Synthesis, characterization, biological evaluation, and molecular docking approach of nickel (II) complexes containing O, N-donor chelation pattern of sulfonamide-based Schiff bases

Article abstract of DOI:10.1002/aoc.6412

A series of Schiff bases (L¹–L⁴) that possess in their structure bioactive sulfonamide group and their nickel (II) complexes have been synthesized. Microanalytical analyses, various spectroscopic methods such as Fourier transform infrared spectroscopy (FT-IR), ¹H nuclear magnetic resonance (NMR), ¹³C NMR, UV–Vis, and MS, are used to explore the nature of bonding and to elucidate the chemical structures. The analytical and magnetic values suggest a range of stoichiometries 1:1, 1:2, and 2:1 (M:L) for the synthesized complexes of almost square planar geometry. The spectral comparative interpretation reveals that L¹ and L² coordinate to the central Ni (II) in tetradentate ONON donor sequence, whereas L³ and L⁴ in bidentate ON pattern through deprotonated phenolic-O and the azomethine-N. Density functional theory (DFT) and MOE-docking approaches are used to evaluate the molecular parameters and the binding propensity of the synthesized ligands and their complexes with 3s7s protein and to signify their inhibition strength. Besides, the anticancer, antimicrobial and antifungal activities have been screened against number of tumor cells and human pathogen strains. These in vitro studies reveal that Schiff base L⁴ and its complex, [Ni(L⁴-H)(OAc)(H₂O)], have superior activities reflecting the importance of inserting bioactive pendant substituents such as thiazole ring and 3-fluorophenylazo to the pharmacophoric sulfonamide moiety. Moreover, some of the synthesized Ni (II) complexes display promising therapeutic effects as novel non-platinum antitumor agents after further preclinical investigations.

Full text of DOI:10.1002/aoc.6412

Received: 22 May 2021
DOI: 10.1002/aoc.6412
Revised: 22 July 2021
Accepted: 2 August 2021
R E S E A R C H A R T I C L E
Synthesis, characterization, biological evaluation, and
molecular docking approach of nickel (II) complexes
containing O, N-donor chelation pattern of sulfonamide-
based Schiff bases
Ahmed M. Ramadan1
| Hoda A. Bayoumi2
| Rehab M. I. Elsamra1
1Chemistry Department, Faculty of
Science, Alexandria University,
Alexandria, Egypt
2Chemistry Department, Girls College for
Arts, Science and Education, Ain-Shams
University, Cairo, Egypt
Abstract
A series of Schiff bases (L1–L4) that possess in their structure bioactive sulfon-
amide group and their nickel (II) complexes have been synthesized. Microana-
lytical analyses, various spectroscopic methods such as Fourier transform
infrared spectroscopy (FT-IR), 1H nuclear magnetic resonance (NMR), 13C
NMR, UV–Vis, and MS, are used to explore the nature of bonding and to
elucidate the chemical structures. The analytical and magnetic values suggest
a range of stoichiometries 1:1, 1:2, and 2:1 (M:L) for the synthesized complexes
of almost square planar geometry. The spectral comparative interpretation
reveals that L1 and L2 coordinate to the central Ni (II) in tetradentate ONON
donor sequence, whereas L3 and L4 in bidentate ON pattern through
deprotonated phenolic-O and the azomethine-N. Density functional theory
(DFT) and MOE-docking approaches are used to evaluate the molecular
parameters and the binding propensity of the synthesized ligands and their
complexes with 3s7s protein and to signify their inhibition strength. Besides,
the anticancer, antimicrobial and antifungal activities have been screened
against number of tumor cells and human pathogen strains. These in vitro
studies reveal that Schiff base L4 and its complex, [Ni(L4-H)(OAc)(H2O)], have
superior activities reflecting the importance of inserting bioactive pendant sub-
stituents such as thiazole ring and 3-fluorophenylazo to the pharmacophoric
sulfonamide moiety. Moreover, some of the synthesized Ni (II) complexes
display promising therapeutic effects as novel non-platinum antitumor agents
after further preclinical investigations.
Correspondence
Ahmed M. Ramadan, Chemistry
Department, Faculty of Science,
Alexandria University, P.O. Box
426, Alexandria 21321, Egypt.
Email: ahmed.m.ramadan@alexu.edu.eg
K E Y W O R D S
anticancer efficacy, antimicrobial activity, coordination modes, DFT calculations, sulfa
drugs
1 | INTRODUCTION
applications.[1–3] They can be synthesized simply by
condensation of primary amines and aldehydes forming
Schiff bases are privileged compounds owing to their
wide range of biological activities and industrial
azomethine moiety. Structural resemblances of these
compounds with natural biological molecules have
Appl Organomet Chem. 2021;e6412.
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https://doi.org/10.1002/aoc.6412

