Synthesis, crystal structures, and biological activity of zinc(II) complexes derived from 2-amino-1,3,4-thiadiazole derivatives

Article abstract of DOI:10.1080/15533174.2016.1149723

Two new similar zinc(II) complexes, [ZnCl₂L1₂] and [ZnCl₂L2₂], derived from the 2-amino-1,3,4-thiadiazole derivatives, were prepared and structurally characterized by X-ray diffraction. The Zn atom in each complex has a tetrahedral coordination and is coordinated by two N atoms of the ligands and two Cl atoms. The urease inhibitory activities of the complexes and the ligands were evaluated.

Full text of DOI:10.1080/15533174.2016.1149723

Synthesis and Reactivity in Inorganic, Metal-Organic, and
Nano-Metal Chemistry
ISSN: 1553-3174 (Print) 1553-3182 (Online) Journal homepage: http://www.tandfonline.com/loi/lsrt20
Synthesis, Crystal Structures and Biological
Activity of Zinc(II) Complexes Derived from 2-
Amino-1,3,4-thiadiazole derivatives
Hui-Long Zhu, Yu-Wei Liu, Zong-Ming Tang, Fu-Jun Yin, Wei-Wei Liu, Zhi-Ling
Cao, Juan Bao, Meng Li, Ling-Yan Qin & Da-Hua Shi
To cite this article: Hui-Long Zhu, Yu-Wei Liu, Zong-Ming Tang, Fu-Jun Yin, Wei-Wei Liu, Zhi-Ling
Cao, Juan Bao, Meng Li, Ling-Yan Qin & Da-Hua Shi (2016): Synthesis, Crystal Structures and
Biological Activity of Zinc(II) Complexes Derived from 2-Amino-1,3,4-thiadiazole derivatives,
Synthesis and Reactivity in Inorganic, Metal-Organic, and Nano-Metal Chemistry, DOI:
10.1080/15533174.2016.1149723
To link to this article: http://dx.doi.org/10.1080/15533174.2016.1149723
Accepted author version posted online: 07
Jun 2016.
Published online: 07 Jun 2016.
Submit your article to this journal
Article views: 8
View related articles
View Crossmark data
Full Terms & Conditions of access and use can be found at
http://www.tandfonline.com/action/journalInformation?journalCode=lsrt20
Download by: [University of California, San Diego]
Date: 25 June 2016, At: 14:30

ACCEPTED MANUSCRIPT
Synthesis, Crystal Structures and Biological Activity of Zinc(II) Complexes Derived from
2
-Amino-1,3,4-thiadiazole derivatives
a
a,b
a
c
a
Hui-Long Zhu , Yu-Wei Liu , Zong-Ming Tang , Fu-Jun Yin , Wei-Wei Liu , Zhi-Ling
a
a
a
a
a,c,d,
Cao , Juan Bao , Meng Li , Ling-Yan Qin , Da-Hua Shi
a
School of Pharmaceutical Sciences, Huaihai Institute of Technology, Lianyungang 222005,
People’s Republic of China
b
College of Pharmaceutical Sciences, Soochow University, Suzhou 215123, People’s Republic of
China
c
Jiangsu Institute of Marine Resources, Lianyungang 222005, People’s Republic of China
d
Co-Innovation Center of Jiangsu Marine Bio-industry Technology, Lianyungang 222005,
People’s Republic of China
Two new similar zinc(II) complexes, [ZnCl L1 ] and [ZnCl L2 ] derived from the
2
2
2
2
2
-amino-1,3,4-thiadiazole derivatives, were prepared and structurally characterized by
X-ray diffraction. The Zn atom in each complex has a tetrahedral coordination and is
coordinated by two N atoms of the ligands and two Cl atoms. The urease inhibitory
activities of the complexes and the ligands were evaluated.

