Homobimetallic zinc(II) dithiocarbamates: Synthesis, characterization and in vivo antihyperglycemic activity

Article abstract of DOI:10.1080/00958972.2015.1136737

This article presents structural characteristic and in vivo antihyperglycemic activities of three new homobimetallic Zn(II) dithiocarbamates (1-3) with general formula [ZnL₂]₂, where L is 4-(3-methoxyphenyl)piperazine-1-carbodithioat

Full text of DOI:10.1080/00958972.2015.1136737

Journal of Coordination Chemistry
ISSN: 0095-8972 (Print) 1029-0389 (Online) Journal homepage: http://www.tandfonline.com/loi/gcoo20
Homobimetallic zinc(II) dithiocarbamates:
synthesis, characterization and in vivo
antihyperglycemic activity
Zia-ur-Rehman, Shaista Ibrahim, Azam Khan, Muhammad Imran,
Muhammad Moazzam Naseer, Imran Khan, Afzal Shah, Muhammad Nawaz
Tahir, Muneeb-ur-Rahman & Iqra Zubair Awan
To cite this article: Zia-ur-Rehman, Shaista Ibrahim, Azam Khan, Muhammad Imran,
Muhammad Moazzam Naseer, Imran Khan, Afzal Shah, Muhammad Nawaz Tahir, Muneeb-
ur-Rahman & Iqra Zubair Awan (2016): Homobimetallic zinc(II) dithiocarbamates: synthesis,
characterization and in vivo antihyperglycemic activity, Journal of Coordination Chemistry, DOI:
10.1080/00958972.2015.1136737
To link to this article: http://dx.doi.org/10.1080/00958972.2015.1136737
Accepted author version posted online: 01
Jan 2016.
Published online: 05 Feb 2016.
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Date: 11 February 2016, At: 04:47

Journal of Coordination Chemistry, 2016
ꢁꢁp://ꢂx.ꢂꢃꢄ.ꢃꢅg/10.1080/00958972.2015.1136737
ꢀ
Homobimetallic zinc(II) dithiocarbamates: synthesis,
characterization and in vivo antihyperglycemic activity
a
a
a
a
Zia-ur-Rehman , Shaista Ibrahim , Azam Khan , Muhammad Imran ,
a
b
a
c
Muhammad Moazzam Naseer , Imran Khan , Afzal Shah , Muhammad Nawaz Tahir
Muneeb-ur-Rahman and Iqra Zubair Awan
d
e
ꢆ
b
dꢇpꢆꢅꢁꢈꢇꢉꢁ ꢃꢊ Cꢀꢇꢈꢄꢋꢁꢅꢌ, Qꢍꢆꢄꢂ-ꢄ-azꢆꢈ uꢉꢄvꢇꢅꢋꢄꢁꢌ, iꢋꢎꢆꢈꢆbꢆꢂ, Pꢆkꢄꢋꢁꢆꢉ; dꢇpꢆꢅꢁꢈꢇꢉꢁ ꢃꢊ Bꢄꢃꢁꢇcꢀꢉꢃꢎꢃgꢌ, Qꢍꢆꢄꢂ-ꢄ-
c
azꢆꢈ uꢉꢄvꢇꢅꢋꢄꢁꢌ, iꢋꢎꢆꢈꢆbꢆꢂ, Pꢆkꢄꢋꢁꢆꢉ; dꢇpꢆꢅꢁꢈꢇꢉꢁ ꢃꢊ Pꢀꢌꢋꢄcꢋ, uꢉꢄvꢇꢅꢋꢄꢁꢌ ꢃꢊ sꢆꢅgꢃꢂꢀꢆ, sꢆꢅgꢃꢂꢀꢆ, Pꢆkꢄꢋꢁꢆꢉ;
ꢂ
ꢇ
dꢇpꢆꢅꢁꢈꢇꢉꢁ ꢃꢊ Pꢀꢌꢋꢄcꢋ, iꢋꢎꢆꢈꢄꢆ Cꢃꢎꢎꢇgꢇ, Pꢇꢋꢀꢆwꢆꢅ, Pꢆkꢄꢋꢁꢆꢉ; dꢇpꢆꢅꢁꢈꢇꢉꢁ ꢃꢊ Cꢀꢇꢈꢄꢋꢁꢅꢌ, lꢆꢀꢃꢅꢇ Cꢃꢎꢎꢇgꢇ ꢊꢃꢅ Wꢃꢈꢇꢉ
uꢉꢄvꢇꢅꢋꢄꢁꢌ, lꢆꢀꢃꢅꢇ, Pꢆkꢄꢋꢁꢆꢉ
ABSTRACT
ARTICLE HISTORY
rꢇcꢇꢄvꢇꢂ 7 mꢆꢌ 2015
accꢇpꢁꢇꢂ 19 nꢃvꢇꢈbꢇꢅ 2015
This article presents structural characteristic and in vivo antihyperglycemic
activities of three new homobimetallic Zn(II) dithiocarbamates (1–3) with
general formula [ZnL ] , where L is 4-(3-methoxyphenyl)piperazine-1-
2
2
KEYWORDS
carbodithioate (1), 4-(4-methoxyphenyl)piperazine-1-carbodithioate (2)
hꢃꢈꢃbꢄꢈꢇꢁꢆꢎꢎꢄc; Zꢉ(ii)
ꢂꢄꢁꢀꢄꢃcꢆꢅbꢆꢈꢆꢁꢇ;
ꢋꢍpꢅꢆꢈꢃꢎꢇcꢍꢎꢆꢅ;
ꢆꢉꢁꢄꢀꢌpꢇꢅgꢎꢌcꢇꢈꢄc ꢆcꢁꢄvꢄꢁꢌ;
in vivo
and 4-benzhydrylpiperazine-1-carbodithiaoate (3). These complexes have
1
been characterized by elemental analysis, FT-IR, multinuclear NMR ( H and
1
3
C), and X-ray single crystal analysis. The latter technique has confirmed the
homobimetallic nature of 1 and 2 in which Zn ions are linked via sulfurs to
form a four-membered ring Zn S . Non-covalent intermolecular interactions
2
2
give a supramolecular ladder-like zigzag chain (1) and layered structure (2).
The antihyperglycemic activities revealed that the blood glucose lowering
−
1
−1
ability follows the trend: glibenclamide (83.0 mg dL ) > 3 (97.6 mg dL ) > 2
−
1
−1
(100.4 mg dL ) > 1 (141.4 mg dL ).
CONTACT Zꢄꢆ-ꢍꢅ-rꢇꢀꢈꢆꢉ
zꢅꢇꢀꢈꢆꢉ@qꢆꢍ.ꢇꢂꢍ.pk
©
2016 tꢆꢌꢎꢃꢅ & fꢅꢆꢉcꢄꢋ

