Nickel(II) Complexes with Polyhydroxybenzaldehyde and O,N,S tridentate Thiosemicarbazone ligands: Synthesis, Cytotoxicity, Antimalarial Activity, and Molecular Docking Studies.

Article abstract of DOI:10.1016/j.molstruc.2021.130815

A series of Schiff base metal complexes with the formulations [Ni(L1)PPh₃]Cl (1), [Ni(L2)PPh₃]Cl (2), [Ni(L3)PPh₃] (3), and [Ni(L4)PPh₃] (4) (where L1 = 2,3,4-trihydroxybenzaldehyde-4-methyl-3-thiosemicarbazone,

Full text of DOI:10.1016/j.molstruc.2021.130815

Journal of Molecular Structure 1242 (2021) 130815
Contents lists available at ScienceDirect
Journal of Molecular Structure
journal homepage: www.elsevier.com/locate/molstr
Nickel(II) Complexes with Polyhydroxybenzaldehyde and O,N,S
tridentate Thiosemicarbazone ligands: Synthesis, Cytotoxicity,
Antimalarial Activity, and Molecular Docking Studies.
Savina Savira, Jonathan Wee Kent Liewb, Indra Vythilingamb, Yvonne Ai Lian Limb,
Chun Hoe Tan c, Kae Shin Simc, Vannajan Sanghiran Leea, Mohd. Jamil Maaha,
Kong Wai Tan a,∗
a Department of Chemistry, Faculty of Science, University of Malaya, 50603 Kuala Lumpur, Malaysia
b Department of Parasitology, Faculty of Medicine, University of Malaya, 50603 Kuala Lumpur, Malaysia
c Institute of Biological Sciences, Faculty of Science, University of Malaya, 50603 Kuala Lumpur, Malaysia
a r t i c l e i n f o
a b s t r a c t
Article history:
A
series of Schiff base metal complexes with the formulations [Ni(L1)PPh3]Cl (1), [Ni(L2)PPh3]Cl
(2), [Ni(L3)PPh3] (3), and [Ni(L4)PPh3] (4) (where L1 2,3,4-trihydroxybenzaldehyde-4-methyl-
3-thiosemicarbazone, L2 2,3,4-trihydroxybenzaldehyde-4-ethyl-3-thiosemicarbazone, L3 2,3,4-
trihydroxybenzaldehyde-4-phenyl-3-thiosemicarbazone, and L4 2,3,4-trihydroxybenzaldehyde-4-(4-
Received 10 January 2021
Revised 21 May 2021
Accepted 30 May 2021
Available online 3 June 2021
=
=
=
=
ethylphenyl)-3-thiosemicarbazone) were synthesised. All compounds were characterised using FT-IR, 1H
NMR, and 13 C NMR. The complexes were further characterised with single crystal X-ray diffraction. The
complexes are four-coordinated and adopt a square planar geometry, in which the Schiff base ligands
bind to the metal centre via their tridentate O,N,S atoms. Ligand L2 and complex 1 showed a higher cy-
totoxic activity than cisplatin with IC50 5.75 0.49 and 4.26 0.29 μM, respectively when tested against
human colorectal carcinoma HCT 116. Besides, complex 3 was found to show a stronger cytotoxic activity
Keywords:
Thiosemicarbazone
Triphenylphosphine
Cytotoxic activity
Antimalarial activity
Molecular docking
with an IC50 7.07
the other hand, complexes 2 and 3 showed moderate in vitro antimalarial activity with IC50 9.88
and 1.06 0.01 μM, respectively. Remarkably, the antimalarial activity increases as the hydrophobicity
0.61 μM than its ligand (L3 IC50 9.82
1.85 μM) when tested against HCT 116. On
0.23
of the substituent group attached at the N(3) position increases. Through molecular docking simulation,
complexes 2 and 3 are predicted to be a minor groove binder with an appreciable DNA binding affinity,
suggesting that 2 and 3 exerted their cytotoxicity and antiplasmodial activity probably via their benzalde-
hyde, triphenylphosphine, aliphatic chain and phenyl moieties interaction with DNA base pairs.
© 2021 Elsevier B.V. All rights reserved.
1. Introduction
forming crosslinks with the purine bases on the DNA and inter-
fering with DNA’s repair mechanism [5]. However, the efficacy of
The global cancer burden is approximated to have increased to
18.1 million new cases and 9.6 million deaths in 2018 [1]. Since
the discovery of cisplatin in 1965 for cancer treatment, the devel-
opment of platinum-based drugs in the field of research have be-
come compellingly in demand [2]. The other platinum compounds
that had entered clinical trials as anticancer agents years ago were
carboplatin, oxaliplatin, and nedaplatin [3]. Approval of cisplatin
for clinical use has led to more constructive treatments against
testicular, ovarian, cervical, bladder, head and neck, and small-cell
lung cancers [4]. Cisplatin induces apoptosis in cancer cells by
platinum drugs are greatly restricted by severe side effects due
to poor specificity, drug resistance, and systemic toxicities such
as nephrotoxicity, neurotoxicity, ototoxicity, and emetogenesis [6].
Hence, new anticancer drugs have to be constantly synthesised to
address the issues caused by the existing drugs. Previous studies
have shown that pyrimethamine which is an antimalarial drug, is
able to induce apoptosis of cancer cells, acting as an antitumor
drug simultaneously [7]. Thus, it would be enthraling if the com-
pounds studied in this paper could have cytotoxic activity and act
as antimalarial drugs at the same time.
Malaria is a vector-borne endemic contagious ailment that is
brought about by parasitic protozoa of the genus Plasmodium. The
four significant species that cause malaria in humans are the P.
∗
Corresponding author.
E-mail address: kongwai@um.edu.my (K.W. Tan).
https://doi.org/10.1016/j.molstruc.2021.130815
0022-2860/© 2021 Elsevier B.V. All rights reserved.

S. Savir, J.W.K. Liew, I. Vythilingam et al.
Journal of Molecular Structure 1242 (2021) 130815
falciparum, P. vivax, P. ovale, and P. malariae. The severe form,
however, is caused by the former [8]. According to the World
Malaria report 2019, 228 million cases of the disease and 405,000
of global malaria deaths were reported in 2018, while most of
the reported mortality are amongst the young children (a child
dies of malaria in every two minutes) [9]. Factually, chloroquine
(CQ), a 4-aminoquinoline drug, has been the most established anti-
malarial drug due to its satisfactory potency, low toxicity, and low
cost [10]. However, the P. falciparum has become resistant to CQ
[11,12], along with other antimalarial drugs such as sulfadoxine–
pyrimethamine (SU-PY), mefloquine (MQ), and artemisinin. Hence,
discoveries of chloroquine followed by artemisinin were able to
ward off malarial infection for some time until the parasite ac-
quired resistance towards these drugs. Soon after, the therapeu-
tic potential of ferroquine (FQ), which was once considered the
most potent organometallic antimalarial drug was explored. FQ
was found to be exceedingly active in vitro against both CQ-
resistant and CQ-susceptible P. falciparum and P. vivax isolates from
different endemic areas [13,14]. Unfortunately, treatment with FQ
was found to result in gastrointestinal side effects and central ner-
vous disorders [15]. Hence, the discoveries of new drugs are crucial
to address the issue of resistance and adverse effects.
antimalarial activities of a metal complex. Besides, complexation of
transition metals with compounds having antimalarial activity fur-
ther enhances the pharmacological and chemical properties such
as potency, selectivity, chemical stability, and lipophilicity of the
compound [29]. Having mentioned that, the lipophilic nature of
the metal helps with the cellular uptake process of the parasite as
it aids in the transportation of the metal-free thiosemicarbazones
into cellular components. In a nutshell, metal chelators can deprive
parasites from metal ions crucial for their survival and utilize the
newly formed metal-chelator hybrid (complex) to induce oxidative
insult to the parasites.