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RAMADAN ET AL.
evoked versatile pharmacological performances including
anti-inflammatory, antiviral, antibacterial, antifungal,
wound healing, and nerve breakdown protection.[2–5]
Also, the metal complexes of Schiff bases are known for
their free radicals scavenging power protecting living
cells from the adverse consequences of these radicals.[6,7]
For decades, there are a growing number of researches in
the area of complexation of Schiff base derivatives with
various donor N, O, and S atoms especially those con-
taining sulfa drug units. The main objective of most of
these efforts is to increase the synergistic properties
of Schiff base ligands by combination of different bioac-
tive moieties such as sulfonamide, acyl pyrazolones, and
diazenyl linkages.[7–9] Besides, there is an increasing con-
sideration for synthesis and development of novel non-
platinum metal complexes to overcome the unresolved
clinical complications associated with using carboplatin
or cisplatin in cancer treatment.[10,11] Recently, there is
an increasing demand for designing potentially effective
anti-pathogenic and anti-COVID-19 agents to overcome
the developed resistance of many microbes and viruses
attacking human.[12,13] Toward achieving these goals
herein presented the synthesis, characterization of newly
Ni (II) complexes derived from Schiff base ligands whose
structures contain combination of 3-fluorophenylazo, sul-
fonamide, and/or thiazole substituents.
the reference. For Ni (II) complexes, the metal content
was estimated by convenient indirect titration with stan-
dard EDTA,[14] and by atomic absorption technique at
the central lab, Alexandria University. Simultaneous
thermal analyses (TGA/DTGA) of the nickel complexes
were carried out at heating rate 10ꢁC minꢀ1 using Bruker
LINSEIS STA PT 1000 under N2 flow of 20 cm3 minꢀ1
.
GAUSSIAN 09 software was used for the calculations of
molecular orbital parameters based on the density func-
tional theory (DFT)(B3LYP/6-31G) level of theory. The
optimized structures were visualized in GAUSSIAN-
VIEW.[15] Optimization was achieved without con-
straining the geometry of the inspected compounds.
Docking investigation was attained by MOE 2015.10 soft-
ware. The intial steps to prepare the tested compound for
the docking process included hydrogen atoms addition,
removal of water molecules, atomic charges clarifying
and then energy minimization by MMFF94x force
field.[16] The inhibition strength was deduced from the
magnitude of scoring energy and the number of effective
ligand-protein bonds in the simulated poses.[17]
2.2 | Antibacterial, antifungal and
anticancer activities
Compounds (L1–L4) were tested in vitro for their antimi-
crobial activities by agar diffusion method as previously
described.[18] The utilized organisms were two Gram-
positive bacteria (Streptococcus pneumoniae and Bacillus
subtilis), two Gram-negative bacteria (Pseudomonas
aeruginosa and Escherichia coli), and two fungal strains
(Aspergillus fumigatus and Candida albicans). The
observed mean zone diameter of inhibition in mm is con-
sidered as an index of the antimicrobial activity of the
tested samples. Besides, the minimal inhibitory concen-
tration (MIC, μg/ml) was estimated by applying broth
microdilution assay as previously depicted in a study con-
ducted by our group.[19] Ampicillin, gentamycin, and
amphotericin B were used as standard references for
antibacterial and antifungal activities.
In addition, the synthesized ligands and some
selected nickel (II) complexes were preliminarily assessed
for their anticancer efficacy against human hepatocellu-
lar carcinoma cells (HepG-2), colon carcinoma cells
(HCT-116), and breast carcinoma cells (MCF-7) by crystal
violet viability method as described.[20] Cisplatin and
imatinib were utilized as positive controls under the
same assessment conditions. Furthermore, some com-
pounds were evaluated against oral epithelial cell line
(OEC) to gauge their toxicity on normal cells under the
same assay conditions. OEC cell line (PCS-200-014) was
obtained from the American Type Culture Collection
2 | EXPERIMENTAL
2.1 | Materials, instruments, and
methodology
The purity of the compounds was checked by precoated
TLC plates (MERCK) using chloroform: methanol (7:3)
mixture. All the chemical materials used are of analytical
reagent grade and used without further purifications.
3-Fluoroaniline, Ni (OAc)2.4H2O, sulfanilamide (SNM),
and sulfathiazole (STZ) were purchased from Sigma–
Aldrich and Fluka companies. All solutions used
throughout the experiments were prepared freshly in
ultrapure water obtained from ultrapure water system
in which water was distilled and deionized. Gallenkamp
MFB-595 device was utilized to record melting points. IR
spectra were recorded using KBr disc method on Fourier
transform infrared spectroscopy (FT-IR) Bruker tensor
37 within 400–4000 cmꢀ1 spectral range. Mass spectra
were recorded on Shimadzu Qp-2010 plus mass spec-
trometer at 70 eV, Faculty of Science, Cairo University.
The nuclear magnetic resonance (NMR) spectra (1H,
500 MHz; 13C, 125 MHz) were recorded at room tempera-
ture using Bruker AC-500 spectrometer. Chemical shifts
are expressed in δ (ppm) with tetramethylsilane (TMS) as

RAMADAN ET AL.
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(ATCC, Rockville, MD). Antimicrobial and cytotoxicity
evaluations were performed by Regional Center for
Each reactant was dissolved in a minimum amount of
ethanol and followed by addition of 2-ml glacial acetic
acid. The solution was refluxed for 8 h then cooled to
room temperature and poured into ice cold water. The
isolated colored Schiff bases (Scheme 2) were collected
through filtration and then dried using drying oven at
80ꢁC. The products were purified by repeated recrystalli-
zation in ethanol/H2O solvents and then dried.
Mycology
&
Biotechnology (RCMP) at Al-Azhar
University, Cairo, Egypt.
2.3 | Synthesis of 5-(3-fluorophenylazo)
salicylaldehyde (3-FAS)
The newly 3-FAS compound was prepared by the usual
diazotization process (Scheme 1).[21] The required
3-fluoroaniline (0.05 mole, d = 1.156, 4.8 ml) in 15-ml
HCl (37%) was diazotized below 5ꢁC with a solution of
NaNO2 (0.05 mole, 3.45 g) and 20-ml distilled water. The
diazonium chloride was coupled with an alkaline solu-
tion of salicylaldehyde (0.05 mole, d = 1.1655, 5.23 ml).
The crude dye was filtered, washed with distilled H2O,
and dried in vacuum over P4O10, (C13H9N2O2F Yellow
color, m.p. 140–142ꢁC).
2.4.1 | 4-([2-Hydroxybenzylidene]amino)-
benzenesulfonamide (L1)
Bright yellow crystals, yield (73%), m.p. 208–209ꢁC; UV–
Vis. (DMF) λmax/nm: 232, 273, 342; IR (KBr) νmax/cmꢀ1
:
3341 νasym (NH2), 3245 νsym (NH2), 3,060 ν (OH), 3,028 ν
(CH-sp2), 1,617 ν(C=C), 1571 ν(C=N), 1368 νasym (SO2),
1182 νsym (SO2); 1H NMR (500 MHz, DMSO-d6):
δppm = 12.65 (1H, s, OH); 9.00 (1H, s, C7-H); 7.90 (2H, d,
C10-H, C12-H); 7.71 (1H, d, C6-H); 7.57 (2H, d, C9-H, C13-
H); 7.47 (1H, t, C4-H); 7.42 (2H, s, NH2); 7.02 (1H, d, C5-
H); 7.00 (1H, d, C3-H); 13C-NMR (500 MHz, DMSO-d6):
2.4 | General method for the synthesis of
a series of Schiff base ligands (L1–L4)
δppm = 116.7 (C3); 119.3 (C1); 119.4 (C5); 121.8 (2C, C9,
C13); 127.4 (2C, C10, C12); 132.5 (C6); 133.9 (C4); 142.0
(C11); 151.2 (C8); 160.2 (C7H=N); 164.9 (C2-OH);
276 (M+, 100); 212 (19.10); 195 (90.5); 167 (33.4);
108 (39.1); 92 (60.4); 77 (33.5); 65 (76.1); 51 (30.2); Anal.
Calcd. for C13H12N2O3S (276.31): C, 56.51.28; H, 4.38; N,
10.14; S, 11.60%, Found: C, 56.73; H, 4.25; N, 9.96; S,
11.79%.
The Schiff base ligands were prepared by reaction of
equimole (10 mmole) of sulfa drug (SNM or STZ) with
salicylaldehyde or substituted salicylaldehyde (3-FAS).[22]
2.4.2 | 4-([2-Hydroxybenzylidene]amino)-N-
(1,3-thiazol-2-yl)benzenesulfonamide (L2)
Golden yellow crystals, yield (82%), m.p. 218–220ꢁC; UV–
Vis. (DMF) λmax/nm: 279, 345; IR (KBr) νmax/cmꢀ1: 3145
ν (NH), 3115, 2800 ν (OH), 3017 ν (CH-sp2), 1616
ν(C=C), 1580, 1532 ν(C=N), 1362 νasym (SO2), 1182 νsym
SCHEME 1 Synthesis of 5-(3-fluorophenylazo)salicylaldehyde
(3-FAS)
1
(SO2); H NMR (500 MHz, DMSO-d6): δppm = 12.59 (1H,
s, OH); 10.75 (1H, s, NH); 8.97 (1H, s, C7-H); 7.87 (2H, d,
C10-H, C12-H); 7.69 (1H, d, C15-H); 7.52 (2H, d, C9-H, C13-
H); 7.45 (1H, t, C4-H); 7.29 (1H, d, C6-H); 7.00 (1H, t, C5-
H); 6.86 (1H, d, C3-H); 6.56 (1H, d, C16-H); 13C-NMR
(500 MHz, DMSO-d6): δppm = 108.3 (C16); 116.7 (C3);
117.2 (C1); 119.3 (C5); 121.8 (2C, C9, C13); 127.7 (2C, C10,
C12); 129.2 (C6); 132.5 (C4); 136.4 (C15); 140.1 (C11); 151.4
(C8); 160.7 (C7H=N); 165.0 (C2-OH); 168.9 (C14); MS m/z
(%): 359 (M+, 26.6); 295 (24.5); 196 (100); 176 (62.6);
167 (24.9); 99 (9.44); 92 (13.0); 77 (22.0); 65 (16.9);
51 (18.6); Anal. Calcd. for C16H13N3O3S2 (359.42): C,
53.47; H, 3.65; N, 11.69; S, 17.84%, Found: C, 53.58; H,
3.55; N, 11.54; S, 18.01%.
SCHEME 2 Structures of Schiff base ligands (L1–L4)

