Results in Chemistry 6 (2023) 101052

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Results in Chemistry
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Synthesis, characterization, and biological evaluation of some metal

complexes containing N and S donor atoms
Tanzimjahan A. Saiyed a, Jerry O. Adeyemi c, Moganavelli Singh d, Sunday N. Okafor e,
Damian C. Onwudiwe a, b, *
a
Material Science Innovation and Modelling (MaSIM) Research Focus Area, Faculty of Natural and Agricultural Science, North-West University (Mafikeng Campus),
Private Bag X2046, Mmabatho, South Africa
b
Department of Chemistry, Faculty of Natural and Agricultural, Science, North-West University (Mafikeng Campus), Private Bag X2046, Mmabatho 2735, South Africa
c
Postharvest and Agroprocessing Research Centre (PARC), Department of Botany and Plant Biotechnology, University of Johannesburg, P.O. Box 524, Auckland Park,
Johannesburg 2006, South Africa
d
Nano-Gene and Drug Delivery Laboratory, Department of Biochemistry, University of KwaZulu-Natal, Private Bag X54001, Durban 4000, South Africa
e
Department of Pharmaceutical and Medicinal Chemistry, University of Nigeria, Nsukka 41001, Nigeria

A R T I C L E I N F O A B S T R A C T

Keywords: Eight new bipyridine adducts of Zn(II) and Ni(II) dithiocarbamate complexes have been prepared from the re­
N-donor ligands action of Zn(II) and Ni(II) complexes of N-ethyl-N-phenyldithiocarbamate and 4,4′ dipyridine, 4,4′-dimethyl-2,2′-
S-donor ligands bipyridine, 4,4′-dimethoxy-2,2′-bipyridine, 4,4′-ditertbutyl-2,2′-bipyridine. The resulting adducts were repre­
Cancer cells
sented as [M(L1)2(DP)], [M(L1)2(DMeB)], [M(L1)2(DMxB)] and [M(L1)2(DTB)] respectively (where M = Zn or
Dithiocarbamate
Biological studies
Ni). The structural configuration of these adducts was established using various spectroscopic techniques. The
Molecular docking obtained data from the spectroscopic studies revealed a change in the tetrahedral configuration of the parent
complexes to octahedral coordination in the adducts due to an additional metal-nitrogen bond. The formation of
this bond was established by a considerable shift in the peaks around the metal-nitrogen (M− N) coordination
upon the formation of the adducts. The study of biological properties including cytotoxicity, antioxidant, and
anti-inflammatory properties were carried out. No noticeable trends were reported in all the studies despite the
concentration-dependent profile shown in the assays and the structural similarities of the compounds. These
adducts, nevertheless, showed good antioxidant activity in the DPPH assay, with IC50 ranging between 3.78 and
4.87 µg/mL which is better than the standard ascorbic acid (4.96 µg/mL). Also, in the cytotoxicity study, the
adducts [Zn(L)2DMeBp] (1) and [Ni(L)2 DTBp] (6) showed the best activity against the mutating human
cervical cancer (HeLa) and embryo kidney (HEK 293) cell lines and better than the standard 5-Flurouracil. The
molecular docking studies further revealed that the adducts had a good binding affinity to the drug targets used
for the study.

Introduction
Metal ions and their complexes are vital in the human biological
system. Hence, research continues to explore and build novel drugs in
recent times [1]. They are designed to target specific biological sites due
to their vast range of geometries and coordination characteristics [2,3].
Metal ions are electrophiles that play crucial part in about one-third of
enzymes and possess the capacity to conduct various cellular activities
[4]. They form bonds or charge-charge interactions with other atoms
because of their positive charge [1,5]. Metal ions, which have a sizeable
ionic volume and bear a positive charge, may bind with a wide range of
ligands and biomolecules, including DNA, enzymes, and proteins, sur­
rounded by clouds of electrons [4]. As a result of these opposite charges,
metal ions interact with biological molecules [4,5]. Several metal-based
drugs have been developed on this fundamental principle, resulting in
significant discoveries in inorganic chemistry and improved prospects
for employing metal complexes as therapeutic agents. Transition metal
complexes offer a great diversity in their activities, such as antioxidant,
anti-inflammation, anticancer, and antimicrobial [5–7]. In the mecha­
nism of action, the combination of metals with organic ligands can boost

* Correspondence author at: Material Science Innovation and Modelling (MaSIM) Research Focus Area, Faculty of Natural and Agricultural Science, North-West
University (Mafikeng Campus), Private Bag X2046, Mmabatho, South Africa.
E-mail address: Damian.Onwudiwe@nwu.ac.za (D.C. Onwudiwe).