2
ZIAꢀURꢀRꢁHMAN ꢁT AL.
1. Introduction
Material properties are frequently governed by the way in which their constituent molecules are assem-
bled [1]. Therefore, understanding molecular packing is essential in crystal engineering and structural
chemistry to deliberately engineer molecules for desired properties and functions. However, predetermi-
nation of molecular packing and self-assembly processes is a challenge, as knowledge of intermolecular
forces that hold molecules in the solid state is still inadequate [2]. The role of weak interactions such
as CH⋯O, CH⋯N, and CH⋯π [3–5], where C–H is a hydrogen bond donor, as a directing tool in the
organization of molecules has been recognized in both chemistry and biology, and applied in crystal
engineering [6] and supramolecular self-assemblies [7]. CH⋯π interactions may be the weakest of the
hydrogen bonds that occur between a soft acid CH and a soft base π-system [8], but has been found
to play an important role in the physical, chemical, and biological properties of a variety of substances.
For such interactions to occur, the hydrogen may be slightly offset outside the phenyl ring plane as it is
not a necessary condition for the hydrogen to be positioned directly above the phenyl ring plane [9].
The number of diabetic patients increases day by day. Diabetes mellitus is a chronic metabolic
disorder associated with absolute or relative deficiency in insulin secretion from the beta cells of the
pancreas and/or desensitization of insulin receptors (American Diabetes Association, 2010). Diabetic
cadavers show 50% decrease in pancreatic Zn concentration as compared to non-diabetic cadavers,
which suggests a strong relationship between pancreatic Zn concentration and diabetes [10]. The insu-
linomimetic activity of Zn ion was first reported in 1980 by Coulston and Dandona [11]. Zn is essential
in β cells for the biosynthesis of insulin and also for the maturation of insulin secretory granules [12].
Studies on animal models and clinical reports also support the idea that in diabetic condition, deficiency
of Zn occurs, and the diabetes-induced Zn deficiency can be restored via supplementation of Zn [13,
1
4]. After this discovery, a wide variety of Zn complexes with different coordination environments
around Zn was synthesized and studied for their antidiabetic activities in vitro and in vivo [15, 16]. The
most important advancement in this context was designing various ligands to reduce the toxicity, and
improve stability and absorption ability of Zn compounds [17, 18]. Yoshikawa et al. have found orally
active Zn(II), dithiocarbamates, bis(dimethyldithiocarbamato)zinc(II), bis(diethyldithiocarbamato)zinc(II),
bis(N-ethyl-N-phenyldithiocarbamato)zinc(II), and bis(pyrrolidine-N-dithiocarbamate)zinc(II) that can
be used at low doses for the treatment of DM [19]. Metal dithiocarbamates have been used as single
source precursors for preparation of thin films or nanoparticles for harvesting solar energy [20].
We have synthesized zinc(II) dithiocarbamates having functionalities capable of participating in
aforementioned weak hydrogen bonds to generate fascinating supramolecular architectures, and
screened them for their in vivo antihyperglycemic activity.
2. Experimental
2
.1. Materials and methods
Chemicals used in the synthetic work were of high purity. Analytical grade zinc(II) nitrate hexahy-
drate and piperazine derivatives were purchased from Fluka and Sigma–Aldrich chemical companies,
respectively. CS was obtained from Reidel-de-Haen. Solvents such as methanol and diethyl ether were
2
purchased from ꢁ-Merk, and DMSO from Fluka.
Melting point was determined in a capillary tube using an electrothermal melting point apparatus
model MP-D Mitamura Riken Kogyo (Japan). Infrared spectra were recorded on a Perkin ꢁlmer spectrum
−1 1
1
000 (USA) from 4000 to 200 cm . H NMR spectral analysis was carried out in DMSO using a Bruker
Avance 300 MHZ NMR instrument.
2
.2. Synthesis of ligand salts and complexes 1–3
To a methanolic solution of substituted piperazine, an equimolar amount of aqueous sodium hydroxide was
added with continuous stirring for 1 hour, followed by dropwise addition of a methanolic solution of CS2