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RAMADAN ET AL.
2.4.3 | 4-((5-[3-fluorophenylazo]-
2-hydroxybenzylidene)amino)-benzene-
sulfonamide (L3)
2.5 | General procedure for the synthesis
of nickel (II) complexes
A solution of Ni (CH3COO)2.4H2O (2.49 g, 10 mmol) in
EtOH (10 ml) was added to a stirred solution of Schiff
base (L1-L4) (5 mmol) in hot EtOH (25 ml). Few drops of
DMF was added to help the solubility of the Schiff base
before mixing. Then, NaOAc (0.41 g, 5 mmol) dissolved
in least amount of H2O was added to make the medium
slightly basic. The mixture was heated at 60ꢁC for 1 h
under stirring. The precipitated complex was filtered and
washed with MeOH, and then air dried. The analytical
and physical properties of the synthesized metal com-
plexes were collected in Table 1.
Red powder, yield (61%), m.p. 206–208ꢁC; UV–Vis.
(DMF) λmax/nm: 408, 465; IR (KBr) νmax/cmꢀ1: 3364
νasym (NH2), 3261 νsym (NH2), 3075 ν (OH), 3029 ν
(CH-sp2), 1619 ν(C=C), 1,570 ν(C=N), 1493 ν(N=N),
1
1334 νasym (SO2), 1153 νsym (SO2); H NMR (500 MHz,
DMSO-d6): δppm = 11.71 (1H, s, OH); 9.17 (1H, s, C7-
H); 8.38 (1H, s, C6-H); 8.22 (1H, s, C15-H); 8.11 (1H,
d, C4-H); 7.93 (1H, d, C19-H); 7.77 (1H, t, C18-H); 7.64
(2H, d, C10-H, C12-H); 7.43 (2H, d, C9-H, C13-H); 7.21
(1H, d, C17-H); 6.89 (2H, s, NH2); 6.59 (1H, d, C3-H);
13C-NMR (500 MHz, DMSO-d6): δppm = 107.4 (C15);
107.5 (C3); 112.4 (2C, C9, C13); 117.6 (C1); 119.6 (C17);
121.8 (C19); 122.7 (C6); 124.1 (C4); 127.4 (2C, C10, C12);
129.9 (C18); 131.2 (C11); 142.3 (C5); 144.6 (C14); 150.8
(C8); 153.5 (C7H=N); 163.7 (C16-F); 163.9 (C2-OH); MS
m/z (%): 398 (M+, 49.1); 275 (39.3); 215 (1.9);
198 (1.4); 195 (77.1); 167 (59.3); 123 (7.6); 95 (100);
93 (10.6); 77 (11.7); 65 (68.7); Anal. Calcd. for
C19H15FN4O3S (398.41): C, 57.28; H, 4.77; N,
14.06; S, 8.05%, Found: C, 57.35; H, 4.55; N, 13.91; S,
8.16%.
3 | RESULTS AND DISCUSSION
3.1 | Structure elucidation of the
synthesized Schiff base ligands (L1–L4) and
their complexes
The synthesized sulfonamide-based Schiff bases (L1–L4)
showed a considerable ability to form chelates with
diverse stoichiometric ratios (Table 1) 1:1, 1:2 or 2:1
(M:L). This coordination capability is attributed to the
presence of many binding sites (oxygen, nitogen, and sul-
fur atoms) (Scheme 2).
2.4.4 | 4-((5-[3-fluorophenylazo]-
2-hydroxybenzylidene)amino)-N-(1,3-thiazol-
2-yl)-benzene-sulfonamide (L4)
3.1.1 | Fourier transform infrared
spectroscopy, nuclear magnetic resonance, MS,
and coordination modes
Orange powder, yield (71%), m.p. 236–237ꢁC; UV–Vis.
(DMF) λmax/nm: 406, 468; IR (KBr) νmax/cmꢀ1: 3135 ν
(NH), 3092, 2801 ν (OH), 3020 ν (CH-sp2), 1619
ν(C=C), 1568, 1539 ν(C=N), 1481 ν(N=N), 1329 νasym
Microanalytical and various spectroscopic methods such
as FT-IR, 1H NMR, 13C NMR, and MS, (Table 1 and
Figure 1), were used in order to assign the chemical
structures of the synthesized compounds. Full interpreta-
tions of all spectral data are elaborated in Section 2 and
in the supporting information (Table S1 and Figures S1–
S13). Characteristic infrared spectral band of the precur-
sor 3-FAS appeared at 1478 cmꢀ1 due to ν(N=N)
(Figure S1) indicating the formation of the azo derivative
from the reaction of 3-fluoroaniline with salicylaldehyde
(Scheme 1). Also, the sharp strong band in the IR
spectrum of 3-FAS at 1671 cmꢀ1 corresponding to
ν(C=O) was disappeared in the ligand's spectra
(Figures 1 and S2) inferring Schiff condensation with sul-
fanilamide (SNM) or sulfathiazole (STZ) (Scheme 2).
Besides, the synthesized Schiff base ligands (L1–L4)
showed a new strong to moderate band in the range
1568–1580 cmꢀ1 assigned to azomethine ν (HC=N)
linkage.[23] Further, the twin broad bands in the IR
1
(SO2), 1143 νsym (SO2); H NMR (500 MHz, DMSO-d6):
13.26 (1H, s, OH); 12.54 (1H, bs, NH); 9.12 (1H, s,
C7-H); 8.36 (1H, s, C6-H); 8.06 (1H, d, C4-H); 7.89 (1H,
d, C22-H); 7.77 (1H, d, C15-H); 7.66 (1H, d, C18-H);
7.63 (1H, t, C21-H); 7.58 (2H, d, C10-H, C12-H), 7.29
(1H, d, C20-H); 7.19 (2H, d, C9-H, C13-H); 6.86 (1H, d,
C3-H); 6.56 (1H, d, C16-H); 13C-NMR (500 MHz,
DMSO-d6): δppm = 107.3 (C18); 107.5 (C16); 112.4 (2C,
C9, C13); 117.6 (C3); 117.8 (C1); 118.4 (C20); 120.1 (C22);
122.5 (C6); 124.3 (C4); 127.7 (2C, C10, C12); 129.9 (C21);
131.2 (C15); 131.3 (C11); 144.5 (C5); 152.1 (C17); 153.3
(C8); 153.4 (C19-F); 161.7 (C7H=N); 163.6 (C2-OH);
168.9 (C14); MS m/z (%): 481 (M+, 61.3); 398 (2.3);
318 (38.8); 215 (3.8); 198 (1.4); 123 (6.1); 95 (100);
93 (19.5); 77 (12.7); 65 (76.5); Anal. Calcd. for
C22H16FN5O3S2 (481.52): C, 54.88; H, 3.35; N,
14.54; S, 13.32%, Found: C, 55.09; H, 3.25; N, 14.47; S,
13.41%.