Previous research on polyhydroxybenzaldehyde thiosemicar-
bazone derivatives suggested that complexes of nickel where the
ligand was coordinated to the metal centre via its tridentate O,N,S
atom was effective towards several cancer cell lines [30]. Although
some ligands of the 2,3,4-trihydroxybenzaldehyde derivatives have
been synthesised and reported [31,32], further characterisation and
biological studies of their metal complexes still warrant further
investigations. Previously, we reported the synthesis, cytotoxicity,
and antimalarial activity of nickel(II) complexes with Schiff base
ligands derived from fluorene-2-carboxaldehyde and thiosemicar-
bazide [33]. In the present, we focus on the synthesis of nickel (II)
complex and triphenylphosphine with Schiff base ligands derived
from polyhydroxybenzaldehydes and thiosemicarbazides. Their cy-
totoxicity, antimalarial activity, and DNA binding affinity were also
reported.
Thiosemicarbazones (TSC) have a wide range of pharmacolog-
ical and biological properties, including antitumor and antimalar-
ial. These properties are dependant upon the chemical nature of
the moiety attached to the C = S carbon atom in TSC [16]. Mostly,
metal complexation by anionic ligands that resulted in charge neu-
tral metal complexes were found to exhibit improved bioactivity
than the neutral ligands because the negative charge of the sulfur
atom enhances the coordination strength [17,18]. In this case, the
thiol tautomer was seen to show better cytotoxicity and improved
antimalarial activity than its original thione form. Their coordinat-
ing ability as chelate ligands has enabled them to be used for the
synthesis of a vast range of complexes. They have been studied
thoroughly as ligands to form complexes with different transition
metals due to the presence of their electron donating functional
groups, which is their O,N,S tridentate binding sites [19]. Many
studies have demonstrated that even slight structure modifications
may result in dramatic chemical and biological changes in metal
thiosemicarbazone complex [20]. Hence, the properties of TSC have
made them adaptable to an extensive array of applications, making
them appealing for further analysis as potential therapeutic agents
aimed at malaria and cancer treatments.
2. Experimental
2.1. Materials and solutions
The chemicals for synthesis (thiosemicarbazides, 2,3,4-
trihydroxybenzaldehyde, nickel(II)chloride hexahydrate, triph-
enylphosphine, and chloroquine phosphate) were purchased from
Sigma Aldrich, Germany and Alfa Aesar, England. Solvents were
purchased from Merck, Germany.
2.2. Physical measurements
Perkin-Elmer Spectrum RX-1 spectrometer was used to record
the FT-IR spectra of all the ligands and metal complexes. They were
recorded as KBr pellets. The NMR spectra was determined in a
DMSO–d6 with a JEOL ECX 400 spectrometer at 400 MHz. The per-
centage of carbon, hydrogen and nitrogen was determined using
A Thermo Finnigan Eager 300 CHN elemental analyser. Any crys-
tals collected as a result of recrystallisation were subjected to X-
RAY using a Rigaku Oxford (formerly Agilent Technologies) Super
Triphenylphosphine (TPP) is used as secondary ligand in this
study because phosphine based compounds have widespread phar-
macological applications such as antiviral, antioxidant, antifungal,
anticarcinogenic, antitumor, and antibacterial by nature [21]. Ex-
plicitly, phosphine based nickel(II) and palladium(II) complexes
have been reported to possess significant bioactivities [22]. In can-
cer treatment, TPP, which is a mitochodriotropic ligand is expected
to transfer the metal ion into the cancer cells [23]. Besides, TPP is
used in the metal complexation process because it acts as a cata-
lyst in the synthesis of organic and inorganic compounds to speed
up the rate of a chemical reaction [24]. An important factor that
influences the antimalarial activity of a compound is its hydropho-
bicity. The higher the hydrophobicity, the more potent its activity
[25,26]. Hence, the hydrophobic aromatic rings in TPP may accen-
tuate the antimalarial activity of the synthesised compounds.
We are enthusiastic in developing nickel complexes of
thiosemicarbazone because they have been reported to have high
cytotoxic activity. Nickel(II) complexes were shown as telomerase
and topoisomerase II inhibitors that induce cancer cell apoptosis
via mitochondrial pathways [27]. In addition, metal complexes are
believed to exhibit cytotoxic and antimalarial activities better than
their free ligands as the latter may show little or no activities at all
[28]. Hence, metal chelating abilities account for the cytotoxic and
˚
Nova Dual diffractometer with Cu Kα (λ = 1.541 84 A) radiation at
160−170 K.
2.3. Syntheses
•
Synthesis of 2,3,4-trihydroxybenzaldehyde-4-methyl-3-thiosemi
carbazone (L1)
The ligand was prepared by following a published procedure
with slight changes [31]. The ethanolic solution containing 2,3,4-
trihydroxybenzaldehyde and 4-methyl-3-thiosemicarbazide was re-
fluxed for 4 h. The brown powder formed from cooled solution
was recrystallized with ethanol. Yield: 0.27 g, 81%. Anal. Calc.
for C9H11 N3O3S: C, 44.80; H, 4.60; N, 17.42. Found: C, 44.13; H,
4.45; N, 16.86%. IR (KBr disc, cm-1): 3452 s, 3202 w, 3180 m,
1637s, 1346 w, 1283s, 823 s (s, strong; m, medium; w, weak). 1H
NMR signals (DMSO–d6, TMS, ppm): 11.19 (s, 1H, N(2)H), 9.53 (s,
1H, OH), 8.96 (s, 1H, OH), 8.41 (s, 1H, N(3)H), 8.23 (d, 1H, OH,
=
J = 4.58 Hz), 8.19 (s, 1H, CH N), 7.12 (d, 1H, aromatic, J = 8.70 Hz),
2

S. Savir, J.W.K. Liew, I. Vythilingam et al.
Journal of Molecular Structure 1242 (2021) 130815
6.32 (d, 1H, aromatic, J = 8.70 Hz), 2.95 (d, 3H, CH3, J = 4.58 Hz).
13C NMR signals (DMSO–d6, TMS, ppm): 177.51 (C = S), 141.87
The ethanolic solution containing the ligand (L1), triph-
enylphosphine and nickel(II)chloride hexahydrate was refluxed for
6 h. The solution was left aside for slow evaporation. Brown pre-
cipitate formed was then recrystallized with either ethanol or a
mixture of DMF and acetonitrile in a 1:2 ratio to promote crystal
growth. Yield: 0.18 g, 63%. Anal. Calc. for C27H25ClN3NiO3PS.H2O:
C, 54.35; H, 4.22; N, 7.04. Found: C, 54.99; H, 4.74; N, 6.63%. IR
(KBr disc, cm-1): 3427, 3310 s, 3169 m, 1616s, 1434s, 1380 m,
1273s, 1084s, 788 m, 689 s, 533 m, 509 s, 488 m (s, strong; m,
medium; w, weak). 1H NMR signals (DMSO–d6, TMS, ppm): 11. 17
–
–
–
(C = N), 148.62 (C OH), 146.99 (C OH), 133.20 (C OH), 118.45,
113.15, 108.43 (C-aromatic), 31.33 (CH3).
