Two metal complex derivatives of pyridine thiazole ligand: synthesis, characterization and biological activity

Article abstract of DOI:10.1007/s11243-020-00442-4

In this work, two new metal(II) complexes with ligand based on pyridine thiazolone group, [Zn(L)₂(TsO)₂]2DMF (1), {[Cd(L)(NO₃)₂H₂O)]DMF}_n(2) (where L = 4-(pyridin-4-yl)-2-(2-(pyridin-2- ylm

Full text of DOI:10.1007/s11243-020-00442-4

Transition Metal Chemistry (2021) 46:263–272
https://doi.org/10.1007/s11243-020-00442-4
Two metal complex derivatives of pyridine thiazole ligand: synthesis,
characterization and biological activity
Xunzhong Zou1 · Pingyi Shi1 · Ansheng Feng1 · Meng Mei2 · Yu Li1
Received: 16 October 2020 / Accepted: 8 December 2020 / Published online: 3 January 2021
© The Author(s), under exclusive licence to Springer Nature Switzerland AG part of Springer Nature 2021
Abstract
In this work, two new metal(II) complexes with ligand based on pyridine thiazolone group, [Zn(L)2(TsO)2]2DMF (1),
{[Cd(L)(NO3)2H2O)]DMF}n (2) (where L=4-(pyridin-4-yl)-2-(2-(pyridin-2- ylmethylene)hydrazinyl)thiazole), were pre-
pared and characterized by physicochemical and spectroscopic methods. In addition, the structure of the complexes (1 and
2) was confrmed by single-crystal X-ray analysis. Complex 1 has a discrete monomeric structure where L acts as a bidentate
agent coordinating the zinc(II) atom through pyridine nitrogen and thiazole nitrogen, while complex 2 consists of polymeric
{[Cd(L)(NO3)2H2O)]DMF}n chains in which cadmium(II) atoms are linked by the bridging ligand. The in vitro antimicrobial
and antitumor activities of the ligand and complexes (1 and 2) were evaluated against seven pathogenic bacterial strains
and four human cancer cell lines, and the results showed that some compounds had absolute specifcity for certain bacterial
strains or cancer cell lines, which thus implied a good application prospect in pharmaceutical use.
Introduction
insulin secretion. Additionally, due to their high bioavailabil-
ity and strong targeting properties, a large number of coor-
dination complexes that contain zinc(II) and cadmium(II)
exhibit good performance in anticancer cell proliferation,
as well as in antibacterial and antifungal activities [5–7].
Pyridine thiazole derivatives are known to have inter-
esting bioactive properties, and can be potentially applied
in various areas including as inhibitors of the detoxifying
enzyme [8], potential anti-diabetes drugs [9], and as potent
antibacterial and anticancer agents [10, 11]. Compounds
with the hydrazone group and its analogs also have phar-
macological potentials due to their unique physiological
activity, multidonor ability and bioactivity properties [12,
13]. Therefore, according to the synergistic efect of drug
combination principles, the introduction of the hydrazone
group into molecules that contain pyridine thiazole is likely
to produce stronger biological activity. As was expected,
our team was able to report a series of pyridine thiazole
derivatives and their complexes, which implied good appli-
cation prospects for them in pharmaceutical use [14, 15]. In
this regard, the synthesis of similar complexes with difer-
ent coordination sites or metal salts is of interest. Herein, a
novel pyridine thiazole derivative of 4-(pyridin-4-yl)-2-(2-
(pyridin-2-ylmethylene) hydrazinyl)thiazole was prepared by
a cyclization reaction, and complexes [Zn(L)2(TsO)2]2DMF
(1), {[Cd(L)(NO3)2H2O)]DMF}n (2) were obtained by
coordinating the ligand with Zn(TsO)2 and Cd(NO3)2,
The successful application of the chemotherapeutic drug
cis-diaminedichloroplatinum(II) (cisplatin) in clinical cancer
treatment represents the potential biological activity of metal
coordination complexes in human diseases [1]. Although
heavy metals are trace elements, they play a very impor-
tant role in all living organisms [2–4]. For example, zinc(II)
is related to more than 50 enzymes, and a small amount
of cadmium(II) can promote fat metabolism and regulate
Electronic supplementary material The online version of this
article (https://doi.org/10.1007/s11243-020-00442-4) contains
supplementary material, which is available to authorized users.