RAMADAN ET AL.
5 of 15
TABLE 1 Analytical data and physical properties for nickel (II) complexes
% Calculated/ (Found)
Complex
(M:L)
Formula Color
Color
μ eff
Λ m
M
C
H
N
S
B.M Ωꢀ1molꢀ1cm2
(1) [Ni2(L1-H)(OAc)3(H2O)].H2O
C19H24N2O11SNi2
Brown
19.38
37.67
3.99
4.62
5.29
0.71
0.59
dia.
0.71
3.45
1.90
2.45
1.63
(2:1)
(19.38) (37.82) (4.09)
17.50 39.38 3.46
(17.42) (39.51) (3.58)
6.34 49.31 3.92
(4.76)
6.26
(5.19)
9.56
(2)
(3)
(4)
[Ni2(L2-H)(OAc)3(H2O)]
C22H23N3O10S2Ni2
Reddish brown
C38H36F2N8O10S2Ni
Dark orange
(2:1)
[Ni(L3-H)2].4H2O
(1:2)
(6.32)
12.11
(9.40)
6.93
(6.12) (49.51) (4.06) (12.36)
9.52 46.77 3.27 11.36
(6.71)
10.41
[Ni(L4-H)(OAc)(H2O)]
C24H20FN5O6S2Ni
Brown
(1:1)
(9.34) (46.82) (3.41) (11.48) (10.28)
Note: All complexes have m.p. > 300ꢁC.
A comparative analysis of the IR spectra of the Schiff
base ligands (L1–L4) and their nickel complexes sheds
light to specify the bonding mode of the surrounding
ligands with the central Ni (II) ion. There are some guide
bands which assist in achieving this target. For instance,
the band ν (CH=N) in the spectra of all free ligands is
considerably lowered in frequency (ꢂ15 cmꢀ1), weak-
ened and appeared as shoulder in the spectra of all com-
plexes (Table S1 and Figures 1 and S2) implying the
involvement of azomethine nitrogen atom in coordina-
tion.[25] Also, the phenolic νOH is vanished in the spectra
of all complexes supporting its participation in coordina-
tion after deprotonation.[26]
In case of complexes (1) and (2) of the type (M2L), the
asymmetric stretching band due to the sulfonyl group
(νasymSO2) is shifted to lower frequency (33–39 cmꢀ1
)
compared to the free ligands L1 and L2 (Table S1) pro-
posing sulfonyl oxygen as an additional coordination
site in these cases. This is accompanied by disappear-
ance of either the twin bands of ν (NH2) or ν (NH) in
case of L1 and L2, respectively, substantiating the
enolization process of the sulfonamide group SO2NH
(H) to SO (OH) = N(H) before coordination as
reported by previous studies of metal-sulfa drugs based
chelates of a dinuclear feature (M2L).[27,28] Accordingly,
there is an interaction between the metal ion with the
sulfonamidic-N and sulfonyl-O atoms of L1 through
four-membered ring formation in case of complex
(1).[29,30] As well, the blue shift and the weakness of
the ν(C=N) at 1532 cmꢀ1 of the thiazole moiety of L2
in the spectra of its complex (2) favoring the chelation
of the thiazole-N atom to give more stable six-
membered ring.[28,31] Unlikely, there is no remarkable
change of the sulfonamide group vibrational modes in
case of L3 and L4 complexes (3) and (4) (Table S1)
ruling out its participation in coordination with Ni
(II) in these cases.
FIGURE 1 FT-IR of (a) L1, (b) [Ni2(L1-H)(OAc)3(H2O)].H2O,
(c) L3, (d) [Ni(L3-H)2].4H2O
spectra of L1 and L3 in the range 3245–3364 cmꢀ1 typified
the asymmetric and symmetric stretching vibrations of
NH2 of the sulfonamide group (Figure 1). Nevertheless,
the IR spectra of the free ligands L2 and L4 showed vari-
ous bands at 2800–3145 cmꢀ1 assigned to νNH of sulfon-
amide and νOH of the phenolic group (Figure S2). The
appearance of OH stretching modes at lower frequencies
than its ordinary position (ꢂ3300–3400 cmꢀ1) could be
attributed to intramolecular hydrogen-bonding (O–H---
N) with the neighbor azomethine group.[24] Moreover,
the two bands that appeared at 1329–1368 and 1143–
1182 cmꢀ1 were correspondingly assigned to the vibra-
tions νasym (SO2) and νsym (SO2) (Table S1).