https://doi.org/10.1016/j.rechem.2023.101052
Received 6 April 2023; Accepted 25 July 2023
Available online 2 August 2023
2211-7156/© 2023 The Author(s). Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-
nc-nd/4.0/).
T.A. Saiyed et al.
the biological activities of the organic component of the metal drug in
the presence of metal ions and minimize the toxicity of metal to host
cells [8]. This increased biological activity might be due to the longer
retention time of metal-based drugs, which allows them to reach their
targeted biological site more quickly [9]. It may also be associated with
the formation of reactive oxygen species (ROS). Meanwhile, toxicity can
be decreased because the metal ion’s transit to the intended site of action
is aided by its complexation with organic molecules [9]. As a result, the
often harmful reactions (such as enzyme inhibition or other damaging
reactions) that might be harmful to health are reduced [10]. Metals such
as zinc and nickel ions are often found in complexes with proteins and
nucleic acids. They are involved in various intermediary metabolism,
genetic information transmission and regulation, peptide hormone
storage, synthesis, action, and structural maintenance of chromatin,
biomembranes, and extracellular matrices [11,12]. Thus, coordination
complexes are more prominent as medications or pro-drugs and have
been widely employed in medicinal chemistry.
Metal cations can easily form complexes with various S, N, O, and P
donor ligands of different compositions and stability [13,14]. The
dithiocarbamate group is one of the interesting sulfur donor ligands and
has been found to play valuable roles in many biological processes [13].
Due to the two sulfur atoms in their structure, dithiocarbamates are
easily complexed with metal atoms. This strong binding ability of metal
dithiocarbamate complexes has received considerable attention in
medicine, especially in enzyme inhibition that directly affects the bio­
logical system [15]. A wide range of dithiocarbamate and their transi­
tion metals and lanthanides derivatives have been investigated to
demonstrate good biological uses due to their extensive structural pos­
sibilities and chelating capabilities [16]. The activity of the zinc and
nickel dithiocarbamate are structure-dependent, and their different
monomers and dimers structures have been extensively reported pre­
viously [17,18]. The alkyl groups on the backbone of zinc and nickel
dithiocarbamate complexes have lower lipophilic character due to their
low electron density and short carbon chain. However, the bulky phenyl
groups have a higher electron density and lipophilicity, which may
result in π-π interactions with biomolecules [5,10]. Similar to the
physiologically active compounds such as amino acids and vitamins
[10], sulfur-containing ligands have been employed along with N-donor
ligands to create novel complexes containing both N and S ligands [5].
The mixture of dithiocarbamate and bipyridine ligands has influenced
diverse biological processes such as antioxidant, anti-inflammation,
anticancer, and antimicrobial [19]. Since N-donor ligands combine
one or two aromatic nitrogen heterocycles into a single molecule, they
can generate a lot of chelating and bridging metal dithiocarbamate
complexes, which are more effective antibiotics than the original
organic ligands. [5].
Over the years, therefore, the transition metal complexes bearing N
and S donor ligands have been the interest of many research findings due
to their encouraging broad-spectrum biological activities than their
respective parent ligands [20]. Notable examples are thio­
semicarbazones [20–23] and adducts of dithiocarbamate complexes
bearing N donor Lewis bases[24–26]. This adduct formation is usually
achieved via the interaction of metal complexes with various ligating
Lewis bases, which allow for the increase in the coordination number of
metal ions in a complex while maintaining the same oxidation state
[27–29]. The propensity for any complex to form an adduct has been
found to be closely related to the nature and geometry of the coordi­
nating ligand, the ionic size of the metal ion, and the ability to accept π
electrons [30]. Adduct formation in dithiocarbamate is, thus, brought
about by the movement of electrons towards the sulfur atoms of the
dithiocarbamate moieties due to the mesomeric effect of the –NR2 group
[27,31,32]. The resulting properties and structure of these adducts are
often significantly different from the parent complexes, which in turn
affect their resulting biological properties [29].
The structural geometry of a metal complex influences the new
ligand field and the electronic structure of the metal ion [33]. Different
2
Results in Chemistry 6 (2023) 101052
ligand field strengths can affect the reactivity and stability of the metal
complex, which can influence its biological activity[33]. Also, the ge­
ometry of a metal complex can impact its ability to bind to biological
targets. Biological targets, such as enzymes or receptors, often have
specific shapes and binding sites [34]. A metal complex with a com­
plementary geometry to the target site may exhibit enhanced binding
affinity and biological activity [34]. This is because metal centers pro­
vide an opportunity to utilize building blocks with increased valency
and a wider range of geometries. For instance, a metal center with an
octahedral coordination environment and six distinct substituents can
generate 30 stereoisomers, whereas chiral carbon centers can only form
two possible isomers [34]. Therefore, metal complexes with simple yet
well-defined rigid shapes exhibit the necessary complexity to achieve
high protein-binding specificity [34]. Also, complexes with a bulky
substituent group may have a larger surface area to interact with the
enzyme or receptor, leading to stronger binding and increased potency
[35]. On the other hand, a complex with a linear or planar geometry may
have a better affinity for specific binding sites due to the shape of the site
and thus exhibit higher biological activity. Therefore, several metal
dithiocarbamate complexes such as zinc, nickel, ruthenium, and iron
with substituted bipyridine ligands have been synthesized and studied
for their biological properties and potential applications in catalysis,
electrochemistry, and material science [36 37 38,39]. Most nickel and
zinc(II) dithiocarbamate complexes, regardless of the type of dithio­
carbamate ligands employed, generally exhibit a tetrahedral geometry.
However, Zn(II) complexes may also exist as dimers in the solid state
[40]. These complexes can further coordinate to Lewis bases bearing
different heteroatoms such as N to form an adduct with the general
formula [M(S2CNR2)(N-donor)x] (M = Zn/Ni; x = 1 or 2). The resulting
adducts exhibit either octahedral or square pyramidal geometries
around the central metal atom. The possibilities for different geometries
of metal complexes can lead to variations in their biological activities. In
addition, the properties and structure of these adducts are often signif­
icantly different from the parent complexes, which in turn affect their
resulting biological properties [41]. Thus, a slight change in either factor
can significantly impact the biological activity of the complex, making
them essential factors to consider in drug design and optimization.
Different factors, such as the arrangement of atoms around the metal
ion (coordination geometry), the oxidation number of the metal, and the
type of ligand employed in the complexation reaction, significantly
impact the properties of metal complexes. These factors also influence
the biological relevance and applications of metal complexes[10]. In
biological systems, the mode of action of most metal complexes is
attributed to the combined effect between the metal ion and the ligand
component. Hence, the chemistry and biological activity of metal
dithiocarbamate complexes arises from the combined characteristics of
the central metal and the dithiocarbamate ligand [42]. The ligand plays
a regulatory role in the associated metal toxicity while enhancing its
properties. Moreover, the C-N backbone of dithiocarbamate and C-S
bonds in its structure allows for potential derivatization, leading to
intriguing chemistry and improved biological efficiency [10]. Conse­
quently, these features contribute to the broad range of valuable bio­
logical properties exhibited by dithiocarbamate complexes due to their
involvement in the formation of diverse biologically useful organic in­
termediates. Metal complexes, such as dithiocarbamate, have been
observed to extend the retention time of organic ligands and decrease
the bioavailability of metals that could harm the host organism of in­
terest [9]. These ligands play a significant role in determining the
characteristics of a secondary coordination sphere involved in identi­
fying possible biological sites [42] because of the weak metal–ligand
interaction, which is known to have an affinity for ligand substitution
and redox reactions. Consequently, it increases the likelihood of organic
ligands easily reaching their targeted sites to carry out their intended
functions [43,44]. Furthermore, studies have identified other factors,
such as the formation of chelating rings, that may contribute to the
beneficial biological properties of metal complexes. Studies have
T.A. Saiyed et al.
indicated that the delocalization of electron density over the chelating
ring promotes the permeability of the complexes through the cell
membranes of various organisms [45].
In chelating complexes, metal ions bond with two or more donor
group atoms from the same ligand, favoring the formation of ring
complexes compared to non-chelates, where two ligands form bonds of