2.4. Melting point: 110–114 °C
•
Synthesis
of
2,3,4-trihydroxybenzaldehyde-4-ethyl-3-thiosemi
carbazone (L2)
Similar to the preparation of (L1) by using 4-ethyl-3-
=
(s, 1H, N(2)H), 8.23 (s, 1H, N(3)H), 8.19 (s, 1H, CH N), 6.44 (d,
thiosemicarbazide. Yield: 0.31 g, 91%. Anal. Calc. for C10H15N3O4S:
C, 43.95; H, 5.53; N, 15.37. Found: C, 44.58; H, 5.32; N, 15.50%. IR
(KBr disc, cm-1): 3439 s, 3349 w, 3170 m, 1632s, 1348 w, 1251s,
798 m (s, strong; m, medium; w, weak). 1H NMR signals (DMSO–
d6, TMS, ppm): 11. 12 (s, 1H, N(2)H), 9.53 (s, 1H, OH), 8.99 (s,
1H, OH), 8.43 (s, 1H, OH), 8.26 (t, 1H, N(3)H, J = 11.45 Hz), 8.19
1H, OH, J = 8.24 Hz), 6.32 (d, 1H, OH, J = 8. 24 Hz), 7.58 (d, 3H,
aromatic, J = 7.33 Hz), 7.39 (s, 12H, aromatic), 7.12 (d, 1H, aro-
matic, J = 8.24 Hz), 7.04 (d, 1H, aromatic, J = 8.24 Hz), 2.93 (d,
3H, CH3, J = 3.66 Hz). 13C NMR signals (DMSO–d6, TMS, ppm):
–
–
177.29 (C = S), 141.65 (C = N), 148.59 (C OH), 146.91 (C OH),
–
134.08 (C O-Ni), 133.15, 130.73, 129.33, 118.26, 112.93, 108.26 (C-
=
(s, 1H, CH N), 7.11 (d, 1H, aromatic, J = 8.24 Hz), 6.32 (d, 1H,
aromatic).
aromatic, J = 8.70 Hz), 3.53 (q, 2H, CH2, J = 20.61 Hz), 1.08 (t,
3H, CH3, J = 14.20 Hz) . 13C NMR signals (DMSO–d6, TMS, ppm):
2.8. Melting point: 180–184 °C
–
–
176.44 (C = S), 142.01 (C = N), 148.64 (C OH), 146.96 (C OH),
–
133.20 (C OH), 118.55, 113.10, 108.16 (C-aromatic), 38.76 (CH2),
•
Synthesis of (2,3,4-trihydroxybenzaldehyde-4-ethyl-3-thiosemi
15.23 (CH3).
carbazonato)-(triphenylphosphine)Ni(II) [Ni(L2)PPh3]Cl, (2)
2.5. Melting point: 108–110 °C
Similar to the preparation of (1) by using ligand (L2). Yield:
0.22 g, 71%. Anal. Calc. for C28H26ClN3NiO3PS.H2O: C, 55.07; H,
4.46; N, 6.88. Found: C, 55.41; H, 5.06; N, 6.23%. IR (KBr disc,
cm-1): 3454, 3218 s, 3161 s, 1610s, 1435s, 1320 m, 1292s, 1091s,
779 m, 691 s, 528 m, 503 s, 494 m (s, strong; m, medium;
w, weak). 1H NMR signals (DMSO–d6, TMS, ppm): 11. 10 (s, 1H,
•
Synthesis of 2,3,4-trihydroxybenzaldehyde-4-phenyl-3-thiosemi
carbazone (L3)
Similar to the preparation of (L1) by using 4-phenyl-3-
thiosemicarbazide. Yield: 0.29 g, 89%. Anal. Calc. for C14 H13N3O3S:
C, 55.43; H, 4.32; N, 13.85. Found: C, 55.34; H, 3.79; N, 13.67%.
IR (KBr disc, cm-1): 3531, 3441 s, 3149 w, 1612s, 1345 w, 1261s,
804 m (s, strong; m, medium; w, weak). 1H NMR signals (DMSO–
d6, TMS, ppm): 11. 56 (s, 1H, N(2)H), 9.89 (s, 1H, OH), 9.58 (s,
=
N(2)H), 8.27 (s, 1H, N(3)H), 8.18 (s, 1H, CH N), 6.33 (d, 1H, OH,
J = 8.24 Hz), 6.05 (s, 1H, OH), 7.42 (s, 16H, aromatic), 7.11 (d,
1H, aromatic, J = 8.70 Hz), 1.27 (s, 2H, CH2), 1.06 (t, 3H, CH3,
J = 13.74 Hz). 13C NMR signals (DMSO–d6, TMS, ppm): 176.35
–
–
(C = S), 141.45 (C = N), 148.60 (C OH), 146.91 (C OH), 134.04
=
1H, OH), 8.46 (s, 1H, N(3)H), 8.31 (s, 1H, CH N), 6.34 (d, 1H, OH,
–
(C O-Ni), 133.14, 132.59, 132.22, 132.12, 131.99, 131.91, 129.32,
J = 8.70 Hz), 7.54 (d, 2H, aromatic, J = 7.79 Hz), 7.31 (t, 3H, aro-
matic, J = 15.57 Hz), 7.13 (t, 2H, aromatic, J = 14.65 Hz). 13C NMR
signals (DMSO–d6, TMS, ppm): 175.54 (C = S), 147.19 (C = N),
118.03, 113.12, 108.23 (C-aromatic), 38.78 (CH2), 15.22 (CH3).
2.9. Melting point: 140–144 °C
–
–
–
153.76 (C OH), 151.42 (C OH), 148.90 (C OH), 142.80, 139.68,
133.19, 129.59, 128.50, 125.80, 125.45, 118.93, 112.93, 108.19 (C-
aromatic).