* Meng Mei
meimeng1992@126.com
* Yu Li
liyuletter@163.com
1
Guangdong Research Center for Special Functional Building
Materials and Its Green Preparation Technology / Foshan
Research Center for Special Functional Building Materials
and Its Green Preparation Technology, Guangdong Industry
Polytechnic, Guangzhou 510006, People’s Republic of China
2
Wuhan Children’s Hospital (Wuhan Maternal and Child
Healthcare Hospital), Tongji Medical College, Huazhong
University of Science and Technology, Wuhan 430015,
People’s Republic of China
Vol.:(0123456789)
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Transition Metal Chemistry (2021) 46:263–272
respectively, and they were then characterized by NMR,
elemental analysis (EA), infrared spectroscopy (IR), and
single-crystal X-ray difraction. The inhibitory activities of
these compounds against seven pathogenic bacterial strains
(Escherichia coli (E. coli, ATCC 25922), Staphylococcus
aureus (S. aureus, CMCC(B) 26003), Salmonella typhimu-
rium (S. typhimurium, CMCC(B) 50071), Bacillus subtilis
(B. subtilis, ATCC 6633), Shigella fexneri (Sh. fexneri,
CMCC(B) 51572), Vibrio Parahemolyticus (V. Parahemo-
lyticus, ATCC 17802), Pseudomonas aeruginosa (P. aerugi-
nosa, ATCC 9027)) and four human cancer cell lines (SK-N-
SH, HCT-116, AGS and MCF-7) were tested.
Synthesis
of 4‑(pyridin‑4‑yl)‑2‑(2‑(pyridin‑2‑ylmethylene)
hydrazinyl)thiazole (L)
The intermediate compounds N-4-Pyridine methylene-thio
semicarbazide hydrochloride and 2-bromoacetylpyridine
hydrobromide were prepared according to the relevant lit-
erature [16, 17]. N-4-Pyridine methylene-thio semicarbazide
hydrochloride (10.8 g, 50.0 mmol) and 2-bromoacetylpyri-
dine hydrobromide (14.5 g, 50.0 mmol) were added into
160 mL of 50% ethanol solution at 25℃. After refuxing
for 2 h, the mixture was cooled to room temperature and
adjusted to neutral pH with 10% sodium hydroxide solu-
tion. The resulting solid was recovered through fltration,
washed repeatedly with ethanol and dried to give L as a yel-
low powder (Scheme 1). Yield 8.7 g (62%). IR (KBr, cm−1):
3110, 3058, 1578, 1554, 1537, 1474, 1453, 1422, 1369.72,
Experimental
Materials and physical measurements
1293, 1237, 618, 533. H NMR (400 MHz, d6-DMSO, δ
1
Isonicotinaldehyde, 1-(pyridin-2-yl)ethan-1-one, hydrazi-
necarbothioamide, bromine, zinc(II) p-toluene sulfonate,
cadmium(II) nitrate, ciprofoxacin and cisplatin were pur-
chased from Adama Reagent Co. Ltd. All the other reagents
and solvents were commercially available and employed as
received or purifed by standard methods prior to use. SK-
N-SH, HCT-116, AGS and MCF-7 were gifts from Doctor
Gong Hongjian. Human embryonic lung cell MRC-5 was
provided by the Stem Cell Bank at the Chinese Academy of
Sciences. Elemental analyses were performed on a Germany
Vario EL analyzer (Elementar) and IR spectra on an Ava-
trar 330 FTIR spectrometer (Thermo Nicolet) with potas-
sium bromide pellets. 1H and 13C-NMR spectra were deter-
mined by Bruker AVANCE-III 500 at room temperature
in d6-DMSO, and MestReNova software was used for data
analysis and chemical shifts (δ values) are reported as ppm.
Biological activity tests were performed on a SpectraMax®
ABS Absorbance Reader (Molecular Devices).
ppm): 12.56 (s, 1H, N–H), 7.56–8.64 (m, 8H, pyridine-H),
8.02 (s, 1H, N=CH), 7.36–7.28 (m, 1H, thiazole-H). 13C
NMR: (100 MHz, d6-DMSO, δ ppm) 168.23 (C from thia-
zole ring), 155.50, 152.56, 150.62, 149.93, 142.01, 137.72,
123.19, 120.69, 108.90, 97.34. Anal. Calcd. for C14H11N5S
(%): C, 59.77; H, 3.94; N, 24.89; S, 11.40. Found (%): C,
59.70; H, 3.86; N, 24.97; S, 11.43. UV-Vis (DMSO, λmax,
nm): 255.0, 355.0. FAB-MS m/z(%): 281.7 (M+ +1).