similar strength [45]. Consequently, chelates derived from donor groups
containing sulfur, oxygen, and nitrogen atoms have attracted research
due to their significance in physiochemical processes and their biolog­
ical relevance, particularly as models for dynamic sites of metal­
loenzymes [45]. According to Tweedy’s chelation theory, the chelation
process surrounding the metal center reduces the polarity associated
with the central metal atom[45]. This reduction in polarity occurs
because the positive charge of the metal is partially shared with the
atoms of the donor groups. Consequently, the delocalization around the
chelate ring is increased, leading to easier permeation through cellular
membranes due to improved lipophilicity. This phenomenon has led to
the observed antimicrobial properties exhibited by many dithiocarba­
mate complexes. Nevertheless, their biological potential varies due to
differences in their permeability through the cell membrane [45]. For
instance, varying antimicrobial properties have been reported for some
Zn and Ni dithiocarbamate complexes and their corresponding phos­
phine adduct [46]. The parent complexes were found to exhibit a
broader spectrum of antimicrobial activities, whereas the adducts were
specific to certain bacteria and fungi. This trend has been corroborated
by other literature reports on the study of antimicrobial property
[46–48]. The four-coordinate structures (tetrahedral/square planar) of
the parent complexes, which make them the least optimally strained
structures among the various dithiocarbamate derivatives, may be
responsible for the observed broad-spectrum activities on microorgan­
isms[49]. Thus, the enhanced biological effect exerted by the four-
coordinate dithiocarbamate complexes is attributed to the formation
of stable square-planar dithiocarbamate complexes facilitated by the
trans-arrangement between the S-donor compounds and the dithiocar­
bamate backbone of -NCSS. In most cases, Zn has demonstrated more
biological potential than its Ni counterpart when using the same ligand
derivatives [47]. In the cytotoxicity studies for many dithiocarbamate
complexes and their corresponding adducts of nitrogen donor Lewis
bases, a similar trend has been reported for the four-coordinate dithio­
carbmate complexes when screened against different cell lines [50]. This
agrees with various studies that demonstrated higher activities for four
coordinated geometries than the six coordinated compounds [50,51].
Previously, we have synthesized and evaluated the biological po­
tential of some transition metal dithiocarbamate complexes and their
pyridine adducts [29,52–54]. In this current study, therefore, we syn­
thesized and characterized different substituted 2, 2ʹ and 4, 4ʹ-dipyridine
adducts derived from previously reported Ni(II) and Zn(II) bis(N-ethyl-
N-phenyldithiocarbamate). Their biological activities in different assays
such as MTT, egg albumin denaturation, DPPH free radical scavenging,
and reducing power assay were used to ascertain their cytotoxicity, anit-
inflammatory, and antioxidant properties, respectively. Furthermore,
the binding affinity study were carried out using a molecular docking
study.
Experimental
Materials and methods
All the chemicals were purchased commercially and used as arrived
without furthur purifications. Merck/Sigma–Aldrich provided the ma­
terials including zinc(II) acetate, nickel(II) chloride, along with different
substituted Lewis bases of bipyridine such as 4,4ʹ-dipyridine (DPy), 4,4ʹ-
dimethyl-2,2ʹ-bipyridine (DMeBp), 4,4ʹ-dimethoxy-2,2ʹ-bipyridine
(DMxBp), and 4,4ʹ-di-tert-butyl-2,2ʹ-bipyridine (DTBp). The Gallenkamp
melting point equipment was used to determine the melting point of
each of the prepared compounds. To record the elemental analysis
3
Results in Chemistry 6 (2023) 101052
(CHNS), The Elementar Vario EL Cube has been used. The infrared
spectra were captured using an FTIR spectrometer, an Alpha Bruker
(frequency range 4000–400 cm1), and a Bruker Avance III 600 MHz. To
get nuclear magnetic resonance (1H and 13C) spectra, NMR spectrometer
has been employed with the solvent CDCL3 and tetramethylsilane as an
internal standard. The multiplicities of the signals in the 1H NMR, are
given with chemical shifts, (s = singlet, d = doublet, t = triplet, q =
quartet, m = multiplet.
Synthesis of Zn(II) and Ni(II) N-ethyl-N-phenyldithiocarbamate adducts
[M(L1)2L2]
The formation of both parent complexes of Zn(II) and Ni(II) bis(N-
ethyl-N-phenyldithiocarbamate) complexes [M(L)2] followed our pre­
viously published procedure with slight modifications [55]. To obtain
high-quality samples for the synthesis of the corresponding adduct, the
precursor complexes were recrystallized in chloroform with slow
evaporation and separated by filteration. To form the adducts [M
(L1)2L2] of Zn(II) and Ni(II) complexes, about 20 mL of hot mixture of
chloroform solution of the Lewis base (L2) (0.02 mol, 0.10 g) (where, L2
= DP, DMeB, DMxB, and DTB) was added into a hot 20 mL chloroform
solution of the precursor complexes [M(L1)2] (0.02 mol, 0.05 g). The
resulting yellowish (Zn) or green (Ni) mixture was refluxed for 2 h [56]
and then cooled, filtered, and allowed to slowly evaporate under the
fume hood. After 48 h, the produced pale-yellow or dark-green solid
extract was obtained. The Lewis bases used and their respective adduct
are represented as 4,4′-dipyridine = [M(L)2(DPy)]; 4,4′-dimethyl-2,2-
bipyridine = [M(L)2(DMeBp)]; 4,4′-dimethoxy-2,2′-bipyridine = [M
(L)2(DMxBp)]; 4,4′-di-tert-butyl-2,2′-bipyridine = [M(L)2(DTBp)].
[Zn (L)2(DPy)] (1): Yield: 0.25 g (73%), M.P 154 – 156 ◦ C; Selected
IR, ʋ (cm− 1): 1457 (C = N), 1273 (C2-N), 994 (C = S) 3040 (aromatic
–CH), 2916 (aliphatic-CH3), 615 (Zn- S), 560 (Zn-N); 1H NMR (CDCl3) δ
ppm = 7.44 – 7.25 (m, 10H, N-C6H5), 4.13–4.10 ((q, 4H) (t, 6H,), N-
C2H5) 8.83((d), 8.82(t) 7.59(t) (m, 8H, DPy)); 13C NMR (CDCl3) δ ppm
= 206.88 (NCS2), 144.45 – 126.92 (N-C6H5), 64.82 (N-CH2 CH3), 10.28
(N-CH2-CH3), 150.72 – 121.83 (DPy);
C45H49 N6 S8 (1047.82): C, 50.93; H, 4.65; N, 7.92; S, 24.17. Found:
C, 50.95; H, 4.67; N, 7.94; S, 24.15.
[Zn(L)2(DMeBp)] (2): Yield: 0.30 g (88%), M.P 163 – 165 ◦ C;
Selected IR, ʋ (cm− 1): 1445 (C = N), 1269 (C2-N), 984 (C = S), 3042
(aromatic –CH), 2917 (aliphatic-CH3), 620 (Zn- S), 546 (Zn-N); 1H NMR
(CDCl3) δ ppm = 7.38–7.26 (m, 10H, N- C6H5), 4.12–4.08 ((q, 4H) (t,
6H), N- C2H5), 8.51((d), 8.50(s) 8.49(t) (m, 6H DMeBp)) 2.42 (–CH3)2)
(s); 13C NMR (CDCl3) δ ppm = 210.84 (NCS2), 148.33 – 128.03 (N-
C6H5), 64.57 (N-CH2 CH3) 10.26 (N-CH2-CH3), 156.06––122.18
(DMeBp) 21.29 (–CH3)2;
C30H36N4S4 (646.27): C, 55.75; H, 5.61; N, 8.67; S, 19.85. Found: C,
55.73; H, 5.63; N, 8.69; S, 19.87.
[Zn(L)2(DMxBp)] (3): Yield: 0.32 g (94%), M.P 176 – 178 ◦ C;
Selected IR, ʋ (cm− 1): 1448 (C = N), 1280 (C2-N), 1015 (C = S) 3040
(aromatic –CH), 2922 (aliphatic-CH3), 625 (Zn- S), 567 (Zn-N); 1H NMR
(CDCl3) δ ppm = 7.48 – 7.26 (m, 10H, N- C6H5), 4.12––3.94 ((q, 4H) (t,
6H), N C2H5), 8.45 ((d), 7.96(s) 7.37(t) (m, 6H DMxBp) 3.61 (O-CH3)2)
(s)); 13C NMR (CDCl3) δ ppm = 210.84 (NCS2), 150.18 – 129.26 (N-
C6H5), 64.47 (N-CH2 –CH3) 10.08 (N-CH2- CH3), 171.30–127.17
(DMxBp) 32.15 (O-CH3);
C28H28N4S4 (646.19): C, 52.04; H, 4.37; N, 8.67; S, 19.85. Found: C,
52.06; H, 4.39; N, 8.69; S, 19.83.
[Zn(L)2(DTBp)] (4) Yield: 0.27 g (80%), M.P 193 – 195◦ C; Selected
IR, ʋ (cm− 1): 1455 (C = N), 1240 (C2-N), 1008 (C = S) 2958 (aromatic
–CH), 2862 (aliphatic-CH3), 608 (Zn- S), 548 (Zn-N); 1H NMR (CDCl3) δ
ppm = 7.54–7.22 (m, 10H, N- C6H5), 4.13––4.09 ((q, 4H) (t, 6H), N
C2H5), 8.76 ((d), 8.32 (s) 7.49(t) (m, 6H DTB)) 1.56 ((–CH3)3) (s)); 13C
NMR (CDCl3) δ ppm = 209.35 (NCS2), 146.21 – 127.50 (N-C6H5), 64.47
(N-CH2 –CH3) 10.08 (N-CH2- CH3)), 150.35 – 171.30 (DTB) 19.02
(–CCH3)3, 32.15 (–C(CH3)3);
T.A. Saiyed et al.
C36H48 N4 S4 (730.43): C, 59.20; H, 6.62; N, 7.67; S, 17.56. Found: C,
59.22; H, 6.64; N, 7.69; S, 17.58.
[Ni(L)2(DPy)] (5) Yield: 0.26 g (75%), M.P 145 – 147 ◦ C; Selected
IR, ʋ (cm− 1): 1457 (C = N), 1273 (C2-N), 994 (C = S), 3040 (aromatic
–CH), 2916 (aliphatic-CH3), 615 (Ni- S), 560 (Ni-N); C45H49 N6 S8
(1047.80): C, 51.98; H, 4.71; N, 8.02; S, 24.48. Found: C, 51.96; H, 4.73;
N, 8.04; S, 24.46.
[Ni(L)2(DMBp)] (6) Yield: 0.28 g (81%), M.P 165 – 167 ◦ C; Selected
IR, ʋ (cm− 1): 1445 (C = N), 1246 (C2-N), 1005 (C = S), 3046 (aromatic
–CH), 2922 (aliphatic-CH3), 627 (Ni- S), 510 (Ni-N); C30H36N4S4
(639.59): C, 56.34; H, 5.67; N, 8.76; S, 20.05. Found: C, 56.36; H, 5.69;
N, 8.78; S, 20.07.
[Ni(L)2(DMxBp)] (7) Yield: 0.24 g (70%), M.P 189 – 191 ◦ C);
Selected IR, ʋ (cm− 1): 1449 (C = N), 1273 (C2-N), 1017 (C = S) 3069
(aromatic –CH), 2925 (aliphatic-CH3), 624 (Ni- S), 566 (Ni-N);
C28H28N4S4 (639.50): C, 52.49; H, 4.41; N, 8.76; S, 20.06. Found: C,
52.47; H, 4.43; N, 8.78; S, 20.08.
[Ni(L)2(DTBp)] (8) Yield: 0.29 g (84%), M.P 204 – 206 ◦ C; Selected
IR, ʋ (cm− 1): 1456 (C = N), 1241 (C2-N), 1005 (C = S) 2959 (aromatic
–CH), 2867 (aliphatic-CH3), 604 (Ni- S), 544 (Ni-N); C36H48 N4 S4
(631.61): C, 59.74; H, 6.68; N, 7.74; S, 17.72. Found: C, 59.76; H, 6.66;
N, 7.76; S, 17.70.
Biological studies
Cytotoxicity studies
In a standard procedure, the in vitro cytotoxicity profiles of the pre­
pared adducts [M(L1)2L2] were screened against the human cervical
cancer (HeLa) and the human embryonic kidney (HEK 293) cell lines
using 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide
(MTT) assay [36]. Both cell lines were obtained from the ATCC, Man­
assas, USA, and cultured in 25 cm2 tissue culture flasks in EMEM (Lonza
BioWhittaker, Verviers, Belgium) containing DMEM (low glucose), 10%
FBS, and antibiotics/antimycotics which formed the main constituents
of the culture medium. The cells were seeded in a 96-well plate at a