JOURNAL OF COORDINATION CHꢁMISTRY
3
at 0 °C. The reaction mixture was further stirred for 4 h. The precipitates thus obtained were washed with
diethyl ether and dried under an IR lamp.The corresponding ligand salt in methanol was treated with aque-
ous zinc(II) nitrate hexahydrate in 2 : 1 ratios. The reaction mixture was stirred for 4 h at room temperature
(scheme 1). The precipitates were filtered off, washed with cold distilled water, and dried under an IR lamp.
These complexes were recrystallized from DMSO (1 and 2) and CHCl :CH OH mixture (3).
3
3
Compound 1: (Yield: 74%). M.p. 250–251 °C. Anal. Calcd (Found) for C H N O S Zn : C, 48.03 (47.99);
4
8
60
8
4
8
2
−1
1
H, 5.04 (5.06); N, 9.33 (9.31); S, 21.37 (21.34) %. IR (cm ): 385 ν(Zn-S), 1010 ν(C–S), 1496 ν(C–N). H NMR
ppm): 3.73 (s, 12H, methoxy), 6.39–7.16 (m, 16H, phenyl), 3.25, 4.16 (t, 32H, piperazine). C NMR (ppm):
1
3
(
5
5.3 (methoxy), 160.6, 105.0, 130.2, 108.6, 151.9, 102.2 (phenyl), 50.9, 48.2 (piperazine), 203.9 (CS2).
Compound 2: (Yield: 77%). M.p. 290–291 °C. Anal. Calcd (Found) for C H N O S Zn : C, 48.03 (47.97);
4
8
60
8
4
8
2
−1
1
H, 5.04 (5.05); N, 9.33 (9.32); S, 21.37 (21.32) %. IR (cm ): 369 ν(Zn-S), 1015 ν(C–S), 1497 ν(C–N). H NMR
ppm): 3.80 (s, 12H, methoxy), 6.61–7.20 (m, 16H, phenyl), 3.55,4.19 (t, 32H, piperazine). C NMR (ppm):
13
(
5
5.7 (methoxy), 161.6, 145.7, 115.6, 115.3 (phenyl), 52.7, 49.1 (piperazine), 202.7 (SCS).
Compound 3: (Yield: 79%). M.p. 201–202 °C. Anal. Calcd (Found) for C H N S Zn : C, 60.02 (59.98);
7
2
76
8
8
2
−1
1
H, 5.32 (5.35); N, 7.78 (7.77); S, 17.80 (17.77) %. IR (cm ): 375 ν(Zn-S), 1003 ν(C–S), 1489 ν(C–N). H NMR
ppm): 4.29 (s, 4H, CH), 7.19–7.44 (m, 40H, phenyl), 2.53, 4.11 (t, 32H, piperazine). C NMR (ppm): 75
CH), 51.3, 51.2 (piperazine), 128.7, 127.8, 127.3, 141.7 (phenyl), 202.2 (SCS) (scheme 1).
1
3
(
(
2
.3. X-ray crystallography and data collection
The X-ray single crystal analysis was done on a Bruker Kappa APꢁX-II CCD diffractometer having a CCD
detector set at 40.0 mm from the crystal. From a sealed ceramic diffraction tube (SIꢁMꢁNS) having
graphite monochromated Mo-Kα radiation, different intensities were determined. Then using Patterson
2
and DIRDIF method, the structure was solved. Further refinement on F was carried out by full matrix
least squares using SHꢁLXL-97.
2
.4. Antihyperglycemic activity
.4.1. Animals used
2
A total of 15 pairs of rabbits having an average weight of 1.24 kg of about 6–7 months of age were
purchased from the local market of Chakdara. Before starting experiments, the rabbits were kept
Scheme 1. sꢌꢉꢁꢀꢇꢋꢄꢋ ꢃꢊ ꢎꢄgꢆꢉꢂ ꢋꢆꢎꢁꢋ ꢆꢉꢂ 1–3.