Synthesis of the complexes 1 and 2
Metal salt (100 μmol) and L (28.0 mg, 100 μmol) were dis-
solved in methanol (5.0 mL) under refux conditions for
30 min. The precipitate was recovered by fltration, and then
washed with methanol for three times. The resulting dried
powder was redissolved with DMF (5.0 mL) and fltered
after stirring for 10 min at room temperature. The crystal
was obtained in a few days by the method of diethyl ether
difusion (Scheme 2).
Scheme 1. Synthesis of ligand L
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Transition Metal Chemistry (2021) 46:263–272
265
Scheme 2. Synthesis of complexes 1 and 2
1. Yellow crystals. Yield 30.2 mg (31%). IR (KBr, cm−1):
3096, 3068, 1611, 1579, 1567, 1469, 1445, 1412.94, 1397,
1385, 1348, 1310, 1241. 1H NMR (400 MHz, d6-DMSO, δ
ppm) 12.51 (s, 2H, N–H), 9.02–8.22 (m, 7H), 8.09 (s, 6H),
7.62 (d, 4H), 7.48 (d, 5H), 7.11 (d, 4H), 2.28 (s, 6H, -CH3).
13C NMR (400 MHz, d6-DMSO, δ ppm) 165.03 (C from thi-
azole ring), 155.53, 150.56, 145.90, 138.26, 128.57, 125.96,
120.85, 21.25 (-CH3). Anal. Calcd. for C48H50N12O8S4Zn
(%): C, 51.63; H, 4.51; N, 15.05; S, 11.49. Found (%): C,
51.73; H, 4.37; N, 14.90; S, 11.24. MW=1116.61. UV–Vis
(DMSO, λmax, nm): 255.0, 355.0, 490.0.
by a full-matrix least-squares method based on F2 against
all refections using SHELXL-2015 [21]. All non-hydrogen
atoms were refned anisotropically, while hydrogen atom
positions were calculated geometrically and refned using a
riding model on their parent C or N atoms. The coordinated
p-toluene sulfonic acid ion in 1 was found partially disor-
dered over two orientations with a refned occupancy ratio
0.51/0.49. The two orientations are approximately related
by a non-crystallographic twofold axis and perpendicular to
the benzene ring. The electron density of DMF molecules in
1 has been treated with the program SQUEEZE [22]. DIA-
MOND [23] was used for molecular graphics.
2. Dark red crystals. Yield 23.3 mg (38%). IR (KBr,
cm−1): 3503, 3119, 2980, 2974, 1601, 1566, 1495, 1464,
1
1413, 1384, 1368, 1288, 1237, 825. H NMR (400 MHz,
Antimicrobial activity
d6-DMSO, δ ppm) 12.94 (s, 1H, N–H), 8.76 (dd, 2H), 8.70
(dd, 2H), 8.15–8.07 (m, 4H), 7.81 (dd, J=5.0, 1.5 Hz, 2H).
13C NMR (101 MHz, d6-DMSO) δ 168.82 (C from thia-
zole ring), 162.79, 147.86, 147.62, 146.56, 144.89, 138.75,
121.61, 121.53, 113.98. Anal. Calcd. for C17H20N8O8SCd
(%): C, 33.53; H, 3.31; N, 18.40; S, 5.27. Found (%): C,
33.36; H, 3.41; N, 18.55; S, 5.37. MW = 608.87. UV-Vis
(DMSO, λmax, nm): 255.0, 355.0.
Using the microplate reader method, a qualitative analysis
for the screening of antibacterial activity was carried out [24,
25]. Mueller–Hinton agar plates were seeded with the indica-
tor bacteria E. coli, S. aureus, S. typhimurium, B. subtilis, Sh.
fexneri, V. Parahemolyticus, P. aeruginosa and cultured for
24 h at 37 °C. Plates were inoculated with bacteria adjusted to
0.5 McFarland turbidity standards (108 cfu/mL). The ligand
and complexes (2.0 mg) were added to DMSO (0.2 mL),
respectively, and an ultrasound was used to increase their sol-
ubility. The resulting solution (10 mg/mL, 2 μL) was added
to the enzyme label plate containing 200 μL of liquid culture
medium and tested against the 7 pathogenic bacterial strains to
determine the inhibitory activity by the absorbance (630 nm)
of the bacterial samples using an enzyme-labeled instrument.
