower LUMO energy of the complex
indicates that adding an electron to the complex ismore accessible than the ligand, suggesting increased
reactivity. The smaller energy gap of the complex
indicates a higher degree of reactivity and potential
for charge transfer or electronic transitions than theligand [78, 79].

Electron distribution characterization via MolecularElectrostatic Potential (MEP)

Electrostatic potential V(r) mappings were computed
to explore the dynamic responses of molecular systems.
These mappings serve as valuable tools for discerning theelectronic charge distribution encompassing the molecular surface, facilitating the anticipation of reaction sites[80]. The cartography of molecular electrostatic potential (MEP) for both the Schiff base ligand (L1) and its
Cd(II) complex was derived using the identical basis set
employed during the optimization process. The generated three-dimensional MEP plots are depicted in Fig. 6.
Analysis of the MEP allows for delineating electron-richregions, denoted by a red coloration on the map, indicative of favorable sites for electrophilic attacks. Conversely,
blue regions represent electron-poor areas, suggestingsusceptibility to nucleophilic attacks [70]. The area characterized by green-colored markers signifies a region ofelectrostatic potential neutrality. It can be seen that the
Schiff base ligand (L1) is stable, having an almost uniform
distribution of charge. These electrostatic potential V(r)maps showed that chelation enhances the reaction sitein L1 metal complexes. In the ligand structure, we canobserve that the oxygen atoms and the imine nitrogenatoms exhibit a higher negative electrostatic potential(red regions), indicating that these atoms are likely to be
the nucleophilic sites or electron-rich centers within theligand. The aromatic rings and alkyl groups show a moreneutral or slightly positive electrostatic potential (blueregions). In the molecular electrostatic potential map of
the [Cd(L1)(L2)Cl] complex, we can observe a more pronounced polarization of the electrostatic potential compared to the free ligand. The chloride ion ­(Cl−) exhibitsa highly negative electrostatic potential (intense redMansour et al. BMC Chemistry(2024) 18:150

region), indicating its strong electronegativity and highelectron density around this ion. This negative charge
is balanced by the positive charge on the cadmium ion­(Cd2+), represented by a blue region, indicating a lower
electron density or positive electrostatic potential. The
ligands (L1 and L2) coordinated with the cadmium ion
also show distinct regions of negative electrostatic potential around the oxygen and imine nitrogen atoms, similar
to the free ligand (L1). However, these negative regions
appear more polarized or enhanced due to the cadmium
ion’s influence and the complex’s overall charge distribution [81].
Antimicrobial activities

Compared to the free Schiff base ligands, the enhanced
antibacterial efficacy observed in metal complexes canbe attributed to the chelation process, where the Schiffbase coordinates with metal ions, endowing the resulting
metal chelates with polar and nonpolar properties[82]. This property is advantageous as it facilitates thepenetration of these complexes into cells and tissues.
The diminished metal ion polarity results notably fromthe overlap of ligand orbitals during chelation, enablinga partial distribution of the positive charge of the metal
ion among the coordinating donor groups. Consequently,
chelation induces heightened π-electron delocalization
across the entire chelate ring, thereby enhancing thepermeability of the complexes through lipid membranes[83, 84]. Additionally, chelation processes augment thehydrophilic and lipophilic characteristics of central metal
ions, potentially amplifying their lipid-soluble properties
and facilitating their penetration through the lipid bilayerof cellular membranes. The coordination also alters
lipophilicity, influencing the rate at which molecules
enter cells. Consequently, the modified nature of themetal complex, as a result of coordination, renders it
more active than the free Schiff base ligand [83, 85]. The
compounds prepared were tested for their antimicrobial
properties against various strains of bacteria and fungi.
The assessment involved Gram (+ ve) bacteria, namely
Streptococcus mutans and Staphylococcus aureus, Gram(−ve) bacteria, including Escherichia coli and Klebsiellapneumonia, as well as two strains of fungi Aspergillus
niger and Candida albicans. The detailed outcomesof these evaluations were tabulated in Table 7 andgraphically depicted in Fig. 7. The collected data revealed
that the Schiff base ligand (L1) exhibited biologicalefficacy against various bacterial species, except forKlebsiella pneumonia and Staphylococcus aureus. The
study further investigated the in-vitro antibacterial andantifungal activities of the Schiff base ligand and its metal