4
ZIAꢀURꢀRꢁHMAN ꢁT AL.
for acclimatization for two months in a well-ventilated BioPark at the Department of Biotechnology,
University of Malakand. The rabbits were allowed green vegetables, tap water, and libitum.
2
.4.2. Acute toxicity studies
In this study, eight pairs of rabbits were used. The rabbits were divided into four groups, each containing
four rabbits. ꢁach group received orally a dose of 2500 μg/kg.b.w of the respective compounds. The
animals were observed for 14 days for mortality, neurological, behavioral, and autonomic responses.
At the end of the second week, no death occurred and also no change in neurological, behavioral, and
autonomic responses was observed. Hence, it was clear from the experiment that the compounds
were safe at the dose of 2500 μg/kg.b.w. In the present study, a dose of 1000 μg/kg.b.w was selected.
2
.4.3. Oral glucose tolerance test
Rabbits were kept in overnight fasting for about 8 h to estimate pretreatment (0 h) blood glucose level.
Rabbits were divided into five groups, each group containing five rabbits. ꢁach group received a dose
of 1000 μg/kg b.w in 7% of DMSO of the respective compounds by esophageal catheter. The negative
control group was administered 7% of DMSO in distilled water. The last positive control group was orally
administered a dose of 300 μg/kg b.w of glibenclamide. After 30 min of compound administration,
homogeneous solution of glucose 2 g/kg b.w was administered to each group of rabbits. Blood glucose
was measured after 0, 1/2, 1, 2, and 3 h by one drop electronic Glucometer (Accu Check, Germany).
The result obtained was statistically analyzed using SPSS Ver. 17 (SPSS Inc., Chicago, USA). The mean
values were compared using Duncan’s Multiple Range Test. The percent increase or decrease in param-
eters of compound treated group from normal control was estimated by the following formula:
Percent change = A − B∕B × 100
where A = value of compounds and B = value of control.
Table 1. rꢇfiꢉꢇꢈꢇꢉꢁ pꢆꢅꢆꢈꢇꢁꢇꢅꢋ ꢃꢊ 1 ꢆꢉꢂ 2.
Crystal data
1
2
Cꢀꢇꢈꢄcꢆꢎ ꢊꢃꢅꢈꢍꢎꢆ
Cꢅꢌꢋꢁꢆꢎ ꢋꢄzꢇ (ꢈꢈ )
fꢃꢅꢈꢍꢎꢆ wꢇꢄgꢀꢁ (g ꢈꢃꢎ )
C h n o s Zꢉ
0.35 × 0.2 × 0.12
600.13
C h n o s Zꢉ
0.35 × 0.2 × 0.12
1200.26
4
8
60
8
4
8
2
48 60
8
4
8
2
3
−1
Cꢅꢌꢋꢁꢆꢎ ꢋꢌꢋꢁꢇꢈ
spꢆcꢇ gꢅꢃꢍp
T (K)
Wꢆvꢇꢎꢇꢉgꢁꢀ (Å)
Cꢇꢎꢎ pꢆꢅꢆꢈꢇꢁꢇꢅꢋ
a (Å)
b (Å)
c (Å)
α (°)
β (°)
mꢃꢉꢃcꢎꢄꢉꢄc
mꢃꢉꢃcꢎꢄꢉꢄc
P2 /c
P2 /c
1
1
296(2)
0.71073
296(2)
0.71073
11.4918(4)
8.4640(3)
27.9084(9)
90.00
98.325(2)
90.00
2685.95(16)
4
1.255
14.892(2)
14.3674(16)
12.3605(16)
90.00
94.859(5)
90.00
2635.2(6)
2
1.279
γ (°)
3
V (Å )
Z
−1
abꢋꢃꢅpꢁꢄꢃꢉ cꢃꢇfficꢄꢇꢉꢁ (ꢈꢈ )
F (0 0 0)
dꢆꢁꢆ cꢃꢎꢎꢇcꢁꢄꢃꢉ
1248.0
1248
2
Θ ꢅꢆꢉgꢇ ꢊꢃꢅ ꢂꢆꢁꢆ cꢃꢎꢎꢇcꢁꢄꢃꢉ
4.3 ꢁꢃ 56.66°
22,112
2.74 ꢁꢃ 52°
20,480
nꢍꢈbꢇꢅ ꢃꢊ cꢃꢎꢎꢇcꢁꢇꢂ ꢅꢇflꢇcꢁꢄꢃꢉꢋ
nꢍꢈbꢇꢅ ꢃꢊ ꢄꢉꢂꢇpꢇꢉꢂꢇꢉꢁ ꢅꢇflꢇcꢁꢄꢃꢉꢋ
Gꢃꢃꢂꢉꢇꢋꢋ-ꢃꢊ-fiꢁ ꢃꢉ F
fꢄꢉꢆꢎ R ꢄꢉꢂꢇxꢇꢋ [I ≥ 2σ (I)]
6580
0.994
5174
1.020
2
R = 0.0458, wR = 0.0773
R = 0.0408, wR = 0.0893
1
2
1
2

JOURNAL OF COORDINATION CHꢁMISTRY
5
3
. Results and discussion
.1. Spectroscopic characterization
In FT-IR spectra of complexes, an absorption at 369–385 cm−1 can be attributed to Zn–S stretching
3
−1
vibration [21]. The band due to C–N stretch was observed at 1489–1497 cm , in agreement with par-
tial double bond character in the C–N bond. The appearance of a single unsplit peak near 1000 cm−
indicated bidentate coordination of dithiocarbamate [21].
1
1
In H NMR spectra of 1–3, multiplets for phenyl protons were at 6.39–7.44 ppm, whereas methyl,
methylene, and methine protons showed singlets at 3.73, 3.79, and 5.28 ppm, respectively. Two triplets
1
3
were observed for piperazine protons. C NMR showed an upfield shift of CS from 211 ppm (in ligand)
2
to 202 ppm (in complexes), confirming synthesis [22]. This upfield shift is due to mobilization of nitrogen
lone pair upon coordination of sulfur, and concomitantly deshielding of NCSS carbon.
Table 2. sꢇꢎꢇcꢁꢇꢂ bꢃꢉꢂ ꢎꢇꢉgꢁꢀꢋ (Å) ꢆꢉꢂ ꢆꢉgꢎꢇꢋ (°) ꢃꢊ 1 ꢆꢉꢂ 2.
Bond length (Å)
Bond angle (°)
Type of bond
1
2
Type of bond
1
2
Zꢉ1–s1
Zꢉ1–s2
Zꢉ1–s3
2.4442(7)
2.3524(7)
2.3802(8)
2.8134(7)
2.3616(8)
1.719(2)
1.727(2)
1.329(3)
1.744(3)
–
2.3335(10)
2.4628(9)
2.3537(9)
–
2.3172(9)
1.726(3)
1.717(3)
1.316(4)
1.735(3)
1.718(3)
–
s1–Zꢉ1–s31
s2–Zꢉ1–s1
153.94(3)
75.38(2)
91.63(2)
117.87(3)
136.75(3)
114.64(3)
91.37(2)
104.78(3)
101.60(3)
69.32(2)
–
–
75.77(3)
1
s2–Zꢉ1–s3
–
1
Zꢉ1–s3
s2–Zꢉ1–s3
s2–Zꢉ1–s4
s3–Zꢉ1–s1
107.81(3)
103.26(3)
116.19(3)
Zꢉ1–s4
s1–C1
s2–C1
1
s3–Zꢉ1–s3
–
n1–C1
s3–C13
s4–C13
s4–Zꢉ1–s1
s4–Zꢉ1–s3
133.65(4)
108.23(3)
1
s4–Zꢉ1–s3
–
–
–
1
s4–C13
1.713(2)
1.320(3)
–
–
n3–C13
1.320(4)
–
Figure 1. Bꢆꢎꢎ-ꢆꢉꢂ-ꢋꢁꢄck ꢂꢄꢆgꢅꢆꢈ ꢃꢊ 1 (ꢍppꢇꢅ) ꢆꢉꢂ 2 (ꢎꢃwꢇꢅ).