6 of 15
RAMADAN ET AL.
Therefore, it is concluded that the ligands are che-
(C7H=N), C2-OH and thiazole (C14) carbons (Scheme 2).
The proposed mode of binding was further scrutinized by
NMR spectral comparison of L3 and its diamagnetic Ni
(II) complex (3) (Figure S3). The phenolic OH signal at δ
11.71 ppm in the spectra of the free ligand (Figure S3a) is
disappeared in complex (3) (Figure S3b) endorsing the
deprotonation of the OH group at C(2) before coordina-
tion. The existence of electron withdrawing substituents
azo (N=N) at C(5) and F atom at C(16) in the adjacent
phenyl moiety may ease this proton removal at C
(2) (Scheme 2). On the other hand, the singlet NH2 pro-
tons peak at δ 6.89 ppm is nearly unchanged in both
ligand and complex (3) spectra (Figure S3b) overruling
any interaction of Ni (II) ion and the amino group of the
sulfonamide part.[30]
Based on the mass spectral data, the molecular ion
peaks (M+•) of the synthesized Schiff base ligands
(Figures S8 and S9) are in good consistency with their
formula weights. Scheme 4 represents the proposed frag-
mentation pattern of L4 as a descriptive example. Also,
the complexes (1) to (4) displayed (M+•) at m/z = 605.94,
671.12, 926.29, and 616.76, respectively, that adequately
support their elucidated chemical structures by other
analytical and spectral techniques (Figures S10–S13). In
this regard, the mass spectrum of the dinuclear complex
(1), [Ni2(L1-H)(OAc)3(H2O)].H2O, exposed a prominent
peak at m/z 276.25 (100%) corresponding to the molecu-
lar ion peak of its precursor L1 (Figure S10). The spec-
trum also displayed a group of peaks at m/z 588.27,
569.72, 510.99, and 329.47 corresponding to dinuclear
cation fragments [Ni2(L1-H)(OAc)3(H2O)], [Ni2(L1-H)
(OAc)3], [Ni2(L1-H)(OAc)2], and [Ni2(L1-H)], respectively.
Besides, the peaks at m/z 453.09, 392.47, 334.08,
and 117.92 could be assigned to the mononuclear cations
[Ni(L1-H)(OAc)2], [Ni(L1-H)(OAc)], [Ni(L1-H)], and
[Ni (OAc)] in sequence. Similarly, the complex [Ni(L4-H)
(OAc)(H2O)] (4) gives monomeric cationic fragments
[Ni(L4-H)(OAc)], [Ni(L4-H)], and [Ni (OAc)] at
m/z = 598.77, 540.36, and 117.74 (Figure S13) upon
losing bulky molecular ions from the inner sphere. Also,
the loss of 3-fluorophenylazo moiety from L4 molecule in
[Ni(L4-H)(OAc)] (4) leads to the appearance of L2 peak at
m/z = 359.46 in the spectra of complex (4), Figure S13.
Interestingly, the appearance of a peak at m/z ffi 59 in all
complexes coincides with the existence of nickel isotope
supporting the complexation process.[34]
lated to the metal ion in two different ways by one or two
bidentate (ON) donor atoms. L1 and L2 both behave as a
monobasic tetradentate (ONON) donor sequence as coor-
dinated to the Ni (II) ion via deprotonated phenolic-O,
the azomethine-N, enolic sulfonamide S(O)OH,
sulfonamidic-N or thiazole-N (Scheme 3). However, L3
and L4 coordinate in a monobasic bidentate fashion
(ON) by only deprotonated phenolic-O and the
azomethine-N. It is worth mentioning that different com-
plexes of L1 and L2 with different stoichiometry (ML2)
have been isolated in previous studies.[25,32] In these
researches, they were bound to the central metal ion as
neutral bidentate ligands and not in the deprotonated
tetradentate fashion (M2L) as in our case. This could be
attributed to the difference in the pH of the medium dur-
ing preparation and the type of the counter anions.[32]
Additionally, the emergence of two new bands in the
ranges 1398–1447 and 1219–1231 cmꢀ1 in the spectra of
complexes (1), (2), and (4) characteristic of the asymmet-
ric and symmetric stretching vibrations of the COOꢀ
group, respectively, points to a monodentate pattern of
the acetate group around the metal ion.[33] Also, the low
frequency bands that are only observable in the spectra
of the metal complexes in 529–595 and 466–481 cmꢀ1
regions due to ν(M-O) and ν(M-N) assert the complex
formation.[31]
1
Likewise, H NMR and 13C NMR spectral data of the
synthesized ligands (L1–L4) have provided additional sup-
port to their structures (Figures S3–S7). In particular, the
OH group at C(2) was found in the range δ 11.71–
1
13.26 ppm as a D2O-exchangeable singlet peak in the H
NMR spectra of all ligands (Figures S4 and S5). Also, the
two NH2 protons of the sulfonamide group of L1 and L3
were located as strong singlet peak at 7.42 and 6.89 ppm,
respectively, inside the aromatic range δ 6.58–8.39 ppm
(Figure S3). However, the singlet peak of NH proton in
the case of L2 and L4 was appeared in the downfield
region at δ 10.75 and 12.54 ppm (Figure S4), respectively.
As for 13C NMR, the compound L4, C22H16FN5O3S2, dis-
played 20 distinct types of carbons (Figure S7) among
which two lines having integration of two carbons of an
identical environment at 112.4 ppm (C9, C13) and
127.7 ppm (C10, C12). Besides, the key peaks at δ 161.7,
163.6, and 168.9 ppm were attributed to azomethine
3.1.2 | UV–Vis, conductivity, and magnetism
measurements
The electronic spectra of L1–L4 series have been recorded
in DMF solvent where absorptions curves of two or three
SCHEME 3 Structure of [Ni2(L2-H)(OAc)3(H2O)] complex (2)

RAMADAN ET AL.
7 of 15
SCHEME 4 Mass fragmentation
pattern of L4
bands within the ranges 232–279, 342–345, and 406–
468 nm were noticed. The bands are related to π ! π*
and n ! π* transitions due to a comparatively long-
conjugated system in the ligand's structure especially in
the case of L3 or L4 where three phenyl groups are linked
by azo and azomethine bridges. Also, the ligands possess
several atoms bearing nonbonding electrons such as oxy-
gen, nitrogen and sulfur atoms (Scheme 2). Similar
absorption bands were obtained in case of complexes
with obvious broadening up to ꢂ500 nm. The broad fea-
ture in this region could be related to charge transfer of
LMCT type that makes it difficult to detect any weak d–d
transitions inside the metal ion.[35]
The molar conductance (Λm) of the complexes in
DMF at a concentration of 1 Â 10ꢀ3 M was recorded in
the range 1.63–3.45 Ωꢀ1 molꢀ1 cm2 (Table 1) supporting
their non-electrolytic behavior and neutrality of the
coordination sphere.[28] The magnetic susceptibility
values (μeff) at 296 K of the Ni (II) complexes (1), (2),
and (4) are in the range 0.59–0.71 B. M (Table 1)
signifying the existence of square planar $ tetrahedral
geometries in the same solid phase.[36] The tetrahedral
percentage (Nt) in this 4-coordinate mixture could be
calculated by using the equation: Nt = [(μobs.)2/
(3.3)2] Â 100, where μobs is the observed room tempera-
ture magnetic moment and 3.3 is the value of
magnetic moment in case of perfect tetrahedral Ni
(II) complexes.[37] Thus, the Nt values of complexes (1),
(2), and (4) lies in the range of 3.20%–4.63%. The low
Nt value hints at the bulkiness effect of the substituents
on phenyl moieties that favors square planar shape.[37]
Nevertheless, the zero μeff value for Ni (II) complex (3)
approves its adopted square-planar geometry with
diamagnetic features. Moreover, the later finding
proposes that the two sulfonamide-based ligand (L3)
molecules in complex (3) are being strong enough to
produce
a considerable ligand-field splitting factor
enhancing the planar form.[38]