Page 21 of 31

complexes. Standard antiseptic, antibiotic, and antifungal
drugs such as ampicillin, gentamycin, and nystatin were
employed for comparison. Upon analyzing the biologicaleffects of the Schiff base ligand (L1), metal (II) complexes,
and standard drugs, a notable observation emerges: all
the complexes exhibit superior inhibitory effects onbacterial growth compared to the original ligand. Several
insights can be drawn from the antibacterial test results(Table 7, Fig. 7):
1. The complexes’ observed antibacterial efficacy is
attributed to imine moieties (-C = N) within them. It
is suggested that their mechanism of action involves
the creation of hydrogen bonds via the (C = O)azomethine group, which interacts with vital cellularcomponents. This interaction may disrupt normal
cellular processes, contributing to the compounds’
antibacterial properties.
2. Chelation with M(II) ions results in decreased
polarity as the positive charge of the metal ion isneutralized by the ligand-donor groups. This processenhances the hydrophobic and lipophilic nature of
the ligands, facilitating their permeation throughthe lipid layers of cell membranes. This penetration
can lead to the deactivation of enzymes involvedin cellular respiration and the inhibition of protein
synthesis, effectively restricting the growth of theorganisms.
3. The data suggests that the Cd-complex exhibits
higher toxicity against bacterial species than mostantibiotics, except for cases where its potency is lessthan that of ampicillin against Streptococcus mutans.
4. In terms of antifungal activity against Candida
albicans, the compounds’ effectiveness ranks in thefollowing order:{[Cd(L1)(L2)(Cl)]) > Nystatin > ([Cu(L1)(L2)(H2O)].Cl
0.2H2O) > (L1) = ( [Co(L1)(L2)(H2O)].Cl.H2O)) > ([Mn(L1)(L2)(H2O)].Cl.H2O)}.
Structure–Activity Relationship (SAR)

Some key structure–activity trends can be observed fromthe antimicrobial data:
1. The cadmium(II) complex was the most potent
overall against gram-positive bacteria and fungi,
indicating the critical role of the more significant,softer Cd(II) metal center [86].
2. The cobalt(II) complex demonstrated strong andselective activity against gram-negative bacteria like

Mansour et al. BMC Chemistry(2024) 18:150

E. coli and K. pneumoniae. The unique propertiesof the kinetically inert Co(II) oxidation state may be
responsible [87].
3. The manganese(II) complex showed limited
antimicrobial efficacy, suggesting manganese may not
be an optimal metal center for these ligand systems[88, 89].
4. Substituting different metal centers into the same
ligand framework resulted in diverse antimicrobial
profiles, highlighting how metal geometry, charge,
and electronic properties can significantly influencebioactivity [90, 91].
These findings suggest that the complexes, formedby the Schiff base ligand with metal(II) ions, exhibit
enhanced antibacterial and antifungal properties
compared to their individual components, owing
to their unique mechanisms of action and chemical
characteristics. Antibacterial action depends on various
factors beyond chelation. The effectiveness against
microbes is significantly influenced by several crucial
elements, including the metal ion’s characteristics,
ligand properties, coordination sites, complex geometry,
concentration, hydrophobicity, and co-ligands’ presence.
Suppose the geometric and charge distribution arounda substance did not match the configuration within thebacterial cell wall pores. In that case, it cannot penetrate
the wall, compromising its compatibility and preventing
toxic reactions inside the pores. This discrepancy might
elucidate the weaker activity of specific complexes[92–97]. Some activities observed could result from thedamage incurred during cell wall synthesis, altering thecell’s permeability and ultimately leading to cell death[98].
Bioactive inhibition targeting H. pylori

The study aimed to assess the inhibitory potential of
Schiff base ligand (L1) and its metal complexes against
H. pylori by measuring inhibition zones, as indicated inTable 8 [19]. Furthermore, the investigation included thedetermination and presentation of the Minimum Inhibitory Concentration (MIC) and Minimum Bactericidal
Concentration (MBC) for both the Schiff base ligand (L1)and its corresponding metal complexes. The results ofthese analyses have been provided in Table 8 and visually
represented in Fig. 8 (where the MIC test demonstrates
the lowest level of antimicrobial agent that significantly
inhibits growth, and the MBC demonstrates the lowest level of antimicrobial agent resulting in microbial
death). The MBC/MIC index delineated in Table 8 andillustrated in Fig. 8 was employed to classify the samples’
bactericidal or bacteriostatic efficacy. If the MBC/MIC
index was ≤ 4, it indicated bactericidal activity, while an