Author for correspondence. Email:shidahua@hhit.edu.cn
ACCEPTED MANUSCRIPT

ACCEPTED MANUSCRIPT
Keywords 1,3,4-thiadiazole derivatives, crystal structure, zinc, urease inhibition
INTRODUCTION
Inhibition of urease (urea amidohydrolase; E.C.3.5.1.5) which is a nickel-containing
metalloenzyme that catalyzes the hydrolysis of urea to form ammonia and carbon dioxide have
[
1-5]
good effects in medicine and agricuture.
recently. Some 1,3,4-thiadiazoles were also reported to possess urease-inhibition activities.
Following our studies on the urease inhibitors, we synthesized two zinc(II) complexes derived
Many urease inhibitors have been discovered
[6]
[7-8]
from 2-amino-1,3,4-thiadiazole derivatives and tested their urease inhibition-activities.
We
report herein the synthesis, crystal structures, and urease inhibitory activities of the two new
similar zinc(II) complexes.
L1
L2
EXPERIMENTAL
Materials and Methods
2-Chlorophenylacetic acid and 4-nitrophenylacetic acid with AR grade were purchased from
Aladdin Industrial Corporation. Zinc chloride, thiosemicarbazide, phosphorus oxychloride and
solvents were purchased from Sinopharm Chemical Regent Co., Ltd. and were used as received.
ACCEPTED MANUSCRIPT

ACCEPTED MANUSCRIPT
TLC was performed on the glassbacked silica gel sheets (Silica Gel 60 GF254) and visualized in
UV light (254 nm). Melting points were determined on a Yanaco melting point apparatus and
1
were uncorrected. H NMR spectra were recorded on a Bruker Avance 400 M Hz instrument
using MeOD. The spectra MS (EI, 70 eV) were recorded using the apparatus AMD-604.
Synthesis of L1 (5-(2-chlorobenzyl)-1,3,4-thiadiazol-2-amine)
A stirring mixture of 2-Chlorophenylacetic acid 10 g (0.059 mol), thiosemicarbazide 8.03 g
o
（
0.089 mol）and POCl3 21.5 mL (0.24mol) was heated at 75 C for 8 h. After cooling down to
room temperature, 100 mL water was added. The reaction mixture was refluxed for 1 h. After
cooling, the mixture was basified to pH 8-9 by the dropwise addition of 50% NaOH solution
under ice bath. The precipitate was filtered and recrystallized from ethanol to gain 8.2 g white
o
1
solid of L1 (5-(2-chlorobenzyl)-1,3,4-thiadiazol-2-amine), yield 62%, mp: 186~189 C; H
NMR(400MHz, MeOD) δ: 7.48-7.04 (m, 4H), 4.18 (S, 2H); ESI-MS: 226.1 (C H ClN S,
9
8
3
+
[
M+H] ).
Synthesis of L2 (5-(4-nitrobenzyl)-1,3,4-thiadiazol-2-amine)
A stirring mixture of 4-Nitrophenylacetic acid 10 g (0.055 mol), thiosemicarbazide 7.54 g
o
（
0.083 mol）and POCl 20.22 mL（0.22 mol） was heated at 75 C for 8 h. After cooling down
3
to room temperature, 100 mL water was added. The reaction mixture was refluxed for 1 h. After
ACCEPTED MANUSCRIPT

ACCEPTED MANUSCRIPT
cooling, the mixture was basified to pH 8-9 by the dropwise addition of 50% NaOH solution
under ice bath. The precipitate was filtered and recrystallized from ethanol to gain 12.4 g light
1
yellow solid of L2 (5-(4-nitrobenzyl)-1,3,4-thiadiazol-2-amine), yield 96%, mp: 188~190℃; H
NMR (400 MHz, MeOD) δ 8.21 (d, J = 8.8 Hz, 2H), 7.54 (d, J = 8.7 Hz, 2H), 4.34 (s, 2H);
+
ESI-MS: 237.1 (C H N O S, [M+H] ).
9
8
4
2
Synthesis of [ZnCl L1 ] (1)
2
2
The L1 (0.1 mmol, 22.5 mg) and ZnCl (0.1 mmol, 13.4 mg) were mixed and stirred in
2
methanol (15 mL) for 30 min at room temperature. The mixture was filtered and the white
block-shaped crystals of 1, suitable for X-ray diffraction, were formed on slow evaporation of
the filtrate in air. Yield: 34%.
Synthesis of [ZnCl L2 ] (2)
2
2
The L2 (0.1 mmol, 23.6 mg) and ZnCl (0.1 mmol, 13.4 mg) were mixed and stirred in
2
methanol (15 mL) for 30 min at room temperature. The mixture was filtered and the yellow
acicular crystals of 2, suitable for X-ray diffraction, were formed on slow evaporation of the
filtrate in air. Yield: 42%.
X-ray Crystallography
ACCEPTED MANUSCRIPT