•
Synthesis of (2,3,4-trihydroxybenzaldehyde-4-phenyl-3-thiosemi
carbazonato)-(triphenylphosphine)Ni(II) [Ni(L3)PPh3], (3)
2.6. Melting point: 124–128 °C
Similar to the preparation of (1) by using ligand (L3). Yield:
0.22 g, 71%. Anal. Calc. for C32H27N3NiO3PS: C, 61.66; H, 4.37;
N, 6.74. Found: C, 61.35; H, 5.08; N, 6.41%. IR (KBr disc, cm-1):
3448, 3370, 1562s, 1436s, 1318 m, 1239s, 1093s, 765 s, 690 s,
529 m, 507 s, 489 m (s, strong; m, medium; w, weak). 1H NMR
signals (DMSO–d6, TMS, ppm): 9.25 (s, 1H, N(3)H), 9. 25 (s, 1H,
•
Synthesis of 2,3,4-trihydroxybenzaldehyde-4-(4-ethylphenyl)−3-
thiosemicarbazone (L4)
Similar to the preparation of (L1) by using 4-(4-ethylphenyl)−3-
thiosemicarbazide. Yield: 0.25 g, 81%. Anal. Calc. for C16 H17 N3O3S:
C, 57.99; H, 5.17; N, 12.68. Found: C, 57.52; H, 4.98; N, 12.25%. IR
(KBr disc, cm-1): 3352, 3341, 3140 s, 1634s, 1378 w, 1271s, 833 m
(s, strong; m, medium; w, weak). 1H NMR signals (DMSO–d6, TMS,
ppm): 11. 51 (s, 1H, N(2)H), 9.84 (d, 1H, OH, J = 16.72 Hz), 9.65 (s,
=
OH), 8.45 (d, 1H, CH N, J = 8.70 Hz), 7.76 (t, 6H, aromatic,
J = 17.86 Hz), 7.62 (d, 3H, aromatic, J = 8.24 Hz), 7.54 (t, 9H,
aromatic, J = 13.28 Hz), 7.18 (t, 2H, aromatic, J = 15.57 Hz), 6.85
(t, 2H, aromatic, J = 16.03 Hz), 6.21 (d, 1H, OH, J = 8.70 Hz),
4.70 (s, 1H, SH). 13C NMR signals (DMSO–d6, TMS, ppm): 164.87
=
1H, N(3)H), 8.33 (s, 1H, CH N), 6.49 (d, 1H, OH, J = 8.24 Hz), 6.37
–
–
(C = N), 164.70 (C = N), 153.42 (C O-Ni), 150.25 (C OH), 146.48
(d, 1H, OH, J = 8.70 Hz), 7.44 (d, 2H, aromatic, J = 8.24 Hz), 7.18
(d, 2H, aromatic, J = 8.24 Hz), 7.10 (d, 2H, aromatic, J = 8.24 Hz),
2.59 (q, 2H, CH2, J = 22.90 Hz), 1.17 (t, 3H, CH3, J = 15.11 Hz).
13C NMR signals (DMSO–d6, TMS, ppm): 175.59 (C = S), 147.16
–
(C OH), 141.92, 134.43, 134.33, 133.70, 131.83, 129.55, 129.45,
128.97, 123.26, 121.51, 118.44, 110.79, 107.86 (C-aromatic).
2.10. Melting point: 264–268 °C
–
–
–
(C = N), 153.76 (C OH), 151.42 (C OH), 148.85 (C OH), 140.99,
137.30, 132.68, 127.78, 125.85, 118.90, 115.91, 112.95, 108.18 (C-
aromatic).
•
Synthesis of (2,3,4-trihydroxybenzaldehyde-4-(4-ethylphenyl)−3-
thiosemicarbazonato)-(triphenylphophine)Ni(II) [Ni(L4)PPh3], (4)
2.7. Melting point: 104–108 °C
Similar to the preparation of (1) by using ligand (L4). Yield:
0.22 g, 71%. Anal. Calc. for C37H43N4NiO7PS: C, 58.44; H, 5.57;
N, 7.37. Found: C, 58.98; H, 5.57; N, 7.83%. IR (KBr disc, cm-1):
3441, 3296, 3187, 1654s, 1436s, 1315 m, 1277s, 1095s, 782 s,
•
Synthesis of (2,3,4-trihydroxybenzaldehyde-4-methyl-3-thiosemi
carbazonato)-(triphenylphosphine)Ni(II) [Ni(L1)PPh3]Cl, (1)
3

S. Savir, J.W.K. Liew, I. Vythilingam et al.
Journal of Molecular Structure 1242 (2021) 130815
693, 531 m, 510 s, 493 m (s, strong; m, medium; w, weak). 1H
NMR signals (DMSO–d6, TMS, ppm): 9.21 (s, 1H, OH), 9.14 (s, 1H,
and AMI-BCC charges where the solvents and a dual metalating/
intercalating DNA binding drug in 1XRW were removed from the
Xray structures. The non-polar hydrogens of the complexes were
merged. In addition, the autodocktools (ADT) was used to set lig-
and to be flexible and perform the docking to the rigid DNA struc-
tures. The binding affinities of docked compounds were estimated
using docking area of a grid box 25 × 25 × 25 with grid spacing of
=
N(3)H), 8.40 (d, 1H, CH N, J = 8.70 Hz), 7.74 (t, 6H, aromatic,
J = 17.86 Hz), 7.52 (t, 9H, aromatic, J = 18.72 Hz), 7.01 (d, 4H, aro-
matic, J = 8.70 Hz), 6.82 (d, 2H, aromatic, J = 8.70 Hz), 6.17 (d, 1H,
OH, J = 8.70 Hz), 4.68 (s, 1H, SH), 2.45 (q, 2H, CH2, J = 5.50 Hz),
1.08 (t, 3H, CH3, J = 15.11 Hz). 13C NMR signals (DMSO–d6, TMS,
˚
0.375 A. The aforementioned dimensions of docking area were ad-
–
ppm): 164.84 (C = N), 164.67 (C = N), 153.06 (C O-Ni), 150.16
equate to include the entire DNA molecule, ensuring that the space
for free rotation of ligand and fitting of the receptor is sufficient.
The simulations obtained from the docking experiment were po-
sitioned in order of increasing energy and clustered in a group of
similar conformation. Optimal binding mode was determined by
the pose with the least energy. The UCSF Chimera 1.14 software
was used to visualise the 3D images of docked conformation [44].
–
–
(C OH), 146.39 (C OH), 139.75, 136.88, 134.43, 134.33, 132.06,
131.96, 131.82, 129.54, 129.44, 129.01, 128.16, 123.18, 118.63, 110.83,
107.81 (C-aromatic), 28.04 (CH2), 16.38 (CH3).
2.11. Melting point: 156–160 °C
2.11.1. X-ray crystallography
In this research, all complexes were recrystallised from
dimethylformamide (DMF). The complexes are all dark brown in
colour. A Rigaku Oxford (formerly Agilent Technologies) Super
3. Results and discussion
3.1. Synthesis of ligands and metal complexes
˚
Nova Dual diffractometer with Cu Kα (λ = 1.541 84 A) radiation
at 160−170 K was used to generate the unit cell parameter and
intensity data. OLEX2 was used to label atoms [34]. The structure
was solved with the SHELXS structure solution program using Di-
rect Methods and refined with the SHELXL refinement package us-
ing Least Squares minimisation [35]. All non-hydrogen atoms were
refined anisotropically and hydrogen atoms were added at calcu-
lated position and refined as a riding model. Whereas, the crystal
structure visualisation and analysis were done using Mercury CSD
2.0 [36]. In addition, the publCIF software was used to edit, vali-
date and format crystallographic information files [37].
The proposed structures of all compounds and their method of
synthesis is shown in Fig. 1 and Scheme 1, respectively. All ligands
and complexes were obtained in good yield with sharp melting
points. Besides, the proposed structures were in good agreement
with the data obtained from various spectroscopic analysis. Results
from elemental analyses for all compounds corroborated with the
proposed formulation from crystal data. The ligands (L1-L4) were
yellowish brown in colour and the complexes (1–4) were blackish
brown in colour. Ligands (L1-L2) were found to be coordinating to
the metal centre in the thione form whereas ligands (L3-L4) were
found to be coordinating to the metal centre in the thiolate form.