density of 2 × 103 cells/well and were incubated at 37 ◦ C overnight
under a humidified atmosphere containing 5% CO2 before assay. Stock
solutions of the compounds and the standard 5-Fluorouracil at various
concentrations (25, 50, 100, and 150 µg/mL) were diluted directly in a
culture medium. After that, cells were then incubated for 48 h at 37 ◦ C,
followed by the MTT solution, and positive control with untreated cells
was included, together with 5-Fluorouracil as a standard. After incu­
bating for 24 h, the medium was removed and washed with PBS, fol­
lowed by the addition of about 20 μL of new MTT solution to each well
and incubation at 37 ◦ C for 4 h. Subsequently, the medium was removed
and 200 μL of DMSO were added. The absorbance of each well was then
determined at 570 nm in a Mindray MR-96A microplate reader (Vacu­
tec, Hamburg, Germany) using DMSO as the blank. The assays were
done in triplicate and the proportion of viable cells was calculated using
the following formula in equation 4:
Mean value of test compound
(%) Inhibition = × 100 (1)
Mean value of unreacted
Anti-inflammation property study using egg albumin denaturation assay
The anti-inflammatory study was adapted with slight modifications
from the literature [57]. The anti-denaturation/anti-inflammatory
properties of the prepared adducts were evaluated using the egg albu­
min denaturation assay. In this method, 2 mL of the complex or standard
drug (diclofenac) at varying concentrations of 50, 25, 12.5, 6.25, 3.12,
and 1.56 μM was combined with a mixture of 2.8 mL of phosphate-
buffered saline solution (pH 6.4) and 0.2 mL of fresh egg albumin.
The resulting mixtures were incubated for 15 min at 37 ◦ C and thereafter
boiled in a water bath for 5 min at 70 ◦ C. This mixture (250 μL) was
cooled and dispensed into a 96-welled microplate. This was followed by
the determination of the absorbance of these mixtures at 655 nm using a
4
Results in Chemistry 6 (2023) 101052
microplate reader (AMR-100 China). The measurement was carried out
in triplicates and the percentage inhibition of protein denaturation was
estimated using equation (3).
[ ]
Vt
% Inhibition = − 1 × 100 (3)
Vc
where Vt = the absorbance of the test sample, Vc = absorbance of the
control.
Antioxidant property studies
(a) 2,2-diphenyl-1picrylhdrazyl (DPPH) free radical scavenging
assay
The DPPH stock solution was prepared in 100 mL of ethanol and
maintained in the dark for 30 min. Following that, a 50 M stock solution
of the adducts and standard ascorbic acid, in DMSO was prepared and
then serially diluted to 25, 12.5, 6.25, 3.12, and 1.56 M by adding more
solvent. To these prepared samples at varying concentrations in a test
tube, 1 mL of 0.1 mM DPPH solution was added. These mixtures were
well mixed and incubated at room temperature for 30 min beforee
transferring about 250 μL of each mixture into a 96-welled microplate.
After that, the absorbance of these mixture was determined at wave­
length of 515 nm using a microplate reader (AMR-100 China). The
mixture of only DPPH and DMSO solution was used as a blank. The
experiment was conducted in triplicate. The % scavenging activities
were determined using Equation (1)
[Ab − As]
(%)inhibition = × 100 (1)
Ab
Ab = absorbance of the control or blank, and As = absorbance of the
sample or standard. The graph of the inhibition percentage of antioxi­
dant activity against the concentration was used to estimate the 50%
inhibition concentration (IC50) values.
(b) Reducing power assay (Ferric reducing power)
This method is based on the ability of Fe+3 to become reduced by a
reducing agent to Fe+2. An equal amount of the adducts (0.2 mL) at
varying concentrations, phosphate buffer, and potassium ferricyanide
were mixed in a test tube. These mixtures were sonicated and incubated
at 50 ◦ C for 20 min. After cooling the mixtures to 25 ◦ C, trichloroacetic
acid (10 %, 0.2 mL) was added and centrifuged for 10 min at 4500 rpm.
After that, 100 μL of the prepared solution was mixed with 20 μL of the
ferric chloride solution and, 100 μL of distilled water. The absorbance of
these mixtures was then at 700 nm. The control was prepared in the
same manner without the test samples. The experiment was conducted
in triplicate.
Molecular docking study
The compounds were drawn using Builder program in Molecular
operating Environment, MOE and subsequently subjected to 3D pro­
tonation and energy minimization up to 0.01 gradient. The 3D structures
of the receptors used for antioxidant study (PDB ID: 3NRZ) and anti-
inflammatory study (PDB IDs: 1CX2 and 1EQG) were retrieved from
Protein Data Bank (http://www.rscb.org). These crystal structures were
imported into MOE. The structure preparation wizard of MOE was
further used to prepare the proteins by fixing all the issues in protein
structures and adding hydrogen atoms in their standard geometry. All
solvent molecules were removed from the structures and then subjected
to energy minimization using MMFF94X forcefield. Triangle matcher
and refinement methods were used for performing docking studies.
Rigid receptor as refinement methodology and GBVI/WSA dG as the
scoring methodology for selection of the best poses. After docking
T.A. Saiyed et al.
Scheme 1. Synthesis scheme of 2,2′-bipyridine and 4,4′-substituted bipyridine adducts of N–ethyl–N–phenyldithiocarbamate.
processes were completed, the obtained poses were studied and the best
ones showing the best acceptable rmsd_refine values with the same
binding mode of the native ligand were selected.
Results and discussion
Synthesis
The Precursor complexes were synthesized by exchanging the cor­
responding amounts of acetate or chloride ions from metal salts with the
dithiocarbamate ligands, resulting in a stable white (Zn) or green (Ni)
solid powder [58]. The formation of the respective adducts [M(L1)2L2]
was through a reaction involving the chloroform solution of the parent
metal complexes with the respective Lewis bases in ratio 1:2 as shown in
Scheme 1. Thus, adducts were formed at high temperatures by refluxing
a mixture of the precursor complexes, Zn(II) bis(N-ethyl-N-phenyl­
dithiocarbamate and Ni(II) bis(N-ethyl-N-phenyldithiocarbamate) for 2
h with a solution of different Lewis bases. The formed adducts were
soluble in warm chloroform and dichloromethane and air-stable at room
temperature. The final structure of 4,4ʹ-bipyridine (DPy) adduct was
different from all other substituted 2,2ʹ-bipyridine adducts as it bonded
with the center metal atom through the axial position (Scheme 3.2) [59].
The charge compensation of the structure has been thought to emerge
from the opposing dithiocarbamate moieties through the two available
sulfur atoms. The geometry of the adduct changes from tetrahedral to
octahedral, due to the electronegativity of nitrogen of the pyridine ring,
affecting the degree of interaction between the dithiocarbamate ligands
and the metal ion [60]. Some physical properties of the resulting adducts
such as colour and melting point were found to be different from the
prepared parent complexes [27]. The observed properties in the adducts
could be attributed to the emergence of some new bonds between the
metal center and the nitrogen of the Lewis bases, in addition to the
already existing M− S bonds. The two newly formed M− N bonds in the
adduct have been described to direct the framework pattern of the
structure [61]. The increased coordination brought about an octahedral
geometry, which consequently resulted in the Ni(II) adducts being
paramagnetic. Thus, the NMR measurements were not conducted for the
5
Results in Chemistry 6 (2023) 101052
Ni adducts similar to other studies [6263].
Infrared spectroscopic studies of adducts of Zn/Ni(II) bis(N-ethyl-N-
phenyldithiocarbamate)
The FTIR spectra of the metal complexes and adducts revealed
distinct absorption bands and compared favorably well to previous
studies [52,64,6558]. Consequently, relevant bands in the spectra of the
adducts have been abstracted and compared to those in the literature
[45,62]. All adducts showed a strong band between 1457 and 1445
cm− 1, which is related to the stretching vibration of the C–N bond and is
lower than the band identified for the parent complex between 1491 and
1453 cm− 1. The observed stretching vibration in both parent complexes
was discovered at a wavelength greater than that observed for a single
bond C–N (1280 – 1240 cm− l). This high stretching vibration has been
ascribed to an increase in the carbon–nitrogen double bond character of
S2C–NR2 due to the delocalization of electrons toward metal atoms and
the attachment of Lewis bases in all adducts [66]. Also, in the infrared
spectra of all adducts, the stretching vibration of ν(C–S) bands appeared
around 1017 – 984 cm− 1 without any splitting, supporting the bidentate
coordination of the dithiocarbamate to the metal center in both Ni and
Zn [67]. Furthermore, the stretching vibration of the M− S was observed
in all adducts, in the far-IR region around 600 – 660 cm− 1 and assigned
to the Zn–S, and Ni–S bonds which are higher when compared to the
parent precursor complexes, supporting the existence of a bond between
the metal and sulfur atoms [68]. New peaks of Zn–N and Ni–N, which
were absent in the parent complexes and informative about the possible
adduct formation, were observed around 566 – 510 cm− 1 [69]. Other
notable stretching vibrational bands such as υ(C-H) attributed to the
pyridine moiety were found somewhat above 3000 cm− 1 in all the ad­
ducts because of the SP2 hybridized –(C=H) [66], while characteristic
peaks associated with the pyridine moiety in the adduct were found
around 1601–1605 cm− 1 [70] and others were concealed by the
dithiocarbamate moiety [13].
T.A. Saiyed et al. Results in Chemistry 6 (2023) 101052