ACCEPTED MANUSCRIPT
Diffraction intensities for the complexes were collected at 296(2) K using a Bruker SMART
APEX-II CCD area-detector with MoK radiation ( = 0.71073 Å). The collected data was
[
9]
reduced with the SAINT program, and multi-scan absorption corrections were performed using
[
10]
the SADABS program. Both structures were solved by direct methods. The complexes were
2
[11]
refined against F by full-matrix least-squares methods using the SHELXTL package. All of
the non-hydrogen atoms were refined anisotropically. Hydrogen atoms were placed in calculated
positions and constrained to ride on their parent atoms. The crystallographic data for the
complexes was summarized in Table 1. Selected bond lengths and angles were given in Table 2.
Crystallographic data for the complexes has been deposited with the Cambridge Crystallographic
Data Center (CCDC 1061717 for 1 and 1061718 for 2).
Urease Inhibition Assay
The measurement of urease inhibitory activities was carried out according to the method
[
12]
reported by Tanaka. Generally, the assay mixture, containing 25 μL of jack bean urease (10
kU/L) and 25 μL of the tested complexes of various concentrations (dissolved in the solution of
DMSO:H O = 1:1 (v/v)), was preincubated for 1 h at 37 ºC in a 96-well assay plate. Then 0.2 mL
2
of 100 mM Hepes [N-(2-hydroxyethyl)piperazine-N’-(2-ethanesulfonic acid)] buffer at pH 6.8
[
13]
containing 500 mM urea and 0.002% phenol red were added and incubated at 37 ºC.
The
reaction time, which was required to produce enough ammonium carbonate to raise the pH of a
ACCEPTED MANUSCRIPT

ACCEPTED MANUSCRIPT
Hepes buffer from 6.8 to 7.7, was measured by a micro-plate reader (570 nm) with the end-point
being determined by the color of phenol red indicator. The acetohydroxamic acid was used as the
standard reference. All the tests were carried out for three times.
RESULTS AND DISCUSSION
The 2-amino-1,3,4-thiadiazole derivatives (L1 and L2) were synthesized from the
corresponding phenylacetic acid derivatives with good yields. These compounds were soluble in
methanol, ethanol but not water. The zinc (II) complexes were prepared according to the same
synthetic procedures. The three crystals were stable in air at room temperature, and were soluble
in DMSO:H O = 1:1 (v/v).
2
Structures of the Complexes
Figures 1 and 2 give perspective views of complexes 1 and 2, respectively. Both complexes
are mononuclear zinc compounds. The crystal of 1 is monoclinic: space group C2/c, a = 22.035
3
(
3), b = 9.7671 (12), c = 12.1156 (14) Å, β = 100.0890 (10)°, V = 2567.1 (5) Å , Z = 22. The
crystal of 2 is monoclinic: space group C2/c, a = 11.5768 (12), b = 15.7252 (16), c = 13.4018
3
(
14), β = 93.2980 (10)°, V = 2438.8 (4) Å , Z = 18. The Zn atom in each complex has a
tetrahedral coordination and is coordinated by two N atoms of the ligand and two Cl atoms. The
tetrahedral coordinations are distorted, as evidenced by the bond angles ranging from 106.8(2) to
115.39(8)° for 1 and from 96.23(9) to 112.88(3)° for 2. The coordinate bond lengths in both
ACCEPTED MANUSCRIPT

ACCEPTED MANUSCRIPT
complexes are comparable to each other and also comparable to those observed in other similar
[
14]
zinc complexes.
The molecular packing diagrams for 1 and 2 are shown in figures 3 and 4, respectively. In 1,
the complex molecules are linked through the intermolecular N–H···N hydrogen bonds. In 2, the
molecules are linked through intermolecular N–H···Cl hydrogen bonds, forming chains running
along the y axis.
Urease Inhibitory Activities
-1
The urease inhibitory activities with 100 μg ml of the complexes, the ligands, ZnCl , and
2
the standard reference acetohydroxamic acid were summarized in Table 3. It can be seen that the
ligand L1 showed weak urease-inhibition activity with 4.30% inhibition rate at the concentration
-1
of 100 μg ml and ligand L2 showed no urease-inhibition activity. The two complexes possessed
better urease-inhibition activities than the ligands with the inhibition-rate of 14.31% and 17.8%,
respectively. The urease inhibitory activities of the two complexes were stronger than that of the
starting ligands and ZnCl , but much weaker than that of the reference. According to the
2
urease-inhibition activities of the complexes, we conculed that some organic ligands without the
enzyme-inhibition activities could possess enzyme inhibitory activities after forming metal
complexes with some metal salts. The complexes could be the leading compounds for the
development of novel enzyme inhibitors for the treatment of diseases.
ACCEPTED MANUSCRIPT