The antimicrobial activity of the compounds was determined
and expressed as the bacteriostatic rate (%). Subsequently, the
compounds with a high inhibitory rate (+++) were selected
for minimal inhibitory concentration (MIC) determination
using the double dilution method with concentrations ranging
X‑ray crystallography
The crystallographic data and structure refnement summary
of 1 and 2 are listed in Table 1. The crystals of 1 and 2 for
X-ray analysis were obtained by ether difusion. The unit cell
and data of the crystals were collected by MoKα radiation
(λ=0.71073 Å) on a SuperNova AtlasS2-CCD difractom-
eter at 100 K. The collected data were reduced and the multi-
scan absorption corrections were performed using CrysAlis-
Pro software [18]. Using Olex2 [19], the structure solution
was carried out using SHELXT program [20] and refned
1 3

266
Transition Metal Chemistry (2021) 46:263–272
Table 1 Crystallographic
data and structure refnement
summary for 1 and 2
1
2
Empirical formula
Mw
Crystal system
space group
C48H50N12O8S4Zn
1116.61
Monoclinic
I2/a
C17H20N8O8SCd
608.87
Monoclinic
P21/n
a/Å
b/Å
c/Å
α/°
19.0782(17)
10.0976(8)
26.484(2)
90
7.5203(5)
14.0164(9)
21.4035(14)
90
β/°
96.693(8)
90
5067.2(8)
1.464
95.211(6)
90
2246.8(3)
1.800
γ/°
V/ Å3
Density/g cm−3
Z
4
4
µ/mm−1
F(000)
0.716
2320
0.13×0.12×0.11
1.128
1224
0.12×0.10×0.08
Crystal size/mm3
Radiation
(Mo-Kα) 0.71073
(Mo-Kα) 0.71073
−22≤h≤15
−10≤h≤9
Index ranges
−10≤k≤12,
−31≤l≤31
−19≤k≤17,
−29≤l≤19
θ range for data collection/°
Goodness-of-ft on F2
Refections collected
2.150–25.026
1.038
10,884
2.401–29.597
1.065
11,736
Independent refections
4484 [Rint =0.0450,
5295
Rsigma =0.0718]
[Rint =0.0368,
Rsigma =0.0621]
Final R indexes [I> =2σ(I)] R1, ωR2
Final R indexes [all data] R1, ωR2
Data/restraints/parameters
0.0709, 0.1653
0.1020, 0.1884
4484/50/369
0.626/-0.465
0.0377, 0.0611
0.0515, 0.0678
5295/0/326
Largest dif. peak/hole / e Å−3
0.670/-0.527
from 50 μg/mL to 3.125 μg/mL. The MIC was recorded as the
lowest concentration at which the inhibitory rate was greater
than 95%. For the blank group, only DMSO was added to the
wells, and Ciprofoxacin was used as positive control for anti-
bacterial activity. All tests and analyses were run in triplicate,
and the results obtained were averaged. The inhibition percent-
age was calculated using the following equation:
positive control. Both compounds were dissolved in DMSO
and diluted with Phosphate Bufer Saline to the required con-
centrations (0, 3.125, 6.25, 12.5, 25, 50, and 100 μg/mL). The
four human cancer cell lines SK-N-SH, HCT-116, AGS and
MCF-7, as well as the normal control cell line human embry-
onic lung cell MRC-5 were plated in 96-multiwell plates (104
cells/well) for 24 h before treatment with diferent concentra-
tions of tested samples to allow cell attachment to the wall
of the plates, and then cultured using RPMI 1640 or DMEM
culture medium containing 10% fetal bovine serum in a 5%
(volume fraction) CO2, 37℃ saturated humidity incubator. All
cells were treated with compounds for 48 h. The cell growth
inhibition rate was determined by using the Microplate Reader
to measure the absorbance of each well at 450 nm.
Absblank − (Abssample − Abscontrol
)
Inhibition(%) =
× 100
Absblank
where Absblank is the absorbance of DMSO + blank medium,
Abscontrol is the absorbance of sample + blank medium, and
Abssample is the absorbance of sample (test samples/standard)
+ bacterial suspension in medium.
Antitumor activity
The viability of the compounds was tested using the Cell
Counting Kit 8 (CCK8) [26–28]. Cisplatin was used as the
1 3

Transition Metal Chemistry (2021) 46:263–272
Results and discussion
267
Solution stability of complexes 1 and 2
As a solvent that is used for the preparation of stock solu-
tions for biological activity experiments, DMSO or DMSO-
d6 was selected to dissolve the complexes and so test the
solution stability of the samples by recording the UV-Vis
Synthesis and chemical characterization
The pyridine thiazolone derivative (L) was prepared by a
cyclization reaction of N-pyridine methylene-thio semi-
carbazide hydrochloride with bromoacetylpyridine hydro-
bromide in ethanol. 1 and 2 were prepared by the reaction
of L with Zn(TsO)2 and Cd(NO3)2 in DMF, respectively,
in a molar ratio of 1:1. Crystals of the complexes are
soluble in DMSO, DMF and slightly soluble in CH3OH.