Besides, all ligands and complexes are soluble in selected polar sol-
vents such as ethanol, methanol, DMF and DMSO. To the best of
our knowledge, spectroscopic data of ligands L1, L2, L3 and L4 are
consistent with similar compounds that were previously reported
[32,45].
2.12. Biological assays
2.12.1. Cell culture and MTT cytotoxicity assay
The assay was performed as previously described [45] using hu-
man colorectal carcinoma HCT 116, prostate adenocarcinoma PC-3,
and breast adenocarcinoma MCF7 cell lines which were purchased
from American Type Culture Collection (ATCC, USA). The IC50 val-
ues were determined by plotting percentage of viability against the
concentration of treatment on a logarithmic scale using GraphPad
Prism 7 software (Graphpad software Inc., CA, USA).
3.2. Infrared spectra
3.2.1. Infrared spectra of ligands (L1-L4)
Table 1 shows the infrared spectra of ligands and complexes.
All ligands have the azomethine imine peak at a range of 1612–
1637 cm-1 [46]. The thioamide v(NC=S) peaks for all ligands
2.12.2. Determination of antimalarial activity by testing on
plasmodium falciparum culture
This experiment was conducted by using the P. falciparum 3D7
strain, according to our previously published procedures [33]. The
drug plates containing culture medium and blood media parasite
mixture (BMPM) were incubated in a gas chamber containing 5%
CO2, 5% O2, and 90% N2 at 37.5–38.0 °C for 36 to 42 h until at least
50% of the ring stage parasites had matured to schizonts [38]. Thick
blood smears were made for each concentration from the erythro-
cytes that remained in the fluid once the supernatants were re-
moved. After thorough drying, they were stained with 10% Giemsa
stain [39]. Microscopic evaluation was done by counting the num-
ber of schizonts with five or more nuclei out of a total 200 asexual
parasites in every thick film. [40]. Results were reported as mean
(
SD) of two different experiments which were performed in du-
plicates each. IC50 values were generated using GraphPad Prism 7
software (Graphpad software Inc., CA, USA).
2.13. Molecular docking studies
The AutoDock Vina 1.12 [41] software was used to perform the-
oretical computational docking calculations for the interaction of
complexes 1, 2, and 3 with DNA structures extracted from Protein
Data Bank (PDB) with PDB entry 1BNA [42] and 1XRW [43]. DNA
and complexes 1, 2 and 3 were minimised using AMBER force field
Fig. 1. Proposed structures of ligands (L1-L4) and complexes (1–4).
4

S. Savir, J.W.K. Liew, I. Vythilingam et al.
Journal of Molecular Structure 1242 (2021) 130815
Scheme 1. Schematic representation for the synthesis of ligands (L1-L4) and complexes (1–4).
Table 1
Infrared spectra of ligands (L1-L4) and complexes (1–4).
Compd.
CH
C = S/C-S
N(2)H
v(cm-1) N(3)H
OH
Ni-S
Ni-N
Ni-O
PPh3
=
N
L1
L2
L3
L4
1
1637
1632
1612
1634
1616
1610
1562
1654
1346/823
1348
3180
3170
3149
3140
3169
3161
–
3202
3349
3441
3341
3310
3454
3370
3439
3452
3439
3531
3352
3427
3218
3448
3534
–
–
–
–
–
–
–
–
/7,981,345
/8,041,378
/8,331,380/788
1320
–
–
–
–
–
–
–
–
488
494
489
493
533
528
529
531
509
503
507
510
1434 1084 689
1435 1091 691
1436 1093 690
1436 1095 693
2
3
/7,791,318
/7,651,315/782
4
–
were observed at a range of 1345–1378 cm-1 [30]. Besides, the
hydrazinic proton v(N(3)H) for all ligands were observed at a
range of 3202–3441 cm-1 [47,48] . The absence of v(S-H) band
at 2570 cm-1 and the presence of the v(N(2)H) band at a range
of 3140–3180 cm-1 indicates that all ligands are in their thione
form [49,50]. The v(OH) peaks for these ligands were observed at
a range of 3352–3531 cm-1 [51,52]. Whereas the peaks belonging
1, indicating that ligands L1 and L2 are coordinated to the metal
centre in their initial thione form [56]. The disappearance of the
v(N(2)H) bands in complexes 3 and 4 presents convincing affirma-
tion that ligands L3 and L4 are coordinated to their metal cen-
tres in the deprotonated thiolate form. Besides, the emergence of
new v(Ni-S), v(Ni-N) and v(Ni-O) at a range of 488–494 cm-1, 528–
533 cm-1 and 503–510 cm-1, respectively guarantees once again
the coordination of ligands to metal centre through their O,N,S tri-
dentate binding sites [57-60]. The v(OH) peak for all complexes
were observed at a range of 3218–3448 cm-1, suggesting that only
one phenolic OH group was involved in metal complexation. The
–
to v(C O) were observed at a range of 1251–1283 cm-1 [53].
3.2.2. Infrared spectra of metal complexes (1–4)
=
In most cases, the azomethine imine peaks v(CH N) of metal
–
v(C O) peaks in metal complexes were found to be at similar
complexes would be found to have shifted to lower wavenumbers
as is the case in complexes (1–3) [54] . However, the mentioned
peak was found to have shifted to higher wavenumber in complex
4. Hence, addition of metal salt can also cause a shift to higher
wavenumbers [55]. This confirms the coordination of all ligands to
their metal centre through the azomethine imine nitrogen atom.
The hydrazinic proton v(N(3)H) in all complexes were found to
have shifted to higher wavenumbers and be at a range of 3310–
3454 cm-1, indicating that complexation has occurred through the
azomethine imine nitrogen atom. However only complexes 1 and 2
showed the presence of v(N(2)H) peak at a range of 3161–3169 cm-
ranges as their free ligands. The bands due to triphenylphosphine
after metal complexation for all complexes were found to be at
ranges of 1434–1436 cm-1, 1084–1095 cm-1 and 689–693 cm-1
[53].
3.3. 1H NMR and 13 C NMR spectra
3.3.1. 1H NMR and 13 C NMR spectra of ligands (L1-L4)
Table 2 shows the proton resonance signals of all ligands and
complexes whereas the carbon resonance signals are shown in
5

S. Savir, J.W.K. Liew, I. Vythilingam et al.
Journal of Molecular Structure 1242 (2021) 130815
Table 2
1H NMR spectra of ligands (L1-L4) and complexes (1–4).
=
Compd.