8 of 15
RAMADAN ET AL.
3.1.3 | Thermal studies
decomposition steps in these stages. Also, the two NiO
residual composition is in conformity with the proposed
dinuclear structure of complex (2) as reported for analo-
gous Schiff bases complexes.[39]
The thermal properties of nickel complexes derived from
Schiff bases (L1–L4) were dissected using TGA and DTGA
methods under N2 gas flow up to ꢂ800ꢁC (Figures 2 and
3). All thermal peaks details, the percentage of mass
losses and their assignments are listed in Table 2. As an
illustrating example, the thermal decomposition of the
[Ni2(L2-H)(OAc)3(H2O)] complex (2) proceeds in three
stages (Figure 2). The first stage at temperature range
ꢂ74–297ꢁC is corresponding to the combined loss of one
H2O and one CH3COOH molecule from the inner coordi-
nation sphere (calc. 11.6%; found 11.4%). The second
stage points to the decarboxylation process of two che-
lated acetate groups accompanied with the starting of
ligand decomposition in the temperature range ꢂ297–
380ꢁC. The mass loss continues in the third stage which
is related to the bulk of the ligand fragment
(C16H9N3OS2) up to 523ꢁC (Table 2) leaving 2 NiO as a
residue (calc. 22.3%; found 22.3%). The variation between
the found and calculated mass losses in second and third
stages is taken as an indication of overlapping of the
It is worthy to mention that the investigated com-
plexes have considerably high thermal stability as plausi-
bly inferred from the first decomposition DTGA peak
maximum (Tm).[33] The bonding between Ni (II) ion and
the ligands (L1–L4) starts to dissociate at Tm values of
ca. 333.9, 351.5, 361.7, and 404.3ꢁC, respectively (Table 2
and Figure 3). Accordingly, L4 displayed the highest
binding capacity with the metal ion which could be
attributed to many factors as inductive effect of the sub-
stituents, bulkiness, geometry, and stoichiometry of the
complex.[40] In addition, the delay of water molecules
removal up to ꢂ162ꢁC in the case of [Ni(L3-H)2].4H2O
complex (3) may be related to strong hydrogen bonds for-
mation between the outer sphere water molecules and
electronegative atoms as fluorine, nitrogen, and oxygen
of two ligands molecules.[40]
3.2 | Theoretical studies
3.2.1 | Chemical reactivity modeling
DFT was applied to estimate the best optimized confor-
mations and to calculate the theoretical parameters of
the synthesized compounds from which the electrophilic
binding sites and the molecular activity were predicted.
The theoretical data of the investigated ligands (L1–L4)
and Ni (II) complexes (2) and (4) as illustrating examples
are collected in Table 3 and Figures 4–7 and S14–S23.
The calculated bond lengths and bond angles of Ni
(II) complexes (2) and (4) typified square planar geome-
try (Table S2). Slight elongation in the bond length was
noticed in N(35) = C(29), O(26)-S(25), N(14) = C(12),
and N(14)-C(15) in complex (2) upon coordination
through phenolic-O, the azomethine-N, enolic S(O)OH,
and thiazole-N in tetradentate mode (Figure 4). The dihe-
dral angles N(13)-Ni(35)-O(10), O(10)-Ni(35)-O(43), N
(13)-Ni(35)-O(36), and O(36)-Ni(35)-O(43) of complex (4)
were 94.92ꢁ, 84.41ꢁ, 90.60ꢁ, and 90.05ꢁ respectively indi-
cating square planar geometry around the Ni (II) ion
(Figure 5). The small discrepancy in coordination sphere
angles than the ideal square planar supported the exis-
FIGURE 2 TGA and DTGA of [Ni2(L2-H)(OAc)3(H2O)]
complex (2) under N2 atmosphere
tence of
a small tetrahedral percentage as early
calculated.
Generally, small energy gap ΔE (ELUMO-EHOMO) is
taken as a good indicator for complexation ability with
neighboring central metal ion having empty d-orbital or
biological receptor as well as softness and hence chemical
reactivity.[19] Among the examined ligands, L4 exhibits
FIGURE 3 TGA of Ni (II) complexes: [Ni2(L1-H)(OAc)3(H2O)].
H2O (1), [Ni(L3-H)2].4H2O (3), and [Ni(L4-H)(OAc)(H2O)] (4)

RAMADAN ET AL.
9 of 15
TABLE 2 Thermal analyses data of Ni (II) complexes derived from L1–L4
Wt. loss/
Residue %
T m
ꢁC
Temp. Range
(ꢁC)
Complex (M:L)
Found
3.29
12.8
37.8
21.5
24.6
11.4
24.4
41.9
22.3
7.52
5.92
78.4
8.12
3.10
20.7
64.2
12.0
Calc. Assignment
[Ni2(L1-H)(OAc)3(H2O)].H2O (2:1)
52.4
35.9–103.4
103.4–309.7
309.7–373.3
373.3–698.7
Residue
2.97
12.9
59.5
—Outer sphere H2O
—Inner sphere H2O, ꢀCH3COOH
201.4
333.9
597.3
—2CH3COOH, Decomposition of ligand
(ꢀC13H8N2OS)
24.7
11.6
66.1
2NiO
[Ni2(L2-H)(OAc)3(H2O)] (2:1)
[Ni(L3-H)2].4H2O (1:2)
143.6
351.5
445.6
73.6–296.9
296.9–379.6
379.6–523.2
Residue
—H2O, ꢀ CH3COOH
—2CH3COOH, Decomposition of ligand
(ꢀC16H9N3OS2)
22.3
7.79
84.1
2NiO
139.5
361.7
545.2
34.8–162.3
220.5–432.6
432.6–698.1
Residue
—4H2O
Decomposition of ligand
(ꢀC38H28F2N8O5S2)
8.07
2.92
85.0
NiO
[Ni(L4-H)(OAc)(H2O)] (1:1)
168.4
404.3
610.5
148.2–238.4
265.7–478.9
478.9–697.6
Residue
—H2O
—CH3COOH, Decomposition of ligand
(ꢀC22H14FN5O2S2)
12.1
NiO
TABLE 3 The molecular parameters of some selected synthesized compounds
ET
(Hartree)
D
EHOMO
(eV)
ELUMO
(eV)
ΔE
(eV)
η
S
χ
ω
Compound
(Debye)
(eV)
2.120
1.952
1.855
1.852
1.013
1.704
(eVꢀ1
)
μ (eV)
(eV)
(eV)
L1
L2
L3
L4
ꢀ1235
ꢀ1803
ꢀ1675
ꢀ2243
7.658
8.197
5.165
4.379
7.989
4.010
ꢀ6.351
ꢀ6.326
ꢀ6.383
ꢀ6.372
ꢀ5.943
ꢀ6.024
ꢀ2.111
ꢀ2.422
ꢀ2.673
ꢀ2.669
ꢀ3.917
ꢀ2.616
4.240
3.904
3.710
3.703
2.026
3.408
0.236
0.256
0.269
0.270
0.494
0.293
ꢀ4.231 4.231
ꢀ4.374 4.374
ꢀ4.528 4.528
ꢀ4.520 4.520
ꢀ4.930 4.930
ꢀ4.320 4.320
4.222
4.901
5.526
5.516
12.00
5.476
Complex (2) ꢀ5581
Complex (4) ꢀ4055
FIGURE 4 Optimized structure of [Ni2(L2-
H)(OAc)3(H2O)] complex (2)