The infrared absorption bands of the main functional
groups on L and 1–2 are listed in Table 2. Addition-
ally, the band at 3415 cm−1 in compound L might be the
stretching vibration band of O–H due to the hygroscopic-
ity of the sample, whereas 2974 cm−1 was the stretching
vibration band of the C–H bond in the N=C–H group,
and the Schiff base ν(C=N) absorption was observed at
1273 cm−1. In complex 1, the bands at 1445, 1611, and
1567 cm−1 were caused by the skeleton vibration of the
benzene ring, while a series of strong bands located at
1154–1009 cm−1 resulted from the antisymmetric and
symmetric stretching vibrations of the SO3 group in
p-toluene sulfonate. 2 exhibits typical bands at 1384,
825 cm−1, which were assigned to the characteristic
absorption peak of NO3− (Fig. S1).
1
and H NMR spectra at diferent times. The spectra were
recorded immediately after dissolution, as well as after 48 h,
respectively. As the 1H NMR spectra remained unmodifed
during this time period, it could be concluded that the cor-
responding N-pyridine and N-thiazole had remained coordi-
nated to the metal atom and that other coordination reactions
did not occur (Fig. S2). Besides, the shape of the spectra
and the intensity of the absorption maxima (λmax = 255.0,
335.0, 490 nm for complex 1; λmax = 255.0, 355 nm for
complex 2) were invariable in the UV-Vis spectra (Fig. S4).
Furthermore, compared with the spectra of ligand, it was
evident that there were no dissociation of metal ions in the
DMSO solution, and thus no free metal ions were afecting
the biological activity of the complexes. Taken together, the
spectroscopic data demonstrated the sufcient stability of
complexes 1 and 2 in DMSO solution.
Crystal structures of complex 1
The X-ray crystal structure of 1, shown in Fig. 1, reveals a
neutral complex molecule that consists of a zinc(II) atom
and two bidentate L ligands. Complex 1 crystallized in a
monoclinic unit cell, I2/a space group. The zinc(II) atom was
six-coordinated by four nitrogen atoms (Zn1–N1=2.138(2)
Å, Zn1–N2 = 2.114(3) Å, Zn1–N1i = 2.138(2) Å, and
Zn1–N2i = 2.114(3) Å) from the ligand and two oxygen
atoms (Zn1–O1 = 2.164(2) Å and Zn1–O1i = 2.164(2) Å)
from two toluene sulfonic acid anion, respectively. The
presence of a deformed trans-N4O2 octahedral geometry
around the central atom was confrmed by the N1–Zn1–N2
and N1i–Zn1–N2i bite angles which were signifcantly<90°,
whereas the N1–Zn1–N1i and N1–Zn1–O1i angles involving
the O atom were much greater (99.51(15)° and 97.71(14)°,
respectively), and also by the slight difference in bond
The 1H NMR spectra showed one single peak at
12.56 ppm for L, at 12.50 ppm for 1 and 12.94 ppm for
2, which were all then assigned to the –NH proton of the
pyridine hydrazone group (Fig. S2). The signal corre-
sponding to the methyl protons for 1 was observed, which
indicated that a coordination reaction had occurred with a
model of ML2. The 13C–NMR peaks at 168.23 ppm for L,
165.03 ppm for 1, 168.82 ppm for 2 were assigned to the
thiazole carbon (Fig. S3). The signals of the methyl car-
bons of p-toluene sulfonate for 1 were observed between
20.0 and 40.0 ppm in the 13C–NMR spectra, as expected.