Table 1
Cell Viabilities (%) of the HeLa and HEK 293 cell lines at different-concentration for adducts of [M(L)2].
HeLa

No Adducts 10 µgmL¡1 25 µgmL¡1 50 µgmL¡1 100 µgmL¡1 IC50µM

Control-1 Cells only 116 ± 0.01 116 ± 0.01 116 ± 0.01 116 ± 0.01 –
Control-2 Cell + 10 µL DMSO 84 ± 0.02 84 ± 0.02 84 ± 0.02 84 ± 0.02 –
5 FU 5-Fluorouracil 76,99 ± 0.03 51,33 ± 0.04 35,07 ± 0.02 11,12 ± 0.02 17.48
1 [Zn(L)2DPy] 56.19 ± 9.38 69.38 ± 16.37 51.93 ± 9.71 28.64 ± 3.63 38.02
2 [Zn(L)2DMeBp] 32.12 ± 17.29 27.49 ± 1.16 32.43 ± 10.09 20.35 ± 5.80 0.13
3 [Zn(L)2DMxBp] 47.01 ± 6.57 36.16 ± 27.70 30.67 ± 6.30 29.16 ± 8.22 5.5
4 [Zn(L)2DTBp] 56.44 ± 10.14 44.57 ± 5.71 40.70 ± 9.88 26.47 ± 7.52 17.38
5 [Ni(L)2DPy] 68.29 ± 0.02 42.23 ± 0.05 30.60 ± 0.03 15.40 ± 0.03 20.66
6 [Ni(L)2DMeBp] 36.87 ± 0.02 23.32 ± 0.04 13.54 ± 0.03 5.59 ± 0.08 3.68
7 [Ni(L)2DMxBp] 42.17 ± 0.004 21.19 ± 0.03 13.72 ± 0.02 5.02 ± 0.01 5.21
8 [Ni(L)2DTBp] 44.11 ± 0.04 25.55 ± 0.03 13.29 ± 0.01 4.45 ± 0.01 6.62