ACCEPTED MANUSCRIPT
Acknowledgements
The financial support of the Science and Technology Project of Lianyungang (CG1202),
Collegiate Natural Science Fund of Jiangsu Province (12KJB350001, 13KJB150006) and
Natural Science Foundation of Jiangsu Province (BK20141246) and A Project Funded by the
Priority Academic Program Development of Jiangsu Higher Education Institutions are gratefully
acknowledged.
REFERENCES
[
1] Karplus, P. A., Pearson, M. A., and Hausinger, R. P. 70 Years of crystalline urease: What have
we learned? Acc. Chem. Res., 1997, 30, 330-337.
2] Sumner, J. B. The isolation and crystallization of the enzyme urease. J. Biol. Chem., 1926, 69,
35-441.
3] Zonia, L. E., Stebbins, N. E., and Polacco, J. C. Essential role of urease in germination of
nitrogen-limited arabidopsis thaliana seeds. Plant Physiol., 1995, 107, 1097-1103.
4] Collins, C. M., and Dorazio, S. E. F. Bacterial ureases: Structure, regulation of expression
and role in pathogenesis. Mol. Microbiol., 1993, 9, 907-913.
5] Montecucco, C., and Rappuoli, R. Living dangerously: how Helicobacter pylori survives in
the human stomach. Nat. Rev. Mol. Cell Biol., 2001, 2, 457-466.
[
4
[
[
[
[
6] Khan, I., Ali, S.; Hameed, S., Rama, N. H., Hussain, M. T., Wadood, A., Uddin, R., Ul-Haq,
ACCEPTED MANUSCRIPT

ACCEPTED MANUSCRIPT
Z., Khan, A., Ali, S., Choudhary, M. I. Synthesis, antioxidant activities and urease inhibition of
some new 1,2,4-triazole and 1,3,4-thiadiazole derivatives. Eur. J. Med. Chem. 2010, 45,
5
200-5207.
7] Shi, D.-H., You, Z.-L., Xu, C., Zhang, Q., and Zhu, H.-L. Synthesis, crystal structure and
urease inhibitory activities of Schiff base metal complexes. Inorg. Chem. Commun., 2007, 10,
04-406.
8] Shi, D.-H., Zhang, L., Ni, L.-L., Bai, S., and You, Z.-L. Synthesis, crystal structures, and
[
4
[
urease inhibitory activities of two isostructural Schiff base cadmium(II) complexes. Synth. React.
Inorg. Met.-Org. Nano-Met. Chem., 2010, 40, 359-363.
[
9] Bruker, SMART (Version 5.628) and SAINT (Version 6.02); Bruker AXS Inc: Madison, WI,
998.
10] Sheldrick, G. M. SADABS. Program for Empirical Absorption Correction of Area Detector;
University of G¨ottingen: G¨ottingen, Germany, 1996.
11] Sheldrick, G. M. SHELXTL V5.1. Software Reference Manual; Bruker AXS: Madison, WI.
997.
12] Tanaka, T., Kawase, M., and Tani, S. Urease activity of simple α,β-unsaturated ketones. Life
Sci., 2003, 73, 2985-2990.
13] Zaborska, W., Krajewska, B., and Olech, Z. Heavy metal ions inhibition of jack bean urease:
1
[
[
1
[
[
Potential for rapid contaminant probing. J. Enzyme Inhib. Med. Chem., 2004, 19, 65-69.
ACCEPTED MANUSCRIPT

ACCEPTED MANUSCRIPT
[
14]
Wang,
B.,
Wan,
R.,
Yin,
L.-H.,
Han,
F.
and
Wang,
J.-T.
Dichloridobis(5-m-tolyl-1,3,4-thiadiazol-2-ylamine-κN3)zinc(II). Acta. Cryst., 2008, E64,
m692–m693.
ACCEPTED MANUSCRIPT