Table 2 Infrared absorption bands of the main functional groups on L and 1–2
L
1
2
Stretching vibration band (N–H)
Skeleton vibration band (Pyridine)
3110 cm−1
3096 cm−1
3119 cm−1
1370, 1578, 1537, 1474 cm−1
1579, 1413, 1397, 1385 cm−1
1566, 1601,
1495,
1464 cm−1
Skeleton vibration band (Thiazole)
Stretching vibration band (C-H on Pyridine)
Stretching vibration band (C=N on ring)
1554, 1453, 1422, 1370 cm−1
3058 cm−1
1469, 1348, 1385 cm−1
3068 cm−1
1413, 1368 cm−1
2974 cm−1
1293, 1237 cm−1
1100–400 cm−1
1310, 1241 cm−1
1000–400 cm−1
1288, 1237 cm−1
1100–600 cm−1
In-plane oscillations band (C–H on Pyridine and
thiazole ring)
1 3

268
Transition Metal Chemistry (2021) 46:263–272
Fig. 1 Molecular structure of 1
with the selected atom number-
ing scheme. Displacement
ellipsoids are drawn at the 30%
probability level. H atoms are
omitted for clarity. (Green lines
indicate the H-bonds)
Table 3 Selected bond lengths (Å) and angles [°] for 1
Crystal structures of complex 2
Zn1–O1i
2.164(2)
2.164(2)
2.138(2)
89.20(13)
168.17(9)
168.17(9)
90.34(10)
90.35(10)
92.50(14)
94.48(9)
Zn1–N1
2.138(2)
2.114(3)
2.114(3)
90.14(10)
90.14(10)
94.48(10)
78.11(10)
78.11(10)
97.35(10)
97.35(10)
2.753(5)
Complex 2 crystallized in a monoclinic system with a space
group of P21/n and a six-coordination model of ML. Com-
pared with the discrete 0D monomer structure of 1, complex
2 represents the basic unit of 1D coordination polymer of
{[Cd(L)(NO3)2H2O)]DMF}n (Fig. 2), which is mostly due
to the coordinated anionic and solvent molecule(s). With
the coordination sphere containing three N atoms from the
pyridine thiazole group and three O atoms from two nitrate
ions and one water molecule in the structure of 2, the ligand
molecules act as a bridge, forming a one dimensional wavy
linear chain with cadmium(II) atoms that works as the con-
nection point (Fig. 2b). The cadmium atom occupies the
center of a distorted octahedron geometry which is attributed
to the diference of N1i-Cd1-N5, N1i-Cd1-N2i, N1i-Cd1-O3
and N1i-Cd1-O7 bite angles (98.93(8), 72.25(8), 121.15(7),
86.37(8), respectively) as expected, and also attributed to
the Cd–N bond (Cd1–N1i =2.380(2), Cd1–N5=2.284(2),
Cd1–N2i = 2.302(2)), which is slightly shorter than the
Cd–O bonds (Cd1–O3 = 2.3587(19), Cd1–O4 = 2.435(2),
Cd1–O7 = 2.334(2)) due to the smaller covalent radius of
oxygen. The Cd–O and Cd–N bond lengths are compara-
ble to the corresponding values reported in the cadmium(II)
complexes with pyridine ligand [31–33]. The strong hydro-
gen bonds (N3–H3…O4 = 2.744(5)) meanwhile, were
observed between the NH group and one of the oxygen
atoms of the nitrate ion. Besides, there was one free DMF
molecule in the unit that was not involved in the coordina-
tion system. The selected bond lengths [Å] and angles [°]
were listed in Table 4.
Zn1–O1
Zn1–N2
Zn1–N1i
Zn1–N2i
O1–Zn1–O1i
N1i–Zn1–O1
N1–Zn1–O1i
N1i–Zn1–O1i
N1–Zn1–O1
N1–Zn1–N1i
N2i–Zn1–O1i
N2–Zn1–N2i
N2–Zn1–O1i
N2i–Zn1–O1
N2–Zn1–O1
N2i–Zn1–N1i
N2–Zn1–N1
N2–Zn1–N1i
N2i–Zn1–N1
N3–H3…O1
173.52(14)
Symmetry transformations used to generate equivalent atoms: (i) 0.5–
x, y, 1–z
lengths between the Zn1-O1 and Zn1–N1 bond. Neverthe-
less, the Zn–O and Zn–N bond lengths are comparable to
the corresponding values reported in zinc(II) complexes
with pyridine thiazole group that are found in the Cam-
bridge Structure Database [14, 15, 29, 30]. The ligand is
slightly twisted with an angle of 1.8(5)° between the thia-
zole ring plane and the neighbouring pyridine ring plane,
and the angles of 12.8(11) between the Schif base hydra-
zone plane and the neighbouring pyridine ring plane. The
selected bond lengths and angles for complex 1 are sum-
marized in Table 3. Relatively strong hydrogen bonding
(N3–H3…O1 = 2.753(5)Å) occurs between the NH group
and the coordinated oxygen atoms of the p-toluene sulfonic
acid anion, and two equivalents of DMF molecules fll inter-
stices between the dimer units.