HEK 293

No Adducts 10 µgmL¡1 25 µgmL¡1 50 µgmL¡1 100 µgmL¡1 IC50µM

Control-1 Cells only 116 ± 0.01 116 ± 0.01 116 ± 0.01 116 ± 0.01 –
Control-2 Cell + 10 µL DMSO 84 ± 0.02 84 ± 0.02 84 ± 0.02 84 ± 0.02 –
5 FU 5-Fluorouracil 45.40 ± 0.04 51.91 ± 0.003 35.40 ± 0.01 11.33 ± 0.01 6.05
1 [Zn(L)2DPy] 100.7 ± 20.41 83.64 ± 16.38 84.45 ± 20.51 54.14 ± 18.52 181.97
2 [Zn(L)2DMeBp] 92.08 ± 12.04 74.68 ± 8.5 74.40 ± 4.76 61.39 ± 10.74 245.17
3 [Zn(L)2DMxBp] 55.83 ± 10.21 56.25 ± 21.78 51.65 ± 3.75 45.53 ± 13.60 56.23
4 [Zn(L)2DTBp] 63.43 ± 12.15 64.33 ± 15.28 41.08 ± 10.00 48.84 ± 15.93 56.23
5 [Ni(L)2DPy] 62.67 ± 0.07 51.45 ± 0.008 32.67 ± 0.01 8.75 ± 0.005 20.79
6 [Ni(L)2DMeBp] 38.81 ± 0.03 30.76 ± 0.03 22.35 ± 0.04 14.77 ± 0.007 3.66
7 [Ni(L)2DMxBp] 87.03 ± 0.01 56.72 ± 0.04 47.21 ± 0.03 23.63 ± 0.03 38.39
8 [Ni(L)2DTBp] 27.50 ± 0.006 24.97 ± 0.005 18.37 ± 0.007 15.78 ± 0.007 0.18

NMR spectroscopy study of zinc(II) bis(N-ethyl-N-phenyldithiocarbamate)
The proton and carbon-13 NMR spectroscopy of the octahedral
nickel adducts [Ni(L)2] were not carried out due to their paramagnetic
nature [63]. As reported in an earlier study that the electronic relaxation
times for octahedral nickel(II) monomers are usually longer; thus,
observed peaks are much broader [63]. Nevertheless, the 1H NMR
Fig. 1. Cytotoxic activity of bipyridyl adducts of Zn/Ni(II) bis(N-ethyl-N-phe­
nyldithiocarbamate) on HeLa (a) and HEK293 (b) cancer cell lines showing a
concentration-dependent activity in comparison to the standard 5-Fluorouracil.
spectra of the adducts of zinc(II) bis(N-ethyl-N-phenyldithiocarbamates)
were carried out and the chemical shifts were carefully compared to the
similar precursor complexes already reported [31,45,61].
In the proton NMR spectra of zinc(II) bis(N-ethyl-N-phenyl­
dithiocarbamates), the proton signal observed in the downfield region
around 7.27 – 7.48 ppm in all adducts has been attributed to the proton
of N-phenyl groups of dithiocarbamate moieties. These chemical shifts
were slightly higher in the adduct than in the parent complex (N-C6H5 =
7.22–7.54 ppm). This observed marginally higher shift in the adducts
could be attributed to the electronegative effects of the bipyridine de­
rivatives and the resulting change in geometry from a four to six-
coordinate structure [13,45,71]. Similar to previous studies, multiplets
signals in all the adducts found in the downfield region around 7.37 –
8.83 ppm have been ascribed to the aromatic protons of phenyl rings
bearing the nitrogen atom of the bipyridine moieties in the respective
Lewis bases attached to the metal center[70–72]. Also, the proton sig­
nals of the methylene (N-CH2-) from N-ethyl derivatives appeared as
quadruplets in the region 4.08 – 4.13 ppm, while protons of the methyl
groups (–CH3) from the N-ethyl moiety resonated as triplets around 1.29
– 1.33 ppm as shown in the supplementary data (F1). These shifts are
slightly lower than those found for the parent complex (N-CH2 = 4.24
ppm; –CH3 = 1.32 ppm). In addition, other proton signal peaks observed
upfield as a singlet between 2.42 and 1.56 ppm have been attributed to
the protons of the substituted alkyl derivatives attached to the 4,4́ po­
sitions of the bipyridine adducts of [Zn(L)2(DMeBp)] [73] and [Zn
(L)2(DTBp)] [74], respectively. Furthermore, due to the deshielding
effects of the electronegative oxygen group, proton signals of the
methoxy group ((O-CH3)2) were found as a singlet between 3.61 ppm in
[Zn(L)2(DMxBp)] [13,45,70].
In the 13C NMR spectra of all adducts, the weak peak of the thiour­
eide carbon bond was found around 206.88 – 210.84 ppm. Due to the
additional deshielding effects of attached bipyridine and its derivatives,
the peak was shifted to about 3.2 ppm compared to the parent precursor
complexes (206.47 ppm). The displacement of electron density from
carbon to nitrogen in the adducts was due to the additional bonding of
the Lewis base to the metal center atom, which initiated a decrease in
the partial double bond character of the C=N bond as supported by the

6
T.A. Saiyed et al. Results in Chemistry 6 (2023) 101052

FTIR spectra [17,75]. Furthermore, two strong carbon signals ascribed Table 2
to the carbon of methylene (N-CH2-) and methyl (–CH3-) group of N- IC50 values of the antioxidant activities (μg/mL) of bipyridyl adducts of [M(L1)2
ethyl-N-phenyldithiocarbamate moiety resonated upfield around 64.59 L2].
– 64.82 and 12.54 – 13.96 ppm similar to other literature [76–78]. In all No Samples name DPPH (µg/mL) Reducing power (µg/mL)
the adducts, phenyl carbon (N-C6H5) signals of the N-ethyl-N-phenyl­ Standard Ascorbic acid 4.96 ± 0.01 4.09 ± 0.08
dithiocarbamate group resonated in the region between 126.92 and 1 [Zn(L)2DPy] 4.06 ± 0.02 13.58 ± 0.03
150.21 ppm. Furthermore, aromatic carbons of bipyridine moieties 2 [Zn(L)2DMeBp] 4.80 ± 0.03 5.04 ± 0.06
resonated around 121.83 –171.30 ppm and agree with the previous 3 [Zn(L)2DMxBp] 6.0 ± 0.02 6.12 ± 0.03
4 [Zn(L)2DTBp] 3.78 ± 0.03 3.90 ± 0.03
studies [79]. Several single peaks appearing upfield in all adducts be­
5 [Ni(L)2DPy] 4.87 ± 0.03 4.41 ± 0.02
tween 32.15 and 21.29 ppm have been assigned to the different methyl 6 [Ni(L)2DMeBp] 11.1 ± 0.04 7.51 ± 0.04
carbons group of the –CH3, (methyl) –OCH3 (methoxy), and –(CH3)3, 7 [Ni(L)2DMxBp] 4.06 ± 0.02 5.10 ± 0.03
(tert-butyl) group of bipyridine moiety which is similar to other reports 8 [Ni(L)2DTBp] 4.11 ± 0.04 6.20 ± 0.04
[70,73,74].

