Synthesis, spectral, thermal and insulin-enhancing properties of oxovanadium(IV) complexes of metformin Schiff-bases

Article abstract of DOI:10.1007/s10973-016-6018-1

A series of VO²⁺ complexes of Schiff-bases of metformin with each of salicylaldehyde (HL¹); 2,3-dihydroxybenzaldehyde (H₂L²); 2,4-dihydroxybenzaldehyde (H₂L³); 2,5-dihydroxybenzaldehyde (H₂L⁴); 3,4-dihydroxybenzaldehyde (H₂L⁵); and 2-hydroxynaphthaldehyde (HL⁶) were synthesized by template reaction. The new compounds are characterized through elemental analysis, conductivity measurements, magnetic moment, IR, UV–Vis, ESR and mass spectroscopy. The complexes have square pyramidal structure with μ values of pentacoordinated vanadyl ion. TG, DTG and DTA confirm the proposed stereochemistry, and a mechanism of thermal decomposition was suggested. Mice treated with the complexes [VOL¹H₂O]·1?H₂O and [VOHL⁴H₂O]·2H₂O showed glucose-lowering effect of 59.31, 58.79% (20?mg?kg^?1) and 64.98, 74.8% (40?mg?kg^?1) compared to metformin.

Full text of DOI:10.1007/s10973-016-6018-1

J Therm Anal Calorim
DOI 10.1007/s10973-016-6018-1
Synthesis, spectral, thermal and insulin-enhancing properties
of oxovanadium(IV) complexes of metformin Schiff-bases
1
2
3
3
Marwa A. Mahmoud
•
Sawsan A. Zaitone
•
Alaa M. Ammar
•
Shehab A. Sallam
Received: 14 July 2016 / Accepted: 26 November 2016
Ó Akad e´ miai Kiad o´ , Budapest, Hungary 2016
2
Abstract A series of VO complexes of Schiff-bases of
?
Introduction
1
metformin with each of salicylaldehyde (HL ); 2,3-dihy-
2
droxybenzaldehyde (H L ); 2,4-dihydroxybenzaldehyde
Vanadium complexes were found to present antimicrobial,
antitumor and insulin-enhancing effects [1]. Oxovana-
dium(IV) sulfate has been demonstrated to possess oral
insulin-like activity similar to that of the vanadates, with
lowered toxicity [2]. Neutral oxovanadium(IV) complexes,
with a variety of coordination environments, have been
examined as potential insulin-enhancing agents ranging
from the common VO(O ) to VO(N O ), VO(N ), VO(S ),
2
3
4
(
H L ); 2,5-dihydroxybenzaldehyde (H L ); 3,4-dihydrox-
2 2
5
ybenzaldehyde (H L ); and 2-hydroxynaphthaldehyde
6
HL ) were synthesized by template reaction. The new
2
(
compounds are characterized through elemental analysis,
conductivity measurements, magnetic moment, IR, UV–
Vis, ESR and mass spectroscopy. The complexes have
square pyramidal structure with l values of pentacoordi-
nated vanadyl ion. TG, DTG and DTA confirm the pro-
posed stereochemistry, and a mechanism of thermal
decomposition was suggested. Mice treated with the
4
2
2
4
4
VO(S O ) and VO(N S ) [3–6].
2
2
2 2
Blood glucose levels of rats with alloxan-induced dia-
betes have dropped from hyperglycemic levels to hypo-
glycemic ones after treatment with bis-salicylidine
ethylenediaminato oxovanadium(IV) complex [7]. In vivo
1
4
complexes [VOL H O]Á1‘H O and [VOHL H O]Á2H O
2
2
2
2
showed glucose-lowering effect of 59.31, 58.79%
-
20 mg kg ) and 64.98, 74.8% (40 mg kg ) compared to
1
-1
0
(
insulin-mimetic activity of [N,N -1,3-propyl-bis(salicy-
metformin.
ladimine)]oxovanadium(IV) has been tested [8]. Oxo-
vanadium(IV) and (V) complexes of acetylpyridine-
derived semicarbazones were able to enhance glucose
uptake and to inhibit glycerol release from adipocytes
which indicate their potential to act as insulin mimics [9].