6
ZIAꢀURꢀRꢁHMAN ꢁT AL.
3
.2. X-ray single crystal analysis of 1 and 2
.2.1. Structural descriptions
3
For 1 and 2, crystal data and refinement parameters are given in table 1, whereas bond lengths and
angles are shown in table 2. A centrosymmetric and dimeric molecular structure [ZnL ] was observed
2
2
for 1 and 2, featuring four dithiocarbamate chelates with two sulfurs bridging two Zn atoms resulting
in five-coordinate geometry as described previously [23]. Due to this dimeric nature of 1 and 2, an
additional four-membered ring (Zn–S–Zn–S) is formed along with Zn–S–C–S which appears due to
the anisobidentate coordination of 1,1-dithiolate. The geometry around Zn in 1 and 2 is distorted
square-pyramidal with τ values of 0.28 and 0.29, respectively. The distance between Zn and its five coor-
dinating sulfurs is different in both 1 [Zn(1)–S(2)=2.35 Å)], [Zn(1)–S(1)=2.44 Å], [Zn(1)–S(4)=2.36 Å)],
[
Zn(1)–S(3)=2.81 Å] and [Zn(1)–S(3)(bridge)=2.38 Å] and 2 [Zn(1)–S(2)=2.46 Å)], [Zn(1)–S(1)=2.33
Å], [Zn(1)–S(4)=2.32 Å)], [Zn(1)–S(3)=2.90 Å] and [Zn(1)–S(3)(bridge)=2.35 Å] (figure 1). However, the
Zn–Sshort and Zn–Slong are comparable with similar structures [24].
Change in position of methoxy from meta (1) to para (2) position on peripheral phenyl rings changes
the electronic nature as well as it affects the stereochemical conformations of the molecules. This
can be visualized clearly by two different modes of intramolecular C–H⋯π interactions in 1 [C(21)–
H(21)⋯Cg 3.34 Å)] and 2 [C(22)–H(22)⋯Cg 2.81 Å)]. Compound 1 containing m-methoxy, p-H and 2
(
a)
(b)
Figure 2. sꢄꢂꢇ vꢄꢇw ꢃꢊ (ꢆ) ꢎꢆꢂꢂꢇꢅ-ꢎꢄkꢇ ꢋꢆꢉꢂwꢄcꢀꢇꢂ ꢋꢍpꢅꢆꢈꢃꢎꢇcꢍꢎꢆꢅ cꢀꢆꢄꢉꢋ ꢂꢅꢄvꢇꢉ bꢌ C–h⋯π cꢃꢉꢁꢆcꢁꢋ, ꢆ ꢋcꢀꢇꢈꢆꢁꢄc ꢂꢄꢆgꢅꢆꢈ (ꢎꢇꢊꢁ), ꢆ
wꢄꢅꢇꢊꢅꢆꢈꢇ ꢈꢃꢂꢇꢎ (ꢅꢄgꢀꢁ), ꢆꢉꢂ (b) zꢄgzꢆg ꢆꢅꢅꢆꢉgꢇꢈꢇꢉꢁ ꢃꢊ ꢂꢄꢈꢇꢅꢄc h-ꢋꢀꢆpꢇꢂ 1 ꢄꢉ ꢁꢀꢇ cꢅꢌꢋꢁꢆꢎ ꢋꢁꢅꢍcꢁꢍꢅꢇ, ꢆ ꢋcꢀꢇꢈꢆꢁꢄc ꢂꢄꢆgꢅꢆꢈ (ꢁꢃp), ꢆ
wꢄꢅꢇꢊꢅꢆꢈꢇ ꢈꢃꢂꢇꢎ (bꢃꢁꢁꢃꢈ).