Page 22 of 31

index > 4 suggested bacteriostatic activity [42]. Table 8shows that all synthesized compounds exhibited substantial anti-H—Pylori activity. In Table 9, the synthesizedcompounds were found to have varying degrees of effectiveness in inhibiting H. pylori, with the order of efficacy
as follows: [Co(L1)(L2)(H2O)].Cl.H2O = [Mn(L1)(L2)(H2O)].Cl.H2O > Schiff base ligand (L1) > [Cd (L1)(L2)
Cl] > [Cu(L1)(L2)(H2O)]. Cl.2H2O.
The data suggests that certain synthesized compounds,
particularly [Co(L1)(L2)(H2O)].Cl.H2O and [Mn(L1)(L2)(H2O)].Cl.H2O displayed significant inhibitory effects
against H. pylori. This inhibition is likely attributed tothe interaction of the metal centers (Co and Mn) in these
Schiff base complexes with essential biomolecules of H.
pylori, disrupting its metabolic processes and growth.
Consequently, the presence of the Schiff base ligand(L1) and its coordination with transition metals like Co(II) and Mn (II) appears to confer inhibitory properties
against H. pylori. These findings exhibit potential for
creating innovative therapeutic agents in chemotherapy,
potentially providing alternative or complementarytreatments for H. pylori infections.
Anticancer activities

Presently, pharmaceutical research stands at theforefront of discovering novel active drugs for treating
cancer. Among the critical areas in this field, thedevelopment of metal-based anticancer drugs holds
significant importance. Numerous transition metal
complexes have been synthesized and analyzed fortheir potential anticancer properties [99]. In laboratory
settings, in vitro studies were carried out to assess
the cytotoxicity of a ligand and its complexes against
MCF-7 (Breast carcinoma) cells. The relationshipbetween the compounds’ concentrations and the cells’
relative viability was graphed, producing survival
curves for each tumor cell line Fig. 9. Table 10 displays
the ­IC50 values, representing the concentration
causing a 50% inhibition of cancer cell growth. The
observations regarding cytotoxicity against MCF-7(Breast carcinoma) cells are as follows:
A) Metal complexes of the Schiff base ligand, specifically Mn(II), Co(II), Cu(II), and Cd(II) complexes,
demonstrated significant activity against cancer cells,with ­IC50 values of 12, 10.2, 9 and 9.5 μg/mL, respectively. These findings classify these compounds as
significant in chemotherapy, where IC50 reflects theconcentration causing a 50% inhibition in cancer cell
growth.
B) The sequence of potency concerning the chelated
metal ions with the ligand follows the order SchiffMansour et al. BMC Chemistry(2024) 18:150

Page 23 of 31

Table 11 Molecular docking 2D and 3D for predicting the possible binding modes of the studied Schiff base ligand (L1) with thereceptors of the crystal structure from the Protein Data Bank of different types of bacterial species and fungi

5JPE

7DAE

6W41

Mansour et al. BMC Chemistry(2024) 18:150

Page 24 of 31

Table 11 (continued)
In addition, PDB co-crystal forms for cancer cell proteinbase Ligand L1 < Mn(II) < Co(III) < Cd(II) < Cu(II)against MCF-7 cells.
C) Comparative analysis of the antitumor activitiesof the free Schiff base ligand (L1) and its metal
complexes suggests that the Cu-complex exhibits
superior antitumor activity compared to the ligand
and its other metal complexes (Table 10).
D) The Schiff base ligand (L1) displayed minimal
cytotoxic effects on the investigated cancer cell line,
while the Cu(II) complex showed notably cytotoxic
solid effects.
E) A discernible correlation exists between antitumor
activities and antimicrobial activities. For instance,
the Cd-complex demonstrated elevated antifungal
and antibacterial activity against the investigatedfungal and bacterial species while exhibiting
robust antitumor activities against MCF-7 (Breast
carcinoma) cells (refer to Table 10).
F) Thecomplex[Cu(L1)(L2)(H2O)].Cl.2H2O
wasidentified as the most active and effective complex,
potentially suitable as an anti-neoplastic agent
targeting breast carcinoma. The heightened efficacyof the synthesized compounds may be ascribed tothe existence of the azomethine group within themacrocyclic chelate ring. The coordination of metal
ions with the nitrogen atom of the azomethine groupin the chelate ring leads to a reduction in the polarityof the metal atoms. This phenomenon is likely aconsequence of the partial sharing of positive charge
between the metal ions and the ligand [100–102].
The observed increase in activity can be attributed
to the augmented π-electron delocalization within
the ligand moiety upon complexation. Consequently,
the penetration of the complexes through cell
membranes’ lipid layers might be augmented, making
it more efficient [103].