Complexes of VOCl2 with 2-pyridineformamide
thiosemicarbazones inhibited glycerol release in a similar
way to that observed with insulin but showed a low
enhancing effect on glucose uptake by rat adipocytes [10].
A series of oxovanadium(IV) symmetrical tetradentate
Schiff-base complexes have been isolated from the reaction
2
?
Keywords Metformin Schiff-bases Á VO complexes Á
Spectral and thermal properties Á Antidiabetes mellitus
&
Shehab A. Sallam
shehabsallam@yahoo.com
of VOSO with Schiff-bases obtained from the condensa-
4
1
tion of 2-hydroxybenzophenone or 2-hydroxy-5-chloros-
alicylaldehyde with various aliphatic diamines [11].
Recently, new insulin-mimetic and hypoglycemic heter-
obinuclear zinc(II)/oxovanadium(IV) complex was syn-
thesized and characterized [12].
Department of Science and Mathematics Engineering,
Faculty of Petroleum and Mining Engineering, Suez
University, Suez, Egypt
2
3
Department of Pharmacology and Toxicology, Faculty of
Pharmacy, Suez Canal University, Ismailia, Egypt
Metformin hydrochloride (MFÁHCl) (1,1-dimethyl-
biguanide) is an oral hypoglycemic agent which is
Department of Chemistry, Faculty of Science, Suez Canal
University, Ismailia, Egypt
123

M. A. Mahmoud et al.
commonly prescribed for the treatment of DM II [13].
There is much interest in MF ligand and its transition metal
complexes which are cationic in nature [14–19]. Also, it
was shown that vanadyl–biguanide complexes are potential
synergistic insulin mimics [20]. Regarding the potential
functions of Schiff-bases, Gao [21] has studied the
antimicrobial activity of copper(II) complex derived from
the condensation of MF with 2-pyridinecarbaldehyde. In
addition, Ni(II) complexes with ligands that resulted in
condensation of MF and pentane-2,4-dione were synthe-
sized and characterized [22]. Thermal behavior of the
complexes was also evaluated [17–19, 22]. Recently, new
decavanates using metformin as counterion with formula
was isolated in the solid state, dried under vacuum and
recrystallized from methanol (m.p. 195 °C). The purity was
checked by TLC using methanol–chloroform solvent
1
mixture (1:10 v/v). HL Schiff-base was characterized
1
using C, H and N analyses, H NMR, UV–Vis and GC-
mass spectra as well as TG, DTG and DTA. Its structure is
shown in Structure 1.
Template synthesis of the complexes
All complexes were prepared according to the following
procedure. Solution of VOSO ÁH O (1 mmol, 0.18 g) in
4
2
5 mL of distilled water was added dropwise to methanolic
solution of the Schiff-base (1 mmol) prepared in the previ-
ous step. The mixture was refluxed on water bath for 2 h with
stirring during which a deep green solution is formed
(
H Metf) [V O ]Á8H O was shown to have pharmaco-
2
3
10 28
2
logical potential as a hypoglycemic, lipid-lowering and
metabolic reagent [23].
In order to modulate the biological activity of MF and to
correlate this activity with structure, a series of vanadium
complexes with Schiff-bases of MF with salicylaldehyde
(pH = 4–4.5), after which NH OH is added dropwise till the
4
complexis precipitated (pH = 6–7). Stirring is continued for
another 1 h at room temperature, and the complex is filtered,
washed thoroughly with water and hot methanol and dried
under vacuum. The following series of complexes were
1
2
(
HL ); 2,3-dihydroxybenzaldehyde (H L ); 2,4-dihydroxy-
2
3
benzaldehyde (H L ); 2,5-dihydroxybenzaldehyde (H L );
4
2
2
5
,4-dihydroxybenzaldehyde (H L ); and 2-hydroxynaph-
1
2
3
obtained: [VOL H O]Á1‘H O (1), [VOHL H O]Á2H O (2),
2
2
2
3 4 5
2
2
6
thaldehyde (HL ) were synthesized by template reaction.
The resulting complexes were characterized using elemental
analysis, conductivity measurements, magnetic moment
values, spectral analysis (UV–Vis, IR, ESR, MS), and TG,
DTG and DTA. Insulin-like activity of the complexes was
evaluated in alloxan-induced Swiss albino mice.