L1
CH
N
N(2)H
δ(ppm) N(3)H
OH
Aromatic
Aliphatic
8.19 (s, 1H)
8.19 (s, 1H)
8.31 (s, 1H)
8.33 (s, 1H)
11.19 (s, 1H)
8.41(s, 1H)
9.53 (s, 1H)
8.96 (s, 1H)
8.23 (d, 1H)
9.55 (s, 1H)
8.99 (s, 1H)
8.43 (s, 1H)
9.89 (s, 1H)
9.58 (s, 1H)
6.34 (d, 1H)
9.84 (d, 1H)
6.49 (d, 1H)
6.37 (d, 1H)
6.46 (d, 1H)
6.32 (d,1H)
6.32–7.12
6.32–7.11
7.13–7.54
7.10–7.44
2.95 (d, CH3)
L2
L3
L4
11.20 (s, 1H)
11.56 (s, 1H)
11.51 (s, 1H)
8.26 (t, 1H)
8.46 (s, 1H)
9.65 (s, 1H)
3.53 (q, CH2)
1.08 (t, CH3)
-
2.59 (q, CH2)
1.17 (t, CH3)
1
2
3
4
8.19 (s, 1H)
8.18 (s, 1H)
8.45 (d, 1H)
8.40 (d, 1H)
11.17 (s, 1H)
8.23 (s, 1H)
8.27 (s, 1H)
9.25 (s, 1H)
9.14 (s, 1H)
7.04–7.58
7.11–7.42
6.85–7.76
6.82–7.74
2.93 (d, CH3)
11.10 (s, 1H)
1.27 (q, CH2)
1.06 (t, CH3)
-
-
-
2.45 (q, CH2)
1.08 (t, CH3)
6.33 (d, 1H)
6.05 (s, 1H)
9.25 (s, 1H)
6.21 (d, 1H)
9.21 (s, 1H)
6.17 (d, 1H)
Table 3
13 C NMR spectra of ligands (L1-L4) and complexes (1–4).
–
Compd.
C = N
C = S
δ(ppm) C
O
Aromatic
Aliphatic
L1
L2
141.87
142.01
177.51
176.44
133.20–148.62
133.20–148.64
108.43–118.45
108.16–118.54
31.33 (CH3)
38.76 (CH2) 15.23
(CH3)
L3
L4
147.19
147.16
175.54
175.59
148.90–153.76
148.85–153.76
108.19–142.80
108.18–140.99
–
28.18 (CH2) 16.17
(CH3)
1
2
141.65
141.45
177.29
176.35
134.08–148.59
134.04–148.60
108.26–133.15
108.23–133.42
31.42 (CH3)
38.78 (CH2)
15.22 (CH3)
-
3
4
164.87
164.70
164.84
164.67
-
-
146.48–153.06
146.39–153.06
107.86–141.92
107.81–139.75
28.04 (CH2)
16.38 (CH3)
Table 3. The singlet proton resonance signal belonging to the
Whilst, the resonance signals caused by aromatic carbons were ob-
served at 108.14–142.80 ppm [72]. Whereas, resonance signals due
to aliphatic carbons caused by -CH2 group and -CH3 group were
spotted at 28.18–38.76 ppm and 15.23–31.38 ppm, respectively [73-
75]. The total number of carbon resonance signals from the spectra
were in tandem with the proposed structures of all ligands.
=
azomethine imine group (CH N) was seen to be at a range of 8.19–
8.33 ppm for all ligands [61]. The fact that all ligands are in their
thioamide form is proved by the absence of resonance signal at
around 4 ppm which belongs to the (S-H) group [50]. The presence
of all ligands in their thioamide form is further confirmed by the
appearance of singlet proton resonance signal at a range of 11.12–
11.56 ppm which belongs to the thiohydrazinic proton (N(2)H) [62-
64]. The hydrazinic (N(3)H) proton resonance signal for all ligands
were found to be at a range of 8.26–9.65 ppm and the shift in
resonance signal is highly dependant on the substituent group at-
tached to it [65,66]. The resonance signal for aromatic ring which
appeared as multiplets were observed at a range of 6.32–9.89 ppm
for all ligands [67]. Also, the phenolic OH resonance signal was ob-
served at a range of 6.34- 9.89 ppm [68,69]. Whilst, the aliphatic
proton resonance signals due to -CH2 and -CH3 groups were seen
to be at a range of 2.95–3.53 ppm and 1.08–2.95 ppm for all lig-
ands [70].
3.3.2. 1H NMR and 13 C NMR spectra of metal complexes (1–4)
=
The azomethine imine nitrogen (CH N) resonance signal was
found to have shifted slightly downfield and resonate at a range
of 8.18–8.45 ppm, proving that the ligands are coordinated to
the metal centre via their azomethine imine nitrogen atom. The
azomethine resonance signal for complexes 3 and 4 were ob-
served as doublets due to coupling with phosphorus atom of triph-
enylphosphine [76]. Complexes 1 and 2 show resonance signals
due to thiohydrazinic proton (N(2)H) at 11.17 ppm and 11.10 ppm,
respectively. Hence, ligands L1 and L2 were found to have coordi-
nated to the metal centre in their thioamide form. However, reso-
nance signal at this range was absent in complexes 3 and 4, indi-
cating that ligands L3 and L4 were coordinated to the metal cen-
tre in their thiolate form. This is further confirmed by the emer-
gence of a new resonance signal belonging to the (S-H) group
at 4.70 ppm and 4.68 ppm for complexes 3 and 4, respectively.
The hydrazinic proton resonance signal (N(3)H) was seen to have
Carbon resonance signals showed by azomethine imine nitro-
gen (C = N) for all ligands were observed at a range of 141.87–
147.19 ppm. The resonance signal for thioamide (C = S) were found
to be at a range of 175.54–177.51 for all ligands, stipulating that the
ligands are in their thione form [71]. Besides, the resonance signal
for phenolic OH were detected at a range of 133.20–153.76 ppm.
6

S. Savir, J.W.K. Liew, I. Vythilingam et al.
Journal of Molecular Structure 1242 (2021) 130815
shifted downfield in complexes 2 and 3 as a result of decrease in
electron density due to the electron withdrawal by metal centre,
sulphur, and deprotonated phenolic OH [77]. However, complexes
1 and 4 were seen to not follow this trend as occasional change
in trend is common. The resonance signal due to phenolic OH in
all complexes were observed at a range of 6.05–9.25 ppm, simi-
lar as their ligands, suggesting that only one phenolic OH group
was involved in metal complexation. Resonance signals of aromatic
protons in all complexes were found to resonate at similar res-
onances as their ligands because aromatic protons were not af-
fected by metal complexation. There isn’t much variation in the
resonance signals produced by aliphatic protons in all complexes
from their respective ligands because aliphatic protons are not in-
volved in metal complexation as well.
Since the azomethine imine nitrogen (C = N) is involved in
metal complexation, their resonance signals were observed at
141.65 ppm and 141.45 ppm for complexes 1 and 2, respectively.
Their thioamide carbon resonance signals (C = S) were spotted
at 177.29 ppm and 176.35 ppm, indicating that ligands L1 and L2
were coordinated to the metal centre in their initial thione form.
Furthermore, a slight upfield shift in the thioamide resonance sig-
nal observed in complexes 1 and 2 is due to lowering of C-S bond
order as a result of metal complexation [78]. However, complexes 3
and 4 produced resonance signals at a range of 164.67–164.87 ppm
which belongs to the azomethine imine nitrogen (C = N). This
downfield shift of the mentioned group reaffirms the coordina-
tion of ligands L3 and L4 to the metal centre via their azome-
thine imine nitrogen atom. Besides, the resonance signal due to
thioamide carbon was absent in these complexes, confirming that
ligands L3 and L4 were coordinated to the metal centre in the thi-
olate form. The resonance signal caused by phenolic OH was spot-
ted at a range of 146.39–150.25 ppm, denoting that only one of
the phenolic OH was involved in metal complexation. Significant
changes were not observed in the resonance signals produced by
aromatic and aliphatic carbon atoms. Once again, the number of
carbon atoms from the spectra were in tandem with the proposed
structures for all complexes.