Cytotoxicity and structure–activity relationships

The in vitro cytotoxic activities of the Schiff base ligand(L1) and its corresponding metal complexes were
evaluated against the MCF7 breast cancer cell line
using the MTT assay. The I­C50 values, representing
the compound concentrations causing 50% cell death,provide insights into their potencies as potential

anticancer agents. The free ligand L1 exhibited modest
cytotoxicity with an ­IC50 of 44.5 μg/mL. However, upon
metal complexation, the bioactivities were significantly
enhanced. The manganese(II) complex [Mn(L1)(L2)(H2O)].Cl.H2O showed an I­C50 of 12 μg/mL, a nearly
fourfold increase compared to the free ligand. Thissuggests the Mn(II) metal center is important inaugmenting the cytotoxic properties. Even greater
potency was observed for complexes 2–4 containing
the heavier Co(III), Cu(II), and Cd(II) metal ions, with
­IC50 values of 10.2, 9.0, and 9.5 μg/mL, respectively.
The high oxidizing Co(II) state likely contributes toenhanced redox activation and generation of reactive
oxygen species. The soft, thiophilic nature of the Cu(II)and Cd(II) centers in [Cu(L1)(L2)(H2O)].Cl.2H2O and[Cd(L1)(L2)Cl] may facilitate targeting biomolecules
like DNA or disrupting redox homeostasis. A notablestructure–activity trend is that the cytotoxicities increaseprogressively from the manganese(II) to cobalt(III) to
copper(II)/cadmium(II) complexes. This correlates wellwith the Irving-Williams order of increasing cellular
uptake and biomolecular binding affinities for divalent
metal ions: Mn(II) < Co(II) < Cu(II) > Cd(II). The chloride
and aqua co-ligands may also influence bioactivity
through effects on hydrophobicity, cellular permeability,
and rates of ligand substitution reactions. Overall,this study demonstrates that metal coordination can
profoundly impact the anticancer properties of the Schiffbase scaffolds. The potent cytotoxicities of the Schiffbase complexes against MCF7 cells warrant further
investigation as potential chemotherapeutic leads.
Additional mechanistic studies probing their modesof action, tumor selectivities, and in vivo efficacies are
merited to evaluate their therapeutic potential fully.
Docking study

The potential interaction sites between Schiff base ligand
L1 and its [Cd(L1)(L2)Cl] complex were examined acrossseven distinct receptors. These include (PDB ID: 3AHU)
the crystal structures of the outer membrane protein Gof YmaH (Hfq) from Bacillus subtilis in complex with an
RNA aptamer. Bacterial Hfq is a protein that is vital in
regulating genes in cooperation with sRNAs [105]. The
crystal structure of the outer membrane protein G of
the ACYL-ENZYME complex of Staphylococcus aureus
BETA-LACTAMASE (PDB ID: 1GHP). Beta-lactamases are enzymes produced by some bacteria, includingMansour et al. BMC Chemistry(2024) 18:150

Page 25 of 31

Table 12 Molecular docking 2D and 3D for exploring the binding configurations of the studied Cadmium [II] complex with thereceptors crystal structure from the Protein Data Bank of different types of bacterial species and fungi
Compound

2D Ligand interaction

3D Ligand interaction
Isolated view

Center view

Inside pocket on thesurface of receptor
protein

3AHU

Mansour et al. BMC Chemistry(2024) 18:150

Page 26 of 31

Table 12 (continued)
In addition, PDB co-crystal forms for cancer cell protein

Table 13 Interaction energy values obtained from docking calculations of Schiff base ligand (L1) with different protein receptors
Type
G+ Bacteria