JOURNAL OF COORDINATION CHꢁMISTRY
7
Figure 3. a ꢋpꢆcꢇfiꢎꢎ ꢅꢇpꢅꢇꢋꢇꢉꢁꢆꢁꢄꢃꢉ ꢃꢊ ꢁwꢃ ꢋꢍccꢇꢋꢋꢄvꢇ ꢎꢆꢌꢇꢅꢋ ꢃꢊ zꢄgzꢆg-ꢎꢆꢌꢇꢅꢇꢂ ꢋꢁꢅꢍcꢁꢍꢅꢇ ꢃꢊ 1, ꢁꢃp vꢄꢇw (ꢁꢃp), ꢋꢄꢂꢇ vꢄꢇw (bꢃꢁꢁꢃꢈ).
having p-methoxy, m-H on peripheral phenyl rings adopts a conformation that can be stabilized by
intramolecular C–H⋯π interactions. The perfect chair conformation of piperazinyl moiety in 1 changes
to twist-boat conformation in 2 (figure 1).
3
.2.2. Molecular packing
A significant effect of electronic and conformational changes on molecular packing was also observed.
There are some general considerations, which are worth discussing before going into the individual
molecular packing of 1 and 2. In 1, where methoxy groups are meta, electron-donating mesomeric effect
of both amino and methoxy group is additive on ortho/para positions. However, more electronegative
methoxy group partially withdraws electron density from nearby ortho positions making them slightly
less electron rich as compared to para positions. So, both ortho and para positions of these substituents
are potential hydrogen bond acceptors for C–H⋯π interactions. In 2, where methoxy groups are at para
position of peripheral aromatic rings, electron density is almost symmetrically distributed favoring C–
H⋯π interactions. Dominating mesomeric effect of amino group makes ortho positions electron rich
and prevents methoxy from mesomeric effect. Therefore, methoxy group only expresses its inductive
effect making its ortho positions slightly electron deficient. The four carbons of piperazine in 1 and 2
are electron deficient, partially due to the electronegativity and partially due to positive character of
nitrogen achieved through delocalization of its lone pairs to the neighboring unsaturated systems. This
Figure 4. sꢍpꢅꢆꢈꢃꢎꢇcꢍꢎꢆꢅ pꢆꢅꢆꢎꢎꢇꢎ ꢇxꢁꢇꢉꢋꢄꢃꢉ ꢃꢊ h-ꢋꢀꢆpꢇꢂ ꢈꢃꢎꢇcꢍꢎꢇꢋ ꢃꢊ 2 ꢁꢃ ꢈꢆkꢇ ꢆ ꢎꢆꢌꢇꢅ, ꢁꢃp vꢄꢇw (ꢎꢇꢊꢁ), ꢋꢄꢂꢇ vꢄꢇw (ꢅꢄgꢀꢁ).

8
ZIAꢀURꢀRꢁHMAN ꢁT AL.
Figure 5. sꢍpꢅꢆꢈꢃꢎꢇcꢍꢎꢆꢅ pꢆꢅꢆꢎꢎꢇꢎ ꢋꢄꢂꢇwꢆꢌꢋ ꢇxꢁꢇꢉꢋꢄꢃꢉ ꢃꢊ h-ꢋꢀꢆpꢇꢂ ꢈꢃꢎꢇcꢍꢎꢇꢋ ꢃꢊ 2 ꢁꢃ ꢈꢆkꢇ ꢆ ꢎꢆꢌꢇꢅ, ꢁꢃp vꢄꢇw (ꢎꢇꢊꢁ), ꢋꢄꢂꢇ vꢄꢇw (ꢅꢄgꢀꢁ).
Figure 6. mꢍꢎꢁꢄꢎꢆꢌꢇꢅꢇꢂ ꢋꢁꢅꢍcꢁꢍꢅꢇ ꢃꢊ 2.
is clearly demonstrated by shorter N–C bond distances in both 1 [N(1)–C(1)S(1)S(2) 1.33 Å, N(3)–C(13)S(3)
S(4) 1.32 Å, N(4)–C(18) 1.41 Å and N(2)–C(6) 1.42 Å] and 2 [N(1)–C(1)S(1)S(2) 1.32 Å, N(3)–C(13)S(3)S(4)
1
.32 Å, N(4)–C(18) 1.41 Å and N(2)–C(6) 1.40 Å]. Therefore, the hydrogens connected to these carbons
are slightly acidic and potential hydrogen bond donors.
3.2.2.1. Molecular packing of 1. A zigzag layer structure of 1 in the solid state is stabilized by four different
types of hydrogen bonds, C–H⋯π, CH⋯S, CH⋯O, and CH⋯C. ꢁvery dimeric H-shaped molecule of 1 is
sandwiched between another two molecules providing infinite 1-D ladder-like supramolecular chains
driven by C–H⋯π [C(5)–H(5B)⋯C(23) 2.73 Å], [C(2)-H(2A)⋯C(19) 2.73 Å], and [C(2)–H(2A)⋯C(23) 2.83 Å]
interactions (figure 2(a)). These H-shaped infinite 1-D supramolecular chains of 1 are zigzag cemented by
multiple weak hydrogen bond contacts [C(4)–H(4A)⋯O(2) 2.66 Å], [C(5)–H(5A)⋯C(24) 2.83 Å], and [C(12)-
H(12B)⋯S(3) 2.93 Å] (figure 2(b)). Sideways extension of these zigzag H-shaped infinite 1-D supramolecular
chains of 1 by weak intermolecular CH⋯S hydrogen bonds [C(3)-H(3A)⋯S(1) 2.97 Å] provide a zigzag-
layered structure (figure 3).
3.2.2.2. Molecular packing of 2. The molecular packing of 2 is different from 1. The layered structure of
2
is stabilized by three different types of multiple hydrogen bonds, CH⋯π, CH⋯S, and CH⋯O. However,
H-shaped molecules of 2 are parallel zigzag in a specific layer to provide an uneven surface of the layer as
compared to head-to-tail zigzag movement of H-shaped molecules in forming the smooth zigzag layer
of 1 (figure 4). A bifurcated CH⋯S [C(5)-H(5A)⋯S(1) 2.92 Å], [C(5)–H(5A)⋯S(3) 2.95 Å], another CH⋯S