1 3

Transition Metal Chemistry (2021) 46:263–272
269
Fig. 2 a The molecular struc-
ture of 2 with the selected atom
numbering scheme. Displace-
ment ellipsoids are drawn at
the 50% probability level and
solvent molecules are omitted
for clarity. b One-dimensional
chain fgure viewed along the a
axis in 2 (H atoms and solvent
molecules are omitted for
clarity. Green lines indicate the
H-bonds)
Table 4 Selected bond lengths (Å) and angles [°] for 2
DMSO and compared with the known antibiotic cipro-
foxacin. The antibacterial results shown in Table 5 implied
that L had a good specifcity to B. subtilis with MICs of
50 μg/mL−1 and all the compounds showed low antibac-
terial activity against S. typhimurium, V. Parahemolyticus,
and P. aeruginosa. Compared with L, 1 and 2 had wider
broad-spectrum antibacterial properties as well as stronger
antibacterial properties against indicator microorganisms at
varying degrees. These results suggested that the coordina-
tion of metal elements played a key role in the inhibition
of the tested microorganisms. As shown in Tables 6, 2 was
newly shown to have a signifcantly improved inhibitory
efect on Sh. Flexneri with the MIC of 3.13 μg/mL−1 and
further shown to have higher antibacterial activity than the
other compounds against all the tested strains. In addition,
when treated with B. subtilis, 1 demonstrated even more
efective activity than ciprofoxacin with the MIC of 3.13 μg/
mL−1. When comparing the antibacterial activities of the
ligand and complexes, the enhancement of antibacterial
activity in the complexes can be explained on the basis of
Overtone’s concept and Tweedy’s chelation theory [34, 35].
Cd1–O3
2.3587(19)
2.435(2)
2.302(2)
70.96(7)
121.15(7)
93.53(7)
84.35(8)
72.25(8)
91.71(8)
153.73(7)
94.35(7)
Cd1–N1i
Cd1–N5
Cd1–O7
N5–Cd1–O4
N5–Cd1–N2i
N5–Cd1–N1i
N5–Cd1–O7
O7–Cd1–O3
O7–Cd1–O4
O7–Cd1–N1i
N3–H3…O4
2.380(2)
2.284(2)
2.334(2)
103.41(8)
170.41(8)
98.93(8)
83.84(8)
152.25(8)
82.49(8)
86.37(8)
2.744(5)
Cd1–O4
Cd1–N2i
O3–Cd1–O4
O3–Cd1–N1i
N2i–Cd1–O3
N2i–Cd1–O4
N2i–Cd1–N1i
N2i–Cd1–O7
N1i–Cd1–O4
N5–Cd1–O3
Symmetry transformations used to generate equivalent atoms: (i)
0.5+x, 0.5–y, –0.5+z; (ii) –0.5+x, 0.5–y, 0.5+z
Biological activities
In vitro antibacterial screening of the ligand and its metal
complexes (Table 5) was tested against seven pathogenic
bacterium at the concentrations of 3.13–50 μg/mL−1 in
1 3

270
Transition Metal Chemistry (2021) 46:263–272
Table 5 Bactericidal activity screening test levels of the compounds (100 μg/mL)
Compounds
Inhibition ratio/%(Levels b)
E. coli a
S. aureus a
S. typhimurium a
B. subtilis a
Sh. fexneri a
V. Parahemo- P. aeruginosa a
lyticus a
L
1
2
71.3 (++)
101.8 (+++)
100.7 (+++)
76.4 (++)
95.5 (+++)
95.3 (+++)
83.1 (++)
60.5 (+)
31.6 (–)
94.0 (+++)
95.4 (+++)
104.4 (+++)
84.7 (++)
89.5 (++)
104.2 (+++)
54.8 (+)
43.2 (–)
68.4 (+)
70.2 (++)
49.7 (–)
56.6 (–)
Bactericidal activity is revealed by the percentage of complexes against bacterial
a
Escherichia coli (E. coli, ATCC 25922), Staphylococcus aureus (S. aureus, CMCC(B) 26003), Salmonella typhimurium (S. typhimurium,
CMCC(B) 50071), Bacillus subtilis (B. subtilis, ATCC 6633), Shigella fexneri (Sh. fexneri, CMCC(B) 51572), Vibrio Parahemolyticus (V. Para-
hemolyticus, ATCC 17802), Pseudomonas aeruginosa (P. aeruginosa, ATCC 9027)
c Activity levels:+ + ≥90%;++ ≥70–89%;+ ≥50–69%;−<50%
Table 6 MIC (μg/mL) of the
Compounds MIC (μg/mL)
compounds against bacterial
strains
E. coli S.aureus S.typhimurium B.subtilis Sh.fexneri V.Para-
P.aeruginosa
hemolyti-
cus
CIPRO a
12.5
–
6.25
6.25
6.25
–
25
12.5
6.25
50
6.25
3.13
3.13
–
–
3.13
6.25
L
–
–
–
–
–
–
–
–
–
1
2
12.5
3.13
Results are expressed as the minimum inhibitory concentration (MIC)
aCiprofoxacin (CIPRO)
The delocalization of the π-electrons changed the lipophilic-
ity of the complexes which thus favored permeation through
the cell membrane.