G− Bacteria
Fungi

Receptor

Ligand moiety

Receptor site

Interaction

Distance ­(Aο)

E (kcal/mol)

3AHU

–

–

–

–

–

1GHP

N8

O THR 128 (A)H-donor

3.06

−2.5

6-ringOG SER 130 (A)

pi-H

3.72

−1.6

2ZIC

C2

6-ring TRP 238 (A)

H-pi

4.55

−0.6

6-ring

NE1 TRP 276 (A)

pi-H

4.62

−1.3

N8

O LEU 91 (D)H-donor

3.42

−0.8

6-ringCH2 TRP 73 (D)

pi-H

4.09

−0.6

1NEK
5jpe

Cancer cells

7dae

COVID 19

6W41

N 12

NZ LYS 263 (A)H-acceptor

2.83

−5.9

6-ring

CD LYS 263 (A)

pi-H

3.69

−0.6

6-ring

CD LYS 263 (A)

pi-H

4.65

−0.6

N 18

N ASN 101 (A)H-acceptor

3.44

−1.1

N8

O ASN 450 (C)H-donor

3.02

−2.1

6-ring

CB SER 349 (C)

pi-H

4.22

−0.9

Table 14 Interaction energy values obtained from docking calculations of Cd (II)-L1 complex with different protein receptors
Type+

G Bacteria

Receptorcomplex moiety

Receptor site

Interaction

Distance ­(Aο)

E (kcal/mol)

3AHU

N 20

N PHE 62 (A)H-acceptor

3.39

−2.4

1GHP

N 29

OE1 GLN 237 (A)H-donor

3.24

−3.0

2ZIC

N9

O GLY 227 (A)H-donor

3.23

−2.8

6-ring

ND2 ASN 222 (A)

pi-H

4.09

−0.7

G− Bacteria

1NEK

N 29

O ALA 5 (D)H-donor

2.94

−2

Fungi

5jpe

N 17

O ARG 386 (A)H-donor

3.06

−10.2

6-ringNH2 ARG 386 (A)pi-cation

4.19

−0.6

Cancer cells

7dae

N8

OE1 GLU 71 (A)H-donor

3.10

−5.1

COVID 19

6W41

N9OD2 ASP 98 (A)H-donor

3.47

−1.5

N 17

OG1 THR 179 (A)H-donor

3.32

−1.2

O 33

N ASN 101 (A)H-acceptor

2.94

−1.8

N8

O ARG 355 (C)H-donor

2.97

−2.5

C 11

N ARG 355 (C)H-acceptor

3.33

−6.8

O 33

N ARG 357 (C)H-acceptor

3.32

−1.9

Staphylococcus aureus, that confer resistance to betalactam antibiotics (such as penicillins and cephalosporins) by hydrolyzing the beta-lactam ring. Understanding
the structural details of these enzymes and their interactions with antibiotics is crucial for developing strategies
to overcome antibiotic resistance [106]. The crystal structure of Streptococcus mutans dextran glucosidase (PDB
ID: 2ZIC), where Dextran glucosidase is an important
enzyme involved in the breakdown of dextran, a glucose polymer produced by S. mutans [107]. The crystal
structure of this enzyme provides valuable insights into
its structure and function, which are important for thefollowing reasons: (A) Dental caries (tooth decay): Streptococcus mutans is a major causative agent of dental caries, one of the most common infectious diseases globally.
(B) The ability of S. mutans to produce and metabolize
dextran is crucial for forming dental plaque, a sticky biofilm that adheres to tooth surfaces and contributes tothe development of caries. Complex II (Succinate Dehydrogenase) from E. coli with ubiquinone bound (PDB
ID: 1NEK), Where Complex II is an important enzyme
complex that plays a crucial role in the citric acid cycle(TCA cycle) and the electron transport chain in cellular respiration [108]. Yeast-specific serine/threonine