[VOHL H O]Á2H O (3), [VOHL H O]Á2H O (4), [VOL
2
2
2
2
6
(H O) ]Á2H OÁ(5), [VOL H O]Á2H O (6).
2
2
2
2
2
Physical measurements
C, H and N were estimated using a Heraeus CHN Rapid
Analyzer. The IR spectra were recorded (KBr disk) in the
-
1
Experimental
Materials
400–4000 cm range on Bruker Vector-22 spectrometer.
Mass spectral data analyses of the complexes were carried
out on Varian MAT-711 spectrometer. The electronic
-
3
absorption spectra were obtained using 10 M DMSO
solution in 1-cm quartz cell using UV-1601PC Shimadzu
spectrophotometer. Magnetic susceptibility measurements
were taken using the modified Gouy method [25] on MSB-
MK1 balance at room temperature. Solid-state X-band ESR
spectra were recorded at 298 K on a Bruker EMX spec-
trometer. TG, DTG and DTA were performed on Shimadzu
H-60 thermal analyzer under a dynamic flow of nitrogen
All chemicals used in this study are of A.R. or equivalent
grade and were used without further purification. Salicy-
laldehyde; 2-hydroxynaphthaldehyde; 2,3-dihydroxyben-
zaldehyde; 2,4-dihydroxybenzaldehyde; 2,5-dihydroxy-
benzaldehyde; and 3,4-dihydroxybenzaldehyde (Koch-
Light Laboratories) were used as such. Metformin HCl was
purchased from El-Nasr Company for Pharmaceutical
Chemicals, Cairo, Egypt. VOSO ÁH O was obtained from
-
1
-1
(30 mL min ) and heating rate 10 °C min from ambi-
ent temperature to 750 °C. Electrical conductivity mea-
surements were taken at room temperature on freshly
4
2
Aldrich Chemical Company. Alloxan monohydrate powder
was purchased from Sigma-Aldrich, St. Louis, MO, USA.
Synthesis of the Schiff-bases
NH
NH
H
OH
The Schiff-bases have been prepared by addition of
methanolic MF solution to a methanolic solution of the
aldehyde in 1:1 ratio in basic medium [24]. The mixture
was refluxed with continuous stirring over water bath for
two hours. The solution turned to yellow color indicating
H C
3
N
N
H
N
CH3
1
1
Structure 1 HL Schiff-base
the formation of the Schiff-base. Only, HL Schiff-base
1
23

Synthesis, spectral, thermal and insulin-enhancing properties of oxovanadium(IV) complexes of…
-
3
prepared 10 M DMSO solutions using WTW conduc-
tivity meter fitted with L100 conductivity cell. Metal
content was obtained by EDTA titration using PAN indi-
cator and acetate buffer.
Collection of blood samples
After the last day of drug treatment, mice were anes-
thetized with ether and killed by cervical dislocation.
Blood samples were collected by cardiac puncture and
centrifuged after standing for 30 min (30009g, 15 min) at
room temperature. Sera were separated and stored at
-20 °C until use for assay of total cholesterol as well as
activities of ALT and AST.
Experimental assay
Experimental protocols were approved by the Research
Ethics Committee (License Number 201410A4) at the
Faculty of Pharmacy, Suez Canal University, Ismailia,
Egypt. Animal suffering during handling or injection was
kept at minimal. Healthy male Swiss albino mice with
original body weight 18–30 g were used in the current
experiment. Mice were provided by the National Authority
of Vaccines (Cairo, Egypt) and were maintained under
suitable laboratory conditions with a normal light–dark
cycle. They were housed in a clean polyethylene cages
with food and water ad libitum and were allowed to
acclimatize for ten days before starting the experiment.
Histopathological examination of pancreas
For dissection of the pancreas, a laparotomy was performed
and the pancreas was immediately isolated and fixed
overnight in 4% paraformaldehyde solution. Cross sections
of 4 lm were cut and processed for routine staining with
hematoxylin and eosin (H&E) and were used for
histopathological examination under a light microscope
(OPTICA). Photographs were then captured, and diameters
of ten random islets of Langerhans in each section were
determined using GIMP 2.8.14 software. Diameters were
then averaged for each animal and compared to determine
the effect of drugs on the diseased islets.