3.4. Crystal structures
The crystal data and refinement parameters of complexes (1–
3) are shown in Table 4. However, the crystal data of complex 4
could not be produced although it was successfully synthesised.
Whereas, Table 5 shows the selected bond lengths and bond an-
gles of complex 1. Selected bond lengths and bond angles of com-
plexes 2 and 3 are shown in Supplementary Information (Table A.
1- Table A. 2). Meanwhile, the crystal structures of complexes (1–
3) are shown in Fig. 2 whereas the unit cell packing of complex 1
is shown in Fig. 3. The unit cell packing of complexes 2 and 3 are
shown in Supplementary Information (Fig. A. 1- Fig. A. 2).
Fig. 2. Ellipsoid plots of complexes (1–3). Hydrogen atoms are omitted and some
of the atoms are not labelled for clarity.
coordination gives rise to an increase of the single bond charac-
ter for C-S bond is true in the case of complex 3 [80]. Besides,
the effect of thione to thiol tautomerization is clearly observed in
complex 3. In addition, the N2-C8 bond lengths were seen at 1.324
˚
˚
˚
3.4.1. Crystal structures of complexes (1–3)
(4) A, 1.328 (4) A and 1.299 (14) A for complexes 1, 2 and 3, re-
spectively. It is interesting to note that the N2-C8 bond lengths
for complexes 1 and 2 were longer than complex 3, suggesting
that the mentioned bond is a single bond in complexes 1 and 2
but a double bond in complex 3 [81]. Similar bond lengths were
observed in thiosemicarbazones reported by previous researches,
stipulating that ligands L1 and L2 were coordinated to the metal
in the original thione form but ligand L3 was coordinated to the
metal in its thiolate form. The bite angle for O1-Ni1-N1, N1-Ni-S1,
S1-Ni-P1 and O1-Ni-P1 which slightly deviate from the ideal 90 °
reflect that the complexes adopt a distorted square planar geom-
etry. Deviations due to restricted bite angle caused by ligands is
common [58,82]. Besides, the O1-Ni-S1 and N1-Ni-P1 bonds were
found to intersect at an approximate angle of 180 ° signifying
It is revealed by single crystal X-ray analysis that complexes 1
and 2 crystallised in triclinic crystal system with P1 space group.
Whilst, complex 3 was found to have crystallised into a monoclinic
lattice with P21 space group. All three complexes were four coor-
dinated and displays a square planar geometry. All ligands were
found to have coordinated to the metal centre via their O,N,S tri-
dentate binding site. The S1-C8 bond lengths for complexes 1, 2
˚
˚
˚
and 3 were seen at 1.721 (3) A, 1.714 (3) A and 1.728 (12) A, re-
spectively. The bond lengths are similar as those observed in other
thiosemicarbazone metal complexes. It is noteworthy that the S1-
C8 bond lengths for complexes 1 and 2 were shorter than complex
3, indicating that the mentioned bond is a double bond in com-
plexes 1 and 2 but a single bond in complex 3 [79]. The fact that
7

S. Savir, J.W.K. Liew, I. Vythilingam et al.
Journal of Molecular Structure 1242 (2021) 130815
Table 4
Crystallographic data summary for complexes (1–3).
Compounds
1
C
2
3
Empirical formula
Formula weight
Crystal system
Space group
Unit cell
27H27ClN3NiO4PS
C28H28ClN3NiO4PS
C32H27N3NiO3PS
623.30
614.70
Triclinic
P1
627.69
Triclinic
P1
Monoclinic
P21
dimensions
9.5562 (4)
12.7600 (5)
13.0135 (7)
97.172 (4)
1387.92 (12)
2
7.9432 (5)
14.000 (1)
14.2845 (9)
91.597 (5)
1448.59 (18)
2
9.6016 (3)
10.6957 (3)
13.5895 (6)
93.499 (3)
1392.98 (8)
2
˚
a (A)
˚
b (A)
˚
c (A)
β (°)
3
˚
V (A )
Z
636
615
646
F(000)
1.471
1.360
1.486
Dcalc (mg m-3
Absorption
coefficient, μ
)
3.46
2.86
2.58
293
293
293
(mm-1
)
0.10 × 0.10 × 0.05
8175
0.10 × 0.10 × 0.05
8468
0.10 × 0.10 × 0.05
2486
T (K)
Crystal size (mm)
Reflections
5313 (0.033)
5533 (0.029)
1618 (0.031)
collected
5313/0/349
0.054
5533/0/358
0.053
1618/1/372
0.044
Independent
reflections (Rint
)
0.151
0.159
0.125
Data/restraints/paramet1e.r0s1
1.03
1.10
R[F2 > 2σ(F2)]
wR(F2)
0.97 and −1.08
0.68 and −0.66
0.43 and −0.44
S
Largest
differencepeak and
-3
˚
hole (e A
)
that all complexes are in a distorted square planar geometry. Each
Table 5
–
molecule of complex 1 is involved in intermolecular O H—O and
˚
Selected bond lengths (A) and bond angles (°) for complex 1.
–
N H—Cl hydrogen bonding interactions. The water molecule and
˚
Bond lengths (A)
Bond angles (°)
chlorine ion served as a bridge to the adjacent ligand through a
network of hydrogen bonding interactions leading to the formation
of a parallel linear chain. The packing of the molecules is stabilised
by a combination of hydrogen bonding and Van der Waals interac-
tion leading to a 2-dimension network along the c-axis (Fig. 3).
Ni1—P1
Ni1—S1
Ni1—O1
Ni1—N1
S1—C8
2.206 (7)
2.148 (7)
1.849 (19)
1.881 (2)
1.721 (3)
1.394 (3)
1.310 (3)
1.324 (4)
1.323 (3)
1.446 (4)
S1—Ni1—P1
O1—Ni1—P1
O1—Ni1—S1
O1—Ni1—N1
N1—Ni1—P1
N1—Ni1—S1
C16—P1—Ni1
C22—P1—C10
C10—P1—Ni1
C22—P1—Ni1
90.27 (3)
88.06 (6)
175.68 (8)
94.09 (9)
168.04 (7)
88.35 (7)
107.92 (9)
107.68 (12)
112.51 (8)
116.75 (8)
–
–
–
Complex 2 is linked by intermolecular O H—Cl, O H—O and N H—
Cl hydrogen leading to the formation of parallel chain along the
a-axis (Figure A1 SI). No hydrogen bonding was observed for com-
plex 3, the packing of the molecules was stabilised by the Van der
Waals interaction between the phenyl ring of the triphenylphos-
phine moiety and the phenyl substituent on the nitrogen atom,
leading to the formation of a zig-zag chain along the b-axis (Figure
A2 SI).