Mansour et al. BMC Chemistry(2024) 18:150

protein phosphatase (PPZ1) of Candida albicans (PDB
ID: 5JEP), Where PPZ1 is an important enzyme thatplays a crucial role in the regulation of various cellular
processes in C. albicans, a major fungal pathogen responsible for invasive candidiasis and other opportunistic
infections in humans. PPZ1 is a potential target for developing new antifungal drugs, as it is essential for the survival and pathogenicity of C. albicans [109]. Microtubule(EPB) in complex with tubulin, a crucial component of
the cytoskeleton and a significant target in cancer treatment (PDB ID: 7DAE) [110]. The structural information
provided by this crystal structure is important for the following reasons: (A) Microtubule dynamics and function:
Microtubules are dynamic polymers that play essential
roles in various cellular processes, including cell division,
intracellular transport, and maintenance of cell shape.
The crystal structure of the microtubule-tubulin complex
provides insights into the molecular architecture andinteractions that govern microtubule assembly, stability,and dynamics. (B) Cancer therapy targeting: Microtubules are a significant target for many anticancer drugs,
such as taxanes (e.g., paclitaxel) and vinca alkaloids (e.g.,vincristine), which interfere with microtubule dynamics and disrupt cell division. The structural informationfrom 7DAE can aid in understanding the binding modes
and mechanisms of action of these drugs and guide thedevelopment of new and improved microtubule-targeted
anticancer agents [110]. The structural conformationof the receptor binding domain (RBD) of SARS-CoV-2
is bound intricately with the human antibody CR3022(PDB ID: 6W41) [111]. This structure provides crucial
insights into the interaction between the viral protein
and the neutralizing antibody, and its importance can behighlighted as follows: (A) Understanding viral entry andneutralization: The RBD of the SARS-CoV-2 spike protein is responsible for binding to the human ACE2 receptor, facilitating viral entry into host cells. The structural
information from 6W41 reveals the specific interactions
between the RBD and the neutralizing antibody CR3022,
shedding light on the mechanisms by which antibodies
can block viral entry and neutralize the virus [111]. (B)Antibody-based therapeutics and vaccine design: The
structural details of the RBD-antibody complex can guidethe design and development of antibody-based therapeutics and vaccines against SARS-CoV-2. Researchers can engineer or optimize antibodies with enhanced
neutralizing potency, breadth, and specificity by understanding the molecular basis of antibody neutralization.
Molecular docking for these seven distinct receptors
interact with Schiff base ligand (L1) and its Cd(II) Complex was carried out by using the MOE 2014.09 program(MOE 2014.09 [112]; The computational software developed by the Chemical Computing Group in Montreal,

Page 27 of 31

Canada, is employed for elucidating and forecasting thebinding conformation within the protein pockets. The
computational operations were executed on a computing system featuring an Intel Pentium processor runningat a clock speed of 1.6 GHz, with 512 MB of memory,and equipped with the Windows XP operating system.
The minimization procedures employed the Molecular Operating Environment (MOE) until reaching a root
mean square deviation (RMSD) gradient of 0.05 kcal/
mol Å. The molecular mechanics force field MMFF94X
was applied during these optimizations, and the determination of partial charges was automatically computed.
In Tables 11 and 12, we present two-dimensional (2D)
and three-dimensional (3D) plots illustrating the docking results of Schiff base ligand L1 and its [Cd(L1)(L2)Cl]complex, respectively. Additionally, the binding energies
for Schiff base ligand L1 and its Cd (II) complex were calculated and are provided in Table 13 for L1 and Table 14
for the [Cd(L1)(L2)Cl] complex. Experimental anticancer
activities data indicated that Schiff base ligand had I­C50
value = 44.5 μg/against breast cancer cell line, and its Cu(II) and Cd (II) complex had the lowest ­IC50 values, 9 and9.5 μg/mL, respectively. To confirm this data, theoretical
docking studies were investigated against Microtubule(EPB) in a complex with tubulin, a crucial cytoskeleton
component and a significant target in cancer treatment(PDB ID: 7DAE). The docking results showed that thelowest binding energies of Schiff base ligand L1 and its
Cd (II) complex were—1.1 and −6.8 kcal ­mol−1, respectively. These indicated the more active the complex thanits parent ligand, and this large decrease occurred dueto the formation of coordination bonds with the Cd (II)ion. Due to the significant activities observed in thesecompounds were further examined for interactions withvarious outer membrane proteins from different bacteria, fungi, and the SARS-CoV-2 receptor. The findings
revealed substantial and effective interactions between
the prepared compounds and these receptors. The primary interaction forces observed between the compounds and the active sites were H‐donor, H‐acceptor,
and π‐H. Notably, the lowest binding energies of Schiffbase ligand L1 and its Cd (II) complex with 3AHU, 1GHP,
2ZIC, 1NEK, 5jpe, and 6W41 receptors were recordedas NA, − 2.5, − 1.3, − 0.8, − 5.9, and − 2.1 kcal ­mol−1 for
the Schiff base ligand L1, and − 2.4, − 3, − 2.8, − 2, − 10.2,