Preparation of drugs and induction of diabetes
mellitus in experimental animals
Alloxan monohydrated was freshly prepared just before use
by dissolution in saline. Metformin and the test complexes
were dissolved in DMSO/saline 1:5 (v/v).
Statistical analyses
Mice were fasted overnight and injected with alloxan
Data were collected, tabulated and expressed as the
mean ± SEM and were analyzed using one-way analysis
of variance (ANOVA) followed by Bonferroni’s post hoc
test, and significance was set at P \ 0.05. Statistical
analysis was performed using the SPSS program (SPSS
Inc., Chicago, IL, USA).
-
150 mg kg day , i.p., daily schedule) [26] in order to
1
-1
(
induce experimental diabetes mellitus. One week after
alloxan injection, hyperglycemia was confirmed by estima-
tion of the level of fasting blood glucose using a blood
sample from the tail vein employing a glucometer (BioSTC,
-
1
USA). Mice with final blood glucose levels[200 mg dL
were considered diabetic and included in the experiment.
Results and discussion
Experimental design
Vanadyl complexes of the metformin Schiff-bases
Diabetic mice were subjected to a therapeutic period (14
doses) of treatment with tested complexes and the standard
All the complexes are air-stable and remarkably soluble in
DMSO and DMF, slightly soluble in MeOH and insoluble in
-
1
metformin (20 or 40 mg kg , i.p.). Mice were randomly
allocated into different groups (six mice each) as follows:
2
?
benzene, acetone and diethyl ether. The complexes of VO
melt in the 200–178 °C range except the complex 1 which
decomposes without melting above 390 °C. Elemental
analysis show 1:1 (metal:ligand) stoichiometry for all the
complexes. The analytical data and some physical properties
of the complexes are shown in Table 1. The molar conduc-
1
2
3
4
5
.
.
.
.
.
vehicle (saline)
diabetic group
diabetic ? metformin
diabetic ? complex 1
diabetic ? complex 4
-
3
tance values of 10 M DMSO solutions of the complexes
are consistent with their non-electrolytic nature [27].
Diabetic control mice received 14 doses of DMSO/sal-
-
1
ine solution (12 mL kg , i.p.) at the same schedule
reported for metformin and the test complexes.
Infrared Spectra
At the end of the experiment, the percent of surviving
mice in each group was recorded and groups with survival
percent [50% were included in the following procedures.
The assignments of the IR bands of the vanadyl complexes
1
have been made by comparing with the bands of HL ligand
123

M. A. Mahmoud et al.
Table 1 Analytical data, conductivity and magnetic moments of the vanadyl complexes of the metformin Schiff-bases
Complex number
Color
Mol wt
Melting and dec. point/°C
Yield/%
Elemental analysis
Found calcd./%
*X
C
H
N
M
1
2
3
4
5
6
Black green
Black green
Olive green
Olive green
Black green
Deep green
342.21
368.21
368.21
368.21
386.21
402.21
[300
198
190
178
188
200
69
66
58
68
66
68
38.2
5.2
5.2
5.4
5.1
5.6
5.1
5.5
5.1
5.6
5.4
5.1
5.2
20.4
20.3
19.1
19.0
19.1
19.0
19.1
19.0
18.2
18.1
17.5
17.4
14.5
14.8
13.9
13.8
13.7
13.8
13.5
13.8
13.7
13.1
12.5
12.6
0.2
0.3
0.3
0.3
0.3
0.4
3
8.4
35.9
5.8
35.5
5.8
35.6
5.8
34.2
4.1
44.8
4.7
3
3
3
3
4
-
10 M in DMSO, ohm cm mol
3
-1
2
-1
*
-
1
and structurally similar molecules (Table 2). The major IR
spectral features of the presented complexes indicate some
characteristic bands of biguanide and Schiff-base moiety.
The strong broad band ascribed to t(OH) of the Schiff-base
3128–3104 cm range assignable to the stretching vibra-
tion of the N–H group. These bands were observed in the
spectra of some complexes with biguanide Schiff-bases
[21, 22]. The strong bands observed in the 1694–1673 and
-
1
-1
at 3456 cm disappeared in the spectra of all vanadyl
complexes which accounts for the deprotonation and coor-
dination of the OH group [24]. The hydrated complexes have
OH stretching frequencies as a broad band in the
1655–1650 cm range can be attributed to t(C=N) [28].