10 of 15
RAMADAN ET AL.
FIGURE 5 Optimized structure of [Ni(L4-H)
(OAc)(H2O)] complex (4)
FIGURE 6 LUMO and HOMO of [Ni(L4-H)
(OAc)(H2O)] complex (4)
FIGURE 7 Molecular electrostatic
potential of L2
the smallest ΔE (3.70 eV) which points to an ease of elec-
tron transfer with Ni (II) d-orbitals owing to its long-
conjugated system of three linked phenyl groups with
several donor atoms such as oxygen, nitrogen, and sulfur
(Figure 6). Also, the higher negative total energy (ET) of
the complexes (2) and (4) compared to their free ligands
(Table 3) implies the greater stability of the isolated com-
plexes. Additional molecular reactivity parameters have
been estimated including, electrophilicity (ω), hardness
(η), softness (S), electronegativity (χ), dipolar moment
(D).[41] Apparently, there is a direct correlation between
these chemical reactivity indices and different biological
inhibition activities. For instance, the relatively low
dipole moment values (D) for L4 and its Ni (II) complex
(4) suggest the feasible ability to penetrate the phospho-
lipid bilayer of the biological cell membrane.[42]

RAMADAN ET AL.
11 of 15
Seemingly, L4 displays the lowest η (1.852 eV) and
highest S (0.270 eVꢀ1) and subsequently it is expected to
have sufficient softness compared to other studied ligands
and hence superior biological activity as confirmed prac-
tically in this research.
Moreover, the electronic charge distribution was
screened theoretically on the surface of the synthesized
ligands to specify the sites of interaction. The areas of
high electron density, denoted in red, are intense on the
sulfonamide as well as the azomethine parts of
the ligands. The electron-rich regions in the case of L2
(Figure 7) are clearly localized on the atoms N(15), N
(37), and O(27) accounting for possible binding sites
which is in harmony with the chelation pattern con-
firmed by the spectroscopic study in this contribution.
3.2.2 | Molecular docking approach
In silico investigation of the inhibition strengths of the
synthesized compounds were achieved by molecular
docking approach versus the 3D crystal structure of 3s7s
protein. The targeted protein represents the human cyto-
chrome P450 aromatase which catalyzes the synthesis of
estrogens and is complexed with breast cancer drugs.[43]
Docking results such as ligand-receptor sites, interaction
type, interaction distances, internal energy (E), and scor-
ing energy (S) are shown in Table 4 and Figures 8 and
S24–S26. The effective ligand-receptor bond lengths for
most of the tested compounds were ≤3.5 Å which give
insight into typical real bonds and high ligand-receptor
binding affinity.[17,44] For instance, the closest interaction
TABLE 4 The docking parameters of synthesized compounds against 3s7s protein
Compound
L1
Ligand site
N 29
N 29
O 28
6-ring
S 32
Receptor site
LEU 372
MET 374
VAL 373
LEU 477
MET 303
ALA 307
MET 311
ARG 115
ARG 435
TRP 141
ALA 438
MET 303
SER 314
CYS 437
CYS 437
VAL 370
THR 310
VAL 370
PRO 429
LEU 477
ALA 306
ASN 75
Interaction type
H-donor
H-donor
H-acceptor
π-H
Distance (Å)
3.13
3.78
3.36
4.39
3.73
3.37
3.73
3.14
3.15
3.13
4.43
3.14
3.01
3.31
3.50
3.91
3.05
3.24
2.15
3.08
3.44
3.13
3.20
3.28
3.51
3.03
3.22
2.68
3.64
E (kcal/mol)
ꢀ2.9
ꢀ2.1
ꢀ0.8
ꢀ0.6
ꢀ0.1
ꢀ0.8
ꢀ0.8
ꢀ1.6
ꢀ3.2
ꢀ1.1
ꢀ0.9
ꢀ2.4
ꢀ0.8
ꢀ1.1
ꢀ1.2
ꢀ0.8
ꢀ4.5
ꢀ0.8
ꢀ1.1
ꢀ0.4
ꢀ1.6
ꢀ2.7
ꢀ1.7
ꢀ1.0
ꢀ1.1
ꢀ1.3
ꢀ1.7
ꢀ9.3
ꢀ1.1
S (kcal/mol)
ꢀ6.6984
L2
L3
H-donor
H-acceptor
H-donor
H-acceptor
H-acceptor
H-acceptor
π-H
ꢀ7.6582
ꢀ7.9185
O 28
C 34
O 27
O 27
N 28
6-ring
O 10
S 44
L4
H-donor
H-donor
H-acceptor
H-acceptor
π-H
ꢀ9.0101
ꢀ6.7220
O 26
N 30
5-ring
O 38
O 47
Ni 41
S 32
Complex (1)
H-donor
H-acceptor
Metal
Complex (2)
Complex (3)
H-donor
H-donor
H-acceptor
H-acceptor
H-acceptor
H-donor
H-donor
H-donor
H-donor
π-H
ꢀ6.0659
ꢀ7.5583
O 46
O 26
N 29
N 30
C 5
LYS 473
LYS 473
MET 303
PRO 429
ALA 306
THR 310
VAL 370
Complex (4)
ꢀ9.3457
S 29
O 43
O 43
5-ring

12 of 15
RAMADAN ET AL.
as H-donors is observed with Serine SER 314 (3.01 Å)
and Threonine THR 310 (2.68 Å) amino acids in the case
of L4 and its complex (4), respectively. In addition, the
ligand-protein binding affinities were predicted from
the scoring energy function based on parameters such as
intermolecular hydrogen bonds, van der Waals interac-
tion, deformation effect, hydrophobic interaction, and
entropy.[45] So, all ligands show an extent of inhibition to
the 3s7s protein following the order L4 > L3 > L2 > L1
which could be related to an increase in the synergistic
properties by a consortium of different bioactive moieties
such as azomethine, sulfonamide, thiazole ring,
3-fluorophenylazo substituent ongoing from L1 to L4.
Remarkably, the binding sites of L4 are O(10), S(44), (O
(26) and N(30)), and the five-ring sites with the Methio-
nine MET 303, Serine SER 314, Cysteine CYS 437, and
Valine VAL 370 amino acids (Figure 8), respectively, with
relatively highest negative scoring energy (ꢀ9.0101 kcal/
mol) (Table 4). The negative value for energies for all
tested compounds means spontaneous binding of the
ligand to the target receptor without requiring energy.
Likewise, the highest inhibition activity and the most sta-
ble interaction with the 3s7s protein among the Ni
(II) complexes was discerned for complex (4) with a scor-
ing energy of ꢀ9.3457 kcal/mol. Furthermore, the surface
mapping of the ligands-protein pockets (Figures 8 and
S24–S26) demonstrated strong interaction between the
protein and the synthesized compounds as the ligands
appeared completely implanted in the cavity of the sur-
rounded amino acids.
3.3 | Biological activity studies
3.3.1 | Antibacterial and antifungal activities
The in vitro antimicrobial assessment of the sulfonamide-
based Schiff bases (L1–L4) revealed varying inhibitory
actions as shown in Table 5. MIC values expressed in μM,
have been estimated only for the tested compounds of
FIGURE 8 Binding features (a) surface maps (b) of the best docked poses of the synthesized L4 and complex (4) against breast cancer
protein 3s7s