ACCEPTED MANUSCRIPT
TABLE 1
Crystallographic data for the complexes
Complex
Formula
1
2
C H N S Cl Zn C H N O S Cl Zn
18
16
6
2
4
18 16
8
4
2
2
FW
587.68
block/white
0.25 × 0.21 × 0.18 0.25 × 0.22 × 0.18
608.8
Crystal shape/colour
Crystal size (mm)
T (K)
acicular /yellow
296(2)
0.71073
monoclinic
C2/c
296(2)
λ (MoKα) (Å)
Crystal system
Space group
a (Å)
0.71073
monoclinic
C2/c
22.035(3)
9.7671(12)
12.1156(14)
90
11.5768(12)
15.7252(16)
13.4018(14)
90
b (Å)
c (Å)
α (º)


(º)
(º)
100.0890(10)
90
92.2980(10)
90
3
V (Å )
2567.1(5)
22
2437.8(4)
18
Z
–
1

(MoKα) (cm )
1.554
1.441
Tmin
Tmax
0.6974
0.7673
1.521
0.7146
0.7814
–
3
D (g cm )
c
1.659
Measured reflections
6525
6506
Unique reflections and 2475 and 0.0170
2394 and 0.0162
ACCEPTED MANUSCRIPT

ACCEPTED MANUSCRIPT
Rint
Observed reflections
2130
2162
data/restraints/paramet 2475/0/141
2394/0/159
ers
2
Goodness of fit on F
R1 [I  2(I)]
1.075
1.039
0.0608
0.1659
0.0695
0.1769
0.0263
wR [I  2(I)]
0.0696
2
R1 (all data)
0.0300
wR (all data)
0.0719
2
Large diff. peak and 2.092, -0.398
0.269, -0.189
–
3
hole (e Å )
TABLE 2
Selected bond lengths (Å) and angles (º) for the complexes
1
Bond lengths
Zn(1)-N(2)
2.038(3)
2.038(3)
Zn(1)-Cl(2)
Zn(1)-Cl(2)
2.2292(12)
2.2292(12)
#
1
#1
Zn(1)-N(2)
Bond angles
#
1
N(2)-Zn(1)-N(2)
106.8(2)
N(2)-Zn(1)-Cl(2)
109.23(10)
107.94(10)
115.39(8)
#
1
#1
N(2)-Zn(1)-Cl(2)
107.94(10)
109.23(10)
N(2) -Zn(1)-Cl(2)
#
1
#1
N(2)#1-Zn(1)-Cl(2)
Cl(2) -Zn(1)-Cl(2)
2
Bond lengths
#
1
Zn(1)-N(3)
2.0315(15)
Zn(1)-N(3)
2.0315(15)
ACCEPTED MANUSCRIPT

ACCEPTED MANUSCRIPT
#
1
Zn(1)-Cl(1)
2.2220(6)
Zn(1)-Cl(1)
2.2220(6)
Bond angles
#
1
#1
#1
N(3) -Zn(1)-N(3)
96.23(9)
111.57(5)
111.75(5)
N(3) -Zn(1)-Cl(1)
111.75(5)
111.57(5)
112.88(3)
#
1
#1
N(3)-Zn(1)-Cl(1)
N(3)-Zn(1)-Cl(1)
N(3) -Zn(1)-Cl(1)
#
1
Cl(1) -Zn(1)-Cl(1)
TABLE 3
Inhibitory activities of urease
a
Tested material
Inhibition rate , %
14.31 ± 1.26
17.80 ± 0.62
4.30 ± 1.23
1
2
L1
b
L2
—
ZnCl2
9.13 ± 1.50
Acetohydroxamic acid
92.34 ± 2.72
a
-1 b
the concentration is 100 μg ml . no urease-inhibition activity
ACCEPTED MANUSCRIPT

ACCEPTED MANUSCRIPT
FIG. 1. Molecular structure of 1 at 30% probability ellipsoids.
ACCEPTED MANUSCRIPT

ACCEPTED MANUSCRIPT
FIG. 2. Molecular structure of 2 at 30% probability ellipsoids.
ACCEPTED MANUSCRIPT

ACCEPTED MANUSCRIPT
FIG. 3. Molecular packing of 1. Hydrogen bonds are shown as dashed lines.
ACCEPTED MANUSCRIPT

ACCEPTED MANUSCRIPT
FIG. 4. Molecular packing of 2. Hydrogen bonds are shown as dashed lines.
ACCEPTED MANUSCRIPT