High values for stretching frequency of the azomethine
group were observed with transition and non-transition
metal complexes of MF ligand [19]. A band appearing in the
-
1
-1
3
416–3389 cm region. IR spectra of the complexes 1–4
and 6 show broad intense band in the 3291–3208 and
1571–1556 and 1276–1275 cm interval has been assigned
to symmetric and asymmetric N–C–N stretching [19]. The
Table 2 IR spectral data of the vanadyl complexes of the metformin Schiff-bases
Complex number
t(H
t(OH)
2
O)
t(NH)
t(C=N)
t(N–C-N)
t(C-O)
t(V=O)
t(M–O)
t(M–N)
1
HL [24]
3456 m
3370 s
1643 s
1599 s
1564 s
1673 s
1655 s
1680 s
1651 s
1686 s
1651 s
1684 s
1652 s
1642 s
1594 s
1498 m
1291 m
1230 m
3
3
297 s
172 s
–
–
1
2
3
4
5
3414 s
3410 s
3393 s
3393 s
3416 s
3208 m
104 m
3256 m
127 m
3291 m
126 m
3270 m
128 m
3387 m
1571 m
1556 m
1566 m
1565 m
1510 m
1276 m
1236 m
1275 m
1229 m
1275 m
1238 m
1276 m
1239 m
1286 m
978 s
978 s
990 s
983 s
982 s
595 s
520 m
594 s
480 m
593 s
480 m
596 s
482 m
597 m
–
3
3
3
3
3
3
282 m
160 m
6
3389 s
3287 m
106 m
1694 s
1650 s
1568 m
1275 m
1241 m
976 s
593 s
3
479 m
s strong, m medium
1
23

Synthesis, spectral, thermal and insulin-enhancing properties of oxovanadium(IV) complexes of…
2
2
band assignable to t(C–O) is recorded as a medium fre-
quency in the 1241–1229 cm region confirming deproto-
spectra of the complexes 5 and 6 show the xy ? x - y
transition at 519 and 572 nm, while the complex 3 shows
-
1
2
?
2
nation and coordination of the phenolic oxygen to the VO
the xy ? z transition at 425 nm. All the complexes under
ion [29]. Characteristic stretching frequencies of the V=O
bond in oxovanadium(IV) complexes generally occur in the
study indicate the xy ? xz, yz transition in the 890–870 nm
region. The electronic spectra are typical of five-coordi-
nated vanadyl complexes which were previously observed
with other vanadyl Schiff-base complexes [11, 37–39].
-
1
region 930–1030 cm [30]. In the present work, all vana-
dium complexes exhibit a strong band in the range
-
1
9
90–976 cm which have assigned to t(V=O) in a mono-
meric square pyramidal geometry [11, 31]. The nature of
metal–ligand bonding is confirmed by the newly formed
Mass spectra
-
1
bands at 596–593 and 520–479 cm in the spectra of the
complexes which are tentatively assigned to m(V–O) and
m(V–N), respectively [32].
The mass spectra of the complexes 3 and 5 were analyzed
to determine their molecular weight and fragmentation
pattern. They give mononuclear species in the positive ion
spectra under MS conditions employed. The parent ion is
observed for the complex 5, while it is not for the first one
as the lattice water is readily lost. The complexes continue
losing the coordinated water followed by HN(CH ) spe-
The complex 5 has IR data showing t(NH), t(C=N) and
t(N–C–N) at 3387, 3282, 3160; 1642, 1594 and
-
510 cm . These values are different from the rest of the
1
1
complexes and nearly similar in number and position to the
1
free HL Schiff-base frequencies. This indicates the non-
3
2
cies and ending with rest of the Schiff-bases. The obtained
results are given in Table 4.
participation of either the azomethine or C=NH groups in
bonding in the complex. Also, in this complex, t(C–O)
-
1
appears as medium band at 1286 cm , while the other
complexes show this band at lower frequency. The V–N
frequency is not present in the IR spectrum of the complex
ESR spectra
ESR spectra of all the oxovanadium(IV) complexes were
recorded in polycrystalline state at room temperature, and
the spectral parameters are summarized in Table 5. The ESR
spectrum of the complex 2 displayed well-resolved axial
-
1
2