JOURNAL OF COORDINATION CHꢁMISTRY
9
−
1
Table 3. Gꢎꢍcꢃꢋꢇ ꢎꢃwꢇꢅꢄꢉg ꢆcꢁꢄvꢄꢁꢌ ꢃꢊ 1, 2, ꢆꢉꢂ 3 ꢆꢁ ꢆ ꢂꢃꢋꢇ ꢃꢊ 1000 μg kg b.w ꢄꢉ ꢉꢃꢉ-ꢂꢄꢆbꢇꢁꢄc gꢎꢍcꢃꢋꢇ-ꢄꢉꢂꢍcꢇꢂ ꢀꢌpꢇꢅgꢎꢌcꢇꢈꢄc
ꢅꢆbbꢄꢁꢋ.
ꢁ
xperimental groupsabcde
Negative
Positive
−1
−1
−1
−1
−1
Time (hour)
control (mg dL ) control (mg dL )
1 (mg dL )
2 (mg dL )
3 (mg dL )
F value
ꢆ
ꢆ
ꢆ
ꢆ
ꢆ
0
85.8 ± 3.56
86.6 ± 4.81
+0.93%)
82.2 ± 6.14
(−4.19%)
133.4 ± 5.41
(+4.05%)
128.0 ± 5.00
(−9.47%)
122.2 ± 3.63
(+3.73%)
88.8 ± 4.86
(+3.39%)
146.4 ± 5.72
(+14.19%)
133.6 ± 5.45
(−5.51%)
116.4 ± 3.64
(−1.18%)
88.8 ± 4.76
(+3.49%)
148.0 ± 4.35
(+15.44%)
135.8 ± 4.65
(−3.96%)
118.8 ± 3.34
(+0.84%)
1.324
(
ꢆ
ꢆ
ꢆ
b
bc
½
1
128.2 ± 5.89
133.0 ± 6.81
+3.74%)
10.207
9.118
(
141.4bꢂ ± 5.16
122.6 ± 3.62
−13.29%)
ꢆ
ꢆc
bc
cꢂ
(
b
ꢆ
bc
b
b
2
117.8 ± 4.12
107.8 ± 7.70
−8.48%)
16.653
43.445
(
c
ꢆ
cꢂ
b
b
3
109.2 ± 3.07
83.0 ± 4.31
−0.22%)
115.4 ± 3.13
(+5.67%)
100.4 ± 5.12
(−8.05%)
97.6 ± 4.21
(−10.62%)
(
ꢆ
aꢎpꢀꢆbꢇꢁꢄcꢆꢎ ꢃꢅꢂꢇꢅ ꢄꢋ ꢆccꢃꢅꢂꢄꢉg ꢁꢃ ꢄꢉcꢅꢇꢆꢋꢄꢉg ꢈꢇꢆꢉ vꢆꢎꢍꢇꢋ.
Vꢆꢎꢍꢇꢋ ꢆꢅꢇ ꢈꢇꢆꢉꢋ ꢆꢉꢂ ꢋꢁꢆꢉꢂꢆꢅꢂ ꢂꢇvꢄꢆꢁꢄꢃꢉ ꢃꢊ ꢁꢀꢅꢇꢇ ꢅꢇpꢎꢄcꢆꢁꢇꢋ.
b
c
mꢇꢆꢉꢋ ꢋꢀꢆꢅꢄꢉg ꢆ ꢎꢇꢁꢁꢇꢅ ꢄꢉ cꢃꢈꢈꢃꢉ ꢆꢅꢇ ꢉꢃꢁ ꢋꢄgꢉꢄficꢆꢉꢁꢎꢌ ꢂꢄffꢇꢅꢇꢉꢁ ꢆꢁ p < 0.05.
ꢂ
mꢇꢆꢉꢋ ꢋꢀꢆꢅꢄꢉg ꢉꢃ ꢎꢇꢁꢁꢇꢅ ꢄꢉ cꢃꢈꢈꢃꢉ ꢆꢅꢇ ꢋꢄgꢉꢄficꢆꢉꢁꢎꢌ ꢂꢄffꢇꢅꢇꢉꢁ ꢆꢁ p < 0.05.
Vꢆꢎꢍꢇꢋ ꢄꢉ pꢆꢅꢇꢉꢁꢀꢇꢋꢇꢋ ꢄꢉꢂꢄcꢆꢁꢇ pꢇꢅcꢇꢉꢁ ꢄꢉcꢅꢇꢆꢋꢇ (+) ꢃꢅ ꢂꢇcꢅꢇꢆꢋꢇ (−) ꢄꢉ pꢆꢅꢆꢈꢇꢁꢇꢅꢋ ꢃꢊ cꢃꢈpꢃꢍꢉꢂ-ꢁꢅꢇꢆꢁꢇꢂ ꢅꢆbbꢄꢁ gꢅꢃꢍp ꢊꢅꢃꢈ ꢉꢃꢅꢈꢆꢎ
cꢃꢉꢁꢅꢃꢎ ꢅꢆbbꢄꢁ gꢅꢃꢍp.
ꢇ
Figure 7. tꢄꢈꢇ ꢅꢇꢋpꢃꢉꢋꢇ cꢀꢆꢉgꢇ ꢄꢉ gꢎꢍcꢃꢋꢇ ꢎꢇvꢇꢎ ꢃꢊ ꢀꢌpꢇꢅgꢎꢌcꢇꢈꢄc, cꢃꢉꢁꢅꢃꢎ ꢆꢉꢂ ꢁꢅꢇꢆꢁꢇꢂ gꢅꢃꢍpꢋ.
[C(14)–H(14B)⋯S(4) 3.00 Å], and CH⋯π [C(17)–H(17B)⋯C(19) 2.86 Å] interactions stabilize this parallel
zigzag arrangement of molecules in packing of 2. Sideways extension of this parallel zigzag molecular
arrangement by weak CH⋯O contacts [C(10)–H(10)⋯O(2) 3.34 Å] completes a layer (figure 5). Various
layers are connected by CH⋯π [C(11)–H(11)⋯C(20) 2.86 Å, C(17)–H(17B)⋯C(20) 2.86 Å], a bifurcated
CH⋯S [C(5)–H(5A)⋯S(1) 2.92 Å], [C(5)–H(5A)⋯S(3) 2.95 Å], another CH⋯S [C(14)–H(14B)⋯S(4) 3.00 Å],
and CH⋯O [C(3)–H(3B)⋯O(2) 2.65 Å, C(10)-H(10)⋯O(2) 2.71 Å] interactions to provide a multilayered
structure (figure 6).
4
. Biological activity
.1. Antihyperglycemic activity
Globally, 347 million people are reported to have diabetes mellitus, with prevalence rates of 9.8 and
.3% for men and women, respectively [25]. A large number of therapeutics have been developed to
4
9