Biological evaluation
N N

Cytotoxicity activity study

MTT assay has been used as a core procedure to examine the effect of
the compounds on cellular mitochondrial metabolism. In this method,
two cell lines, including human cervical carcinoma (HeLa) and human
embryo kidney (HEK 293) cell lines, were used to evaluate the cyto­
toxicity characteristics. The obtained data are summarized in Table 1,
and the minimum inhibition concentration values (IC50) of each adduct
and standard 5 Flurouracil (5 FU) are presented in Fig. 1. The activity for
N N
each adduct followed a concentration-dependent trend similar to other
metal dithiocarbamate complexes [68]. The level of toxicity of the ad­
ducts against the used cell line was estimated as a measure of the
calculated IC50 values that were observed between 0.13 and 17.38 µg/
mL. The estimated IC50 values of tested adducts were superior to the
standard 5-Fluorouracil (17.48 µg/mL). Amongst the prepared adducts
of 4,4ʹ-bipyridyl derivatives, [Zn(L)2DMeBp] and [Ni(L)2DMeBp]
showed the best toxicity against the HeLa cell line, with an IC50 value of
0.13 and 3.68 µg/mL, respectively. In addition, all the 4,4ʹ-bipyridine
adducts displayed higher cytotoxicity against HeLa cells, but 2,2ʹ- Fig. 2. Histogram chart of antioxidant activities of bipyramidal adducts of Zn
bipyridyl derivatives, which are complexes 1 and 5, displayed weaker (a) Ni (b) bis(N-ethyl-N-phenyl dithiocarbamates) (1–8) along with standard
toxicity, which may be due to selectivity. Thus, in the HeLa cell line, the ascorbic acid.
most active adducts bear the 4,4ʹ-dimethyl-2,2ʹ-bipyridine moiety in
both Ni and Zn derivatives. This claim agrees with the literature report µg/mL) as shown in Fig. 1 (b) and Table 1. The estimated IC50 values for
that the introduction of methyl groups at the different positions of all zinc adducts in HEK 293 cell lines were high compared to the stan­
bipyridine increases the cytotoxicity of the molecule [80]. This is dard, which might be attributed to the cell line selectivity. Hence, The
because the bipyridyl nitrogen atom next to the methylated carbon be­ order of cytotoxic activity (from highest to lowest) based on their
comes more negatively charged, boosting its propensity to donate evaluated IC50 values is presented as follows:
electrons. According to this report, the methylated derivative should
have beneficial electrical characteristics, primarily impacting the 8 > 6 > 5FU > 5 > 7 > 3; 4 > 1 > 2
oxidizing power of the metal center, which might explain its enhanced Order of activity in comparison to 5-Flurouracil (HEK cell lines –
cytotoxic property. This is consistent with the methylation action on the 6.05 µg/mL)
bipyridyl nitrogen at 4,4ʹ positions for [Zn(L)2]DMeBp] (2) and [Ni
(L)2DMeBp] (6) [81]. However, it should be noted that other 4,4ʹ- Generally, compounds bearing nitrogen and sulfur-containing het­
dimethoxy-2,2ʹ-bipyridine and 4,4ʹ-di-tert-butyl-2,2ʹ-bipyridine de­ erocyclic compounds are known to show notable biological activities,
rivatives were not as cytotoxic as [Zn(L)2DMeBp] (2), which thus which also agree with other literature and are validated by the results
suggest that the donating power of the substituents may not be the only presented for the adducts as well as data from previous studies [40,83].
reason for the observed activity. Also, based on other reports in the Nonetheless, in both HeLa and HEK 293 cell lines, the observed IC50
literature, the presence of more than one heterocyclic dipyridine ring values generally revealed that most Ni adducts of N-ethyl-N-phenyl­
and phenyl rings of dithiocarbamates complexes may enhance the lip­ dithiocarbamates exerted better cytotoxicity than Zn. This observed
ophilicity, hence the displayed potency for most of the adducts [82]. The activity might indicate the potential of the synthesized adducts as an
order of cytotoxic activity (from highest to lowest) based on their effective cytotoxic agent against cancer cell lines upon additional
evaluated IC50 values is presented as follows: screening in other cell lines and optimization in diverse settings,
including clinical trials.
2 > 6 > 3 > 7 > 8 > 4 > 5FU > 5 > 1
Order of activity in comparison to 5-Flurouracil (HeLa cell lines ¡
17.48 µg/mL). Antioxidant activities

Interestingly, against HEK 293 cell lines, only complexes [Ni The scavenging and the reducing power potential of the adduct were
(L)2DMeBp] (6) and [Ni(L)2 DTBp] (8) possessed better IC50 values (6 screened using 2,2-diphenyl-1-picrylhydrazyl (DPPH) and ferric-
= 3.66 µg/mL; 8 = 0.18 µg/mL) than the standard 5-Fluorouracil (6.05 reducing assays. Ascorbic acid was used as a standard. The acquired

7
T.A. Saiyed et al. Results in Chemistry 6 (2023) 101052

Fig. 3. Validation of the docking protocol using the bovine xanthine oxidase in Complex with Hypoxanthine (PDB: 3NRZ).

data from the activity study is presented in Table 2 while the minimum
Table 3.2
inhibition concentration (IC50) value of each adduct is presented in
Anti-inflammation activities (μg/ml) of adducts of [[M(L)2].
Fig. 2 as a histogram. From the observed results all adducts possessed
greater antioxidant activities than the reference drug (Ascorbic acid), No Samples name Anti-inflammation (IC50 µM)

particularly in the DPPH assay (Fig. 2). According to the DPPH assay, all 1 [Zn(L)2DPy] 2.52 ± 0.01
dithiocarbamate adducts of [Zn(L)2] (1–4) and [Ni(L)2] (5–8), showed 2 [Zn(L)2DMeBp] 2.30 ± 0.01
3 [Zn(L)2DMxBp] 2.83 ± 0.02
better IC50 values in the range of 3.78–4.87 µg/mL than standard
4 [Zn(L)2DTBp] 2.29 ± 0.01
ascorbic acid (4.96 µg/mL) with exception of 3 and 6. These could be 5 [Ni(L)2DPy] 2.54 ± 0.02
due to the inclusion of S- and N-donor ligands which brought about 6 [Ni(L)2DMeBp] 2.64 ± 0.03
improved biological characteristics similar to other studies [47]. Among 7 [Ni(L)2DMxBp] 4.12 ± 0.02
all, complexes [Zn(L)2DTBp] (4) and [Ni(L)2DMxBp] (7) exhibited 8 [Ni(L)2DTBp] 2.53 ± 0.02
Standard Diclofenac 2.94 ± 0.01
the best IC50 values with 3.78 µg/mL and 4.06 µg/mL, respectively. This
might be ascribed to the presence of tertiary methyl group (–C(CH3)3)
and methoxy (–OCH3) group having good electron donating ability to­ candidates have been discovered. These include HIV-1 protease in­
wards the metal atom thus, enhancing higher anti-oxidant properties hibitors [87], novel anti-inflammatory and analgesic agents [88], and
[80,84]. The order of activity of all adducts from (highest to lowest) new antioxidant agents [89]. Hence, the molecular docking studies of
according to their minimum inhibition concentration (IC50), with these complexes have been studied to understand the types and nature of
compare to standard ascorbic acid in DPPH assay are as follows: chemical interactions between these ligands and complexes, and their
respective drug targets. The binding free energy, ΔG thus obtained is
4 > 1; 7 > 8 > 2 > 5 > AA > 3 > 6 given in Table 3.
Order of activity in comparison to ascorbic acid (4.96 µg/mL).