Conclusion
This study examines the tridentate Schiff base ligand(L1) and its ternary metal complexes through various
analytical methods, including elemental analysis, molar
conductance, mass spectroscopy, IR, and UV–visible
spectroscopy. The findings from these analyses revealed
the formation of octahedral-shaped complexes with

Mansour et al. BMC Chemistry(2024) 18:150

Co(II), Cd(II), Mn(II), and Cu(II). The antimicrobial
assessment displayed that the Cd-complex exhibited
notably higher toxicity against bacterial and fungal
species, rivaling most antibiotics, albeit falling shortin potency compared to ampicillin in combating
Streptococcus mutans. Furthermore, the (L1) Schiff baseand its metal complexes, particularly Co(II), Cd(II),
Mn(II), and Cu(II), exhibited remarkable inhibitory
effects against H. pylori. The metal complexes of the L1
Schiff base, particularly Co(II), Cd(II), Mn(II), and Cu(II),demonstrated substantial activity against MCF-7 (Breast
carcinoma).
Abbreviations
L1	
Schiff Base Ligand (4-(2-((1E,2E)-1-(2-(p-tolyl)hydrazineylidene)
propan-2-ylidene)hydrazineyl)quinazoline)
DFT	Density functional theory
DMF	N, N‐dimethylformamide
DMSO	Dimethyl sulfoxide
ICP	Inductively coupled plasma
FT-IR	Fourier-transform infrared spectroscopy
UV–Vis	Ultraviolet–Visible spectroscopy
NMR	Nuclear magnetic resonanceH. pylori	Helicobacter pylori
AMX	Amoxicillin
MTZ	Metronidazole
PDB	Protein data bank
LUMO	Lowest unoccupied molecular orbitalχ	Absolute electronegativityσ	Absolute softness
S	Global softness
ΔNmax	Additional electronic charge
IC50	Inhibitory concentration 50%
L2	Glycine
TG	Thermogravimetric analysis
DTG	Differential thermogravimetric analysis
SRB	Sulforhodamine B
TCA​	Trichloroacetic acid
RPMI	Roswell Park Memorial Institute medium
FBS	Fetal bovine serum
MBC	Minimal bactericidal concentration
MIC	Minimal inhibitory concentration
CLR	Clarithromycin
EDTA	Ethylenediaminetetraacetic acid
HOMO	Highest occupied molecular orbital
ΔE	Energy gapη	Absolute hardness
Pi	Chemical potentialω	Electrophilicity index
CFU	Colony-forming units
MCF-7	Breast carcinoma cell line
VERO cells	Normal cell line which is derived from the kidney of an African
green monkey
Acknowledgements
The authors would like to thank Cairo University, Faculty of Science and theChemistry Department for supporting and providing laboratory facilities.
Author contributions
Ahmed A. El-Sherif: conceptualization, methodology, formal analysis, project
administration, resources, supervision. Walaa H. Mahmoud: conceptualization,
methodology, validation, visualization, writing—original draft, project
administration, resources, data curation, writing—review & editing,supervision. Abeer T. Abdelkarim: conceptualization, methodology, validation,
visualization. M.S.A. Mansour: conceptualization, methodology, investigation,
validation, visualization, data curation, software, resources, writing—originaldraft.

Page 28 of 31

Funding
Open access funding provided by The Science, Technology & Innovation
Funding Authority (STDF) in cooperation with The Egyptian Knowledge Bank
(EKB).
Availability of data and materials
The datasets used and/or analyzed during the current study are available fromthe corresponding author upon reasonable request.

Declarations
Ethics approval and consent to participate
Not applicable.
Consent for publication
Not applicable.
Competing interests
The authors declare that they have no competing interests.
Author details
1
Chemistry Department, Faculty of Science, Cairo University, Giza 12613,
Egypt.
Received: 8 February 2024 Accepted: 28 June 2024

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