RAMADAN ET AL.
13 of 15
TABLE 5 Antibacterial and antifungal inhibition zone in mm and MIC (μM) of the synthesized Schiff bases
Gram-positive bacteria
Gram-negative bacteria
Fungi
Compound
S. pneumoniae
B. subtilis
P. aeruginosa E. coli
A. fumigatus
19.8 0.3 (28.3)
C. albicans
L1
L2
L3
L4
17.3 0.6 (113.1) 20.2 0.4 (14.1)
NAa
NA
NA
NA
NTb
15.9 0.4 (226.2)
NA
NA
NA
NA
NT
NT
16.9 0.4 (86.9)
20.6 0.6 (4.89)
19.6 0.6 (16.2)
19.3 0.3 (21.7)
22.4 0.4 (2.46)
20.0 0.3 (8.10)
14.9 0.4 (> 500) 17.9 0.4 (86.9)
16.9 0.6 (78.4)
15.9 0.5 (129.8)
NT
20.3 0.3 (9.79)
21.4 0.6 (4.05)
Ampicillin
Gentamycin
Amphotericin B
23.8 0.20 (2.80) 26.4 0.5 (1.40)
NT
NT
NT
NT
NT
NT
17.3 0.1 (32.7) 19.9 0.3 (8.17)
NT NT
23.7 0.1 (2.11) 25.4 0.1 (1.06)
aNo activity.
bNot tested.
TABLE 6 Cytotoxicity activity
(IC50) in μM of Schiff bases and some of
their complexes
Tumor cell lines
Compounds
HCT-116
25.3 0.9
29.5 0.9
7.98 0.6
92.1 2.8
37.0 1.4
44.1 1.5
8.10 0.7
19.6 1.9
MCF-7
HepG-2
Normal cell line OEC
L1
L2
L4
41.3 1.3
40.6 1.1
12.3 0.8
>100
53.2 1.6
50.6 1.5
16.0 0.7
>100
NT
74.6 5.4
>100
Complex (1)
Complex (2)
Complex (4)
Cisplatin
Imatinib
49.8 4.4
86.3 6.9
>100
41.9 1.8
37.5 1.2
19.0 2.3
49.8 2.3
71.5 2.8
40.3 1.3
12.2 0.6
38.2 2.1
inhibition zone growth above 6 mm. From the data,
Schiff base L4 exposed the highest antifungal activity
against Aspergillus fumigates (MIC 4.05 μM) which is
nearly 50% less potent than amphotericin B. Likewise, L3
exhibited the most significant action against Gram-
positive bacteria S. pneumoniae (MIC 4.89 μM) and
B. subtilis (MIC 2.46 μM) which is about twofold less
effective than ampicillin as a standard drug. These supe-
rior activities of L3 and L4 in comparison to L1 and L2
could be related to the presence of electron withdrawing
group (3-fluorophenylazo) in their structures. In general,
the insertion of substituents with different inductive
effect and bulkiness had been proved to be effective (posi-
tively or negatively) on the antimicrobial activity of many
compounds and should be considered in designing any
novel drugs.[46,47] Nevertheless, all studied ligands
showed negligible to mild activities versus Gram-negative
germs (P. aeruginosa and E. coli) in contrast to Gram-
positive ones (Table 5) reflecting the cell wall structure as
an additional prominent factor in controlling the inhibi-
tion.[48] Clearly, the absence of the outer lipid membrane
in Gram-positive strain wall makes it more vulnerable to
be attacked by the tested compounds despite its thicker
peptidoglycan layer.
3.3.2 | Cytotoxicity assessment
The antiproliferative potency for some selected Schiff
base ligands and their Ni (II) complexes has been
screened as presented in Table 6 and Figures 9, 10, and
S27–S31. There is an apparent steady trend in the IC50
values for the investigated ligands (Figure 9) and their Ni
(II) complexes (Figure 10). All compounds were designed
to possess in their structure benzenesulfonamide group
as a basic unit which is known to impose DNA damage
and hence cell death via apoptosis.[49] In addition, the
ligand modification by inserting other bioactive substitu-
ents to the benzenesulfonamide group would facilitate its
propensity for DNA-binding through hydrogen bonds.
Based on IC50 values in μM, it is evident that L4 has the
prominent activity against the three cancer cell lines
HCT-116 (7.98 μM), MCF-7 (12.3 μM), and HepG-2
(16.0 μM). These low values indicate anticancer

14 of 15
RAMADAN ET AL.
platinum therapeutic drugs were synthesized, character-
ized and examined for their biological activities. The
mass spectral data of complexes (1) to (4) displayed
molecular ion peaks (M+•) that support plentifully their
proposed chemical structures. Also, the thermal
decomposition steps of all complexes confirmed their
high thermal stability. Besides, the slight difference in
coordination sphere angles from the ideal square planar
supported the existence of a small tetrahedral percentage
(Nt) as calculated from magnetic measurement and illus-
trated by the DFT-B3LYP/6-31G method. The docking
simulation outcomes predicted a good propensity to bind
with the breast cancer protein 3s7s in the case of L4 and
its complex (4) that is in accord with their recorded antip-
roliferative potencies. Further preclinical inspections
including intracellular ROS generation, ADMET-score,
clinical trials, and drug approval process should be done
on the most promising chemotherapeutic candidates
such as L4 and [Ni(L4-H)(OAc)(H2O)].
FIGURE 9 The inhibitory dose response curves of some
selected ligands against MCF-7
ACKNOWLEDGMENTS
The authors would like to express their gratitude to
Alexandria University, Alexandria, Egypt for providing
administrative and technical support.
DATA AVAILABILITY STATEMENT
The data that support the findings of this study are
available in the supplementary material of this article.
FIGURE 10 The inhibitory dose response curves of some
ORCID
selected complexes against MCF-7
Ahmed M. Ramadan https://orcid.org/0000-0002-4815-
1487
equipotency impact of L4 in comparison with cisplatin as
a reference control (Table 6). Similarly, complex (4)
as well as complex (2) exhibit about onefold and/or two-
fold less antiproliferative action versus the three tested
cell lines relative to imatinib as an effective drug. The
preceding findings are matched to great extent with the
predicted ones from the docking simulations.
Hoda A. Bayoumi https://orcid.org/0000-0001-7423-
7359
Rehab M. I. Elsamra https://orcid.org/0000-0003-1217-
748X
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How to cite this article: A. M. Ramadan, H.
A. Bayoumi, R. M. I. Elsamra, Appl Organomet
Chem 2021, e6412. https://doi.org/10.1002/aoc.
6412
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