N1—N2
N1—C7
N2—C8
N3—C8
N3—C9
3.5. Cytotoxic activity of ligands (L1–L4) and metal complexes (1–4)
The cytotoxicity of the ligands and metal complexes was tested
against three human cancer cell lines, namely PC-3, HCT 116, and
MCF7, and the results are reported in Table 6. Ligand L1 was inac-
tive against PC-3 but showed a moderate cytotoxic activity against
HCT 116 and MCF7 with IC50 10.34
0.23 and 11.79
0.86 μM,
respectively. Ligand L2 exhibited a potent growth inhibitory effect
against HCT 116 with an IC50 5.75 0.49 μM, which is comparable
with cisplatin (IC50 5.92 0.79 μM), and it also showed a substan-
tial cytotoxicity against MCF7 with an IC50 8.68
ligands L3 and L4 displayed a stronger cytotoxicity than cisplatin
with IC50 9.82 0.69 and 15.66 2.44 μM, respectively when
tested against PC-3, and they exhibited moderate growth inhibitory
effect when tested against HCT 116 (L3, IC50 9.82 1.85 μM; L4,
IC50 9.75 0.54 μM). Overall, L2 exhibited a wider spectrum of
0.11 μM. Both
Fig. 3. Unit cell packing diagram of complex 1. Water molecules and chloride ions
cytotoxicity than the other ligands with reference to the result of
HCT 116 and MCF7. This is consistent with the previous study that
the addition of long aliphatic and lipophilic side chain could en-
–
–
–
bridge the adjacent ligands. Intermolecular O H—Cl, O H—O and N H—Cl hydrogen
bonding observed.
8

S. Savir, J.W.K. Liew, I. Vythilingam et al.
Journal of Molecular Structure 1242 (2021) 130815
Table 6
In vitro cytotoxic activity (IC50 values) of ligands (L1-L4) and complexes
(1–4) against three human cancer cell lines.
Compound
PC-3
IC50 in μM HCT 116
MCF7
L1
>100
82.47
9.82
10.34
5.75
9.82
9.75
4.26
12.68
7.07
>100
5.92
0.23
0.49
11.79
8.68
0.86
0.11
L2
4.14
0.69
L3
1.85
0.54
0.29
29.70
23.80
13.03
24.72
>100
>100
4.38
0.16
1.54
0.69
1.59
L4
15.66
>100
>100
>100
>100
19.45
2.44
1
2
0.72
3
0.61
0.79
4
Cisplatin∗
0.73
0.50
∗
Positive control, cisplatin was used as a reference standard. Values were
expressed as mean
standard deviation (n = 3).
Table 7
IC50 (μM) values for P. falciparum 3D7.
Compound
IC50 (μM)a
L1
>25b
>25b
>25b
>25b
>25b
L2
L3
L4
1
2
9.88
1.06
>25b
(3.25
0.23
3
0.01
4
Chloroquine∗
0.23) х 10–3
∗
Positive control.
a
Mean ( SD) from two different exper-
iments which were performed in dupli-
cates each.
b
R2 < 0.8.
hance the cytotoxicity of the compound (L2), while the introduc-
tion of aromatic ring into the compound (L3 and L4) has no signif-
icant improvement to the cytotoxicity [83].
Generally, our results showed that the complexation did not im-
prove the cytotoxicity of the parent ligands, except for complexes 1
and 3. Notably, the complexation of L1 has significantly enhanced
the cytotoxicity of 1 against HCT 116 to an extent that becoming
more potent than cisplatin with an IC50 4.26
0.29 μM. Interest-
ingly, the complexation of L3 has slightly increased the cytotoxic-
ity and cell line-specificity of the complex 3 towards HCT 116 (IC50
7.07
fore, it exhibited a stronger cytotoxic activity than the latter (IC50
12.68 0.72 μM) when tested against HCT 116, indicating once
0.61 μM). Complex 3 is more hydrophobic than 2, there-
Fig. 4. Molecular docking simulatSSions showing the interactions between com-
plexes and 1BNA where a) ribbon model and b) molecular surface of 1BNA.
again that cytotoxicity is directly proportional to hydrophobicity
[84]. In general, cytotoxicity increases as the lipophilicity of the
alkyl residue at the N3 nitrogen atom increases [85].
3.7. Molecular docking studies
3.6. Antiplasmodium activity of ligands (L1–L4) and metal complexes
(1–4)
The DNA binding affinity of the bioactive complexes 1–3 was
assessed using molecular docking simulations with an attempt to
investigate the cytotoxicity and antiplasmodial mechanisms of the
complexes. Fig. 4 and Fig. 5 show the interactions of these com-
plexes with DNA duplex 1BNA and 1XRW, respectively. The com-
plexes were found to fit into the DNA minor groove instead of
intercalating between the DNA, probably due to their increased
molecular size as a result of complexation that unfavours in-
tercalation. A closer examination into the DNA-complex interac-
tions revealed hydrophobic interactions of the benzaldehyde, triph-
enylphosphine, and phenyl moieties with DNA base pairs. The DNA
binding strength of the complexes was inferred from the bind-
ing energy, whereby the estimated binding energy for complexes
1, 2, 3 are −7.3, −8.5, and −8.4 kcalmol-1, respectively. The bind-
ing energy of these complexes are comparable to those previously
reported active DNA surface binders [88,89], suggesting that the
The Table 7 reports the IC50 of the compounds and the good-
ness of fit of each result, whether it is more or lesser than 0.8. All
ligands were inactive against P. falciparum, while the complexation
of L2 and L3 into complexes 2 and 3 has gained pronounced anti-
malarial activity with IC50 9.88 0.23 μM and 1.06 0.01 μM, re-
spectively. Similar to the MTT cytotoxicity study, 3 has a higher an-
timalarial activity than 2, which again probably due to the higher
hydrophobicity of 3 than the latter [86]. In contrast with complex
3, complex 4 is inactive although 4 is also hydrophobic, suggesting
that the antimalarial activity can only be improved when the hy-
drophobicity is attributed by phenyl group (in 3) but not the longer
and larger ethyl phenyl group (in 4), as the latter tend to lower the
activity [87].
9

S. Savir, J.W.K. Liew, I. Vythilingam et al.
Journal of Molecular Structure 1242 (2021) 130815
plexes 1–3 at the minor groove where their benzaldehyde, triph-
enylphosphine, aliphatic chain and phenyl moieties interact with
DNA base pairs. In future, much focus and importance should be
given to compounds similar to complexes 2 and 3 in the develop-
ment of a single drug with cytotoxic and antimalarial properties.
Declaration of Competing Interest
The authors declare that they have no known competing finan-
cial interests or personal relationships that could have appeared to
influence the work reported in this paper.
CRediT authorship contribution statement
Savina Savir: Writing
- original draft, Validation, Inves-
tigation, Visualization, Data curation, Methodology, Conceptu-
alization. Jonathan Wee Kent Liew: Validation, Investigation.
Indra Vythilingam: Writing
Yvonne Ai Lian Lim: Writing
-
review
review
&
editing, Supervision.
-
& editing, Supervision.
Chun Hoe Tan: Validation, Investigation. Kae Shin Sim: Writing -
review & editing, Supervision. Vannajan Sanghiran Lee: Writing –
review & editing. Mohd. Jamil Maah: Writing - review & editing,
Supervision. Kong Wai Tan: Writing - review & editing, Supervi-
sion.
Acknowledgements
This work is supported by the University of Malaya Research
Grant (grant number RP033A-17AFR), MOHE (FRGS-FP006–2015A)
and MyBrain Scholarship. Special thanks to Prof. Ng Seik Weng for
his help and support in this project.
Supplementary materials
Supplementary material associated with this article can be
found, in the online version, at doi:10.1016/j.molstruc.2021.130815.
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