10
ZIAꢀURꢀRꢁHMAN ꢁT AL.
treat diabetes; however, low efficacy, tolerability, and occasional toxicity limited their use [26–28]. To
identify antidiabetic drugs with increased efficacy, tolerability, and minimal toxicity, researchers diverted
their focus toward synthesis of new drugs [29]. Antidiabetic compounds should be able to reduce the
blood glucose levels in hyperglycemic subjects. In this study, 1, 2, and 3 were screened for their in vivo
antidiabetic potentials (table 3). Antihyperglycemic activity was measured by OGTT. No significant dif-
ference in glucose level was observed at 0 h in the groups (p > 0.05) (figure 7). After 30 min of glucose
administration, an increase in glucose level was observed, and is consistent with a previous report [30].
The glucose level lowering ability of 2 and 3 were almost the same, however, slightly less (p < 0.05) than
the standard drug glibenclamide, after glucose administration. After 1 h, there is continuous reduction
in glucose except in the negative control group where the glucose level was slightly lowered. The glu-
−
1
−1
cose lowering ability after 3 h follows the sequence: glibenclamide (83.0 mg dL ) > 3 (97.6 mg dL )
>
−1
−1
2 (100.4 mg dL ) > 1 (141.4 mg dL ). So, the values of 2 and 3 are nearly the same, and statistically
significant when compared to 1 (p < 0.05). Several studies reported that antidiabetic activity of metal
complexes, such as vanadium and zinc complexes, exhibited in vitro insulinomimetic and in vivo anti-
diabetic activity in experimental animals [31–33]. Yoshikawa et al. also studied the antidiabetic activity
−1
of bis(pyrrolidine-N-dithiocarbamate)zinc(II) complex at a dose of 1000 μg mL . Results revealed that
the high blood glucose level in mice was lowered from approximately 500–350 mg dL− within 6 days,
and the effect was maintained during the administration period [19].
1
5. Conclusion
Three new homobimetallic Zn(II) dithiocarbamates (1–3) of 4-(3-methoxyphenyl)piperazine-1-car-
bodithioate (1), 4-(4-methoxyphenyl)piperazine-1-carbodithioate (2), and 4-benzhydrylpipera-
1
zine-1-carbodithioate (3) have been synthesized and characterized by FT-IR, multinuclear NMR ( H
1
3
and C), and X-ray single crystal analysis (1 and 2). The latter technique has confirmed the dimeric
nature of 1 and 2 in which two molecules are attached via two Zn–S bonds to form a four-membered
ring Zn S . Moreover, the presence of methoxy group at different positions on peripheral phenyl ring
2
2
in 1 (meta) and 2 (para) impact the electronic nature and stereochemical conformations of the mole-
cules. This is well supported by the presence of two different modes of intramolecular C–H⋯π inter-
actions in 1 [C(21)–H(21)⋯Cg 3.34 Å) and 2 [C(22)-H(22)⋯Cg 2.81 Å). In order to make the orientation
feasible for C–H⋯π interactions, the piperazine adopts chair and twist-boat conformation in 1 and 2,
respectively. The antihyperglycemic activity shows that complexes lowered the blood glucose in the
−1
−1
−1
−1
sequence: glibenclamide (83.0 mg dL ) > 3 (97.6 mg dL ) > 2 (100.4 mg dL ) > 1 (141.4 mg dL ).
Complexes 1–3 reduce the deliberately elevated glucose levels and need to be further screened for
the treatment of type 2 diabetes mellitus.
Supplementary material
Single-crystal X-ray diffraction data for the structural analysis have been deposited with the Cambridge Crystallographic
Data Center, CCDC No. 1028973 (1) and CCDC No. 1028974 (2). The copy of this information may be obtained free of charge
from the Director, CCDC, 12 Union Road, Cambridge, CBZ 1ꢁZ, UK (Fax:+44 1223 336033; ꢁ-mail: deposit@ccdc.cam.ac.uk
or www: http://www.ccdc.cam.ac.uk).
Disclosure statement
No potential conflict of interest was reported by the authors.
Funding
This work was supported by the Higher ꢁducation Commission of Pakistan.

JOURNAL OF COORDINATION CHꢁMISTRY
11
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