In the reducing assay study, most of the zinc and nickel di­
thiocarbamates have higher IC50 values, which indicates a poor reducing
property compared to the standard ascorbic acid. However, as seen in Table 3
Molecular docking scores of the ligands and complexes.
Fig. 2 (a), [Zn(L)2DTBp] (4) exerted the lowest IC50 value of 3.90 µg/
mL with the highest reducing potential compared to the standard Antioxidant Anti-inflammatory
Activity: ΔG (kcal/ Activity:
ascorbic acid (4.09 µg/mL), and all other complexes in the group.
mol) ΔG (kcal/mol)

No Samples name 3NRZ 1CX2 for 1EQG for

Anti-inflammatory activities COX-2 COX-1

1 ZnL2 − 4.93 − 4.14 − 6.05

Anti-inflammatory activities are a desirable characteristic of most 2 [Zn(L)2DPy] − 4.46 20.52 − 1.95
anticancer drugs [85]. As a result, the Zn and Ni bipyridyl adducts were 3 [Zn − 4.40 6.82 − 5.68
investigated for anti-inflammatory properties, and the observed IC50 (L)2DMeBp]
4 [Zn − 5.69 1.41 − 2.58
values of each adduct are presented in Table 3 along with standard
(L)2DMxBp]
diclofenac. All the adducts showed IC50 values around 2.29 – 4.12 µg/ 5 [Zn(L)2DTBp] − 6.54 5.07 0.07
mL with potent anti-inflammatory activity compared to the standard 6 NiL2 − 6.00 − 3.81 − 5.01
diclofenac with an IC50 value of 2.94 µg/mL. It can be deduced from the 7 [Ni(L)2DPy] − 5.55 24.31 23.91
presented data that all the adducts, [Zn(L)2DTBp] (4) and [Ni 8 [Ni − 2.67 2.29 − 3.98
(L)2DMeBp]
(L)2DTBp] appeared as an efficient anti-inflammatory agent by dis­
9 [Ni − 3.48 5.12 − 5.25
playing lower IC50 value than standard diclofenac. (L)2DMxBp]
10 [Ni(L)2DTBp] − 5.00 4.22 − 0.29
Molecular docking study 11 Co-crystallized − 5.23 − 9.29 − 7.54
ligand
Standarddrugs Ascorbic acid − 5.71 ND ND
Molecular Docking, which is a component of computer-aided drugs Diclofenac ND ND − 6.22
(CADD) has been extensively applied in rational drug design and dis­ (COX-1)
covery. It is an important tool in the identification of potential drug Celecoxib ND − 9.16 ND
(COX-2)
candidates and reduces both time and cost of drug discovery and
development [86]. Through CADD, many important potential drug *ND = Not determined.

8
T.A. Saiyed et al.
Fig. 4. The stereo views of ZnL2 (A), NiL2 (B), [Zn(L)2DTBp] (C) and (D) [Ni(L)2DTBp] in the active binding site of bovine xanthine oxidase.
Validation of molecular docking
The validation of the Molecular Docking protocols using bovine
xanthine oxidase in a complex with Hypoxanthine is shown in Fig. 3.
The root mean square deviation (RMSD) of the docked hypoxanthine
(orange) and the co-crystallized hypoxanthine (green) were evaluated.
The RMSD was found to be 1.29 Å. The RMSD values express the rela­
tionship between the calculated and crystallographic data of the com­
plexed ligand and must be less than 2.0 Å [13–15]. The similarity in the
overlapping of crystallographic poses (green) and calculated (orange)
was obtained via molecular docking and this shows good results ac­
cording to the literature. These results give a strong indication that the
docking protocols have been fully validated and can be applied in the
molecular docking study between the receptors of the antioxidant ac­
tivity and ligands. The antioxidant activity was evaluated in silico using
bovine xanthine oxidase (PDB ID: 3NRZ). The compounds were also
tested against ovine cox-1 (PDB ID: 1EQG), a COX-1 receptor, and
cyclooxygenase-2 (prostaglandin synthase-2, PDB ID: 1CX2), a COX-2
receptor with a view of understanding their selectivity against these
receptors which mediates inflammation.
From the molecular docking results, [Zn(L)2DTBp] has quite a sig­
nificant binding affinity (− 6.54 kcal/mol) to the bovine xanthine oxi­
dase as shown in Table 3. This is also in corroboration with the in vitro
9
Results in Chemistry 6 (2023) 101052
result (Table 3.2) that showed [Zn(L)2DTBp] being the most active
antioxidant complex, with IC50 of 3.78 ± 0.03 and 3.90 ± 0.03 for DPPH
and reducing power assays respectively. This has prompted an in-depth
study to understand the type and nature of chemical interactions be­
tween the complex and the antioxidant receptor, bovine xanthine oxi­
dase. The stereo views of [Zn(L)2DTBp], as well as ZnL2dtc, NiL2dtc, and
[Ni(L)2DTBp] in the active binding site of bovine xanthine oxidase are
shown in Fig. 4. This reveals a well-fitted complex in the active binding
site of 3NRZ and explains better the observed high binding affinity.
Besides, various atoms of [Zn(L)2DTBp] interacted with the acid resi­
dues of 3NRZ through different chemical interactions. There were strong
H-bonding interactions, as well as pi-H bonding. The N-1 of the complex
formed two H-bonds with the CG and CD1 of Leu648 respectively. Also,
the S-5 and S-6 in [Zn(L)2DTBp] formed another strong H-bonds with
the CG2 of Val1011 and CD2 of Leu1014 respectively. S-8 atom formed
Other H-bonds with Leu873, Phe914, Val1011 while S-9 interacted with
Phe1009. The six-membered aromatic ring of [Zn(L)2DTBp], through pi-
pi interaction, combined with the six-membered ring of Phe914. Finally,
we observed two pi-H interactions in the six-membered ring of the
complex and Phe1013 and Ala1078 respectively. These effective
chemical interactions could possibly explain the strong binding affinity
[Zn(L)2DTBp] has with 3NRZ.
The ligands and complexes did not show appreciable binding affinity
T.A. Saiyed et al.
with the receptors mediating inflammation. However, ZnL2dtc showed a
comparable binding affinity to ovine cox-1 as the standard drug, diclo­
fenac (Fig. 3). It also revealed more selectivity to COX-1 than to COX-2.
Conclusion
The adducts of metal(II) N-ethyl-N-phenyldithiocarbamate repre­
sented as [M(L)2(DPy)], [M(L)2(DMeBp)], [M(L)2(DMxBp)] and [M
(L)2(DTBp)] (where metal, M = Zn and Ni; and DPy = 4,4′-dipyridine
DMeBp = 4,4′-dimethyl-2,2-bipyridine; DMxBp = 4,4′-dimethoxy-2,2-
bipyridine and DTBp = 4,4′-di-tert-butyl-2,2′-bipyridine) have been
successfully prepared and characterized using some analytical tech­
niques. The results of spectroscopic studies revealed a change in ge­
ometry occurred from four to six (tetrahedral to octahedral) around the
metal center upon the addition of the Lewis bases (L2). Their biological
studies showed that the adducts exhibited activities that are
concentration-dependent in mutating human cervical cancer (HeLa) and
kidney 293 (HEK 293) cell lines. Adduct [Zn(L)2DMeBp] (1) and [Ni
(L)2 DTBp] (6) showed the best activity in HeLa and HEK 293 cell lines
respectively. In addition, their antioxidant and anti-inflammatory
studies showed that the most of adducts displayed better activities
than the standard Ascorbic acid (especially in the DPPH assay) and
standard Diclofenac. Adduct [Zn(L)2DTBp] (4) exceptionally exerted
best scavenging/reducing ability in all anti-oxidant assay as well as in
anti-inflammation studies. The good binding affinity of these adducts to
their target, as revealed in the molecular docking studies, showed that
the adducts are promising and the results obtained thus represent a
starting point for further preclinical testing of these new adducts.
CRediT authorship contribution statement
Tanzimjahan A. Saiyed: Methodology, Writing – original draft,
Writing – review & editing. Jerry O. Adeyemi: Conceptualization, Su­
pervision, Methodology, Writing – original draft. Moganavelli Singh:
Methodology, Data curration, Writing-review. Sunday N. Okafor:
Methodology, Data curation, Eriting – original draft. Damian C.
Onwudiwe: Conceptualization, Methodology.
Declaration of Competing Interest
The authors declare that they have no known competing financial
interests or personal relationships that could have appeared to influence
the work reported in this paper.
Appendix A. Supplementary data
Supplementary data to this article can be found online at https://doi.
org/10.1016/j.rechem.2023.101052.
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