coordination with metal ions enhanced the antitumor and
cytotoxicity efect of both complexes 1 and 2, especially
2. However, at a concentration of 12.5 μg/mL, complex 2
showed signifcant antitumor activity with low cytotoxic
efects, which thus implied a promising application pros-
pect. Despite the confrmed increasing antitumor activity,
a detailed molecular mechanism against the cancer cell
lines of the ligand and the complexes remains to be further
explored.
The in vitro antitumor activity of the compounds against
SK-N-SH, HCT-116, AGS, MCF-7 and MRC-5 were meas-
ured by CCK8 assay. As shown in Fig. 3a, compounds L,
1 and 2 showed a dose-dependent inhibitory efect toward
AGS while cisplatin had little efect in its current concentra-
tion. Additionally, the complexation of metal ions enhanced
the anti-human colon cancer cell HCT-116 activity of L,
which was refected by the inhibitory efect of complex 1
in 50 and 100 μg/mL and complex 2 even in 3.125 μg/mL
(Fig. 3b). As for MCF-7, complex 1 and the positive con-
trol cisplatin showed similar antitumor activity, stronger
when compared with L but weaker when compared with 2
(Fig. 3c). All tested compounds reduced the cell viability
of SK-N-SH. Complexes 1 and 2 showed a better inhibi-
tory efect than cisplatin while L did not (Fig. 3d). When
the cytotoxic efects of the compounds were examined,
the results indicated that all the compounds exhibited low
cytotoxicity when the concentration was lower than 25 μg/
mL. The toxicity of complex 2 was signifcantly increased
when the concentration of the compound exceeded 25 μg/
mL, while the toxicity of other compounds was increased
only when reaching 50 or 100 μg/mL (Fig. 3e). Generally,
Conclusions
We have reported the preparation, characterization and
biological activities of a new pyridine thiazolhydrazone
derivative and its transition metal(II) complexes named
[Zn(L)2(TsO)2] (1), [Cd(L)(NO3)2H2O)]DMF) (2). Sin-
gle-crystal X-ray difraction confrmed the geometries of
complexes 1 and 2, showing that 1 featured a mononuclear
molecular structure, while 2 was a one-dimensional chain
structure. The biological activity of the ligands and com-
plexes were tested against seven bacteria strains and four
cancer cell lines. The results showed that complexes coor-
dinated with metal ions had a better antimicrobial and anti-
tumor activity than the corresponding ligand, which might
1 3

Transition Metal Chemistry (2021) 46:263–272
271
Fig. 3 Dose-dependent antitumor efect of the compounds against
human cancer cells. Graphs of cell viability of ligand, the complexes
and cisplatin compounds against AGS (a) HCT-116 (b) MCF-7 (c)
SK-N-SH (d) and MRC-5 (e). Data are presented as mean SEM for
three dependent experiments
provide valuable information for further designing and syn-
thesizing new antimicrobial and antitumor agents.
1 and 2, respectively. These data can be obtained free of
charge via https://www.ccdc.cam.ac.uk/structures/ or the
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: (+44) 1223-336-033; or
e-mail:deposit@ccdc.cam.ac.uk.
Appendix A. Supplementary material
Acknowledgements The authors thank Gong Hongjian from Wuhan
Children’s Hospital for providing SK-N-SH, HCT-116, AGS and
MCF-7 cell line. This work was fnancially supported by Guangzhou
Science and Technology program (201904010381), Youth innovation
Talent project of Guangdong province (2018GkQNCX033), Natural
Science Foundation of Guangdong Industry Polytechnic (KJ2019-024).
Supplementary data associated with this article can be
found in the online version, at http://dx.doi.org/ These data
include MOL fles and InChiKeys of the most important
compounds described in this article. CCDC:1,997,854,
1,997,609 contain supplementary crystallographic data for
1 3

272
Transition Metal Chemistry (2021) 46:263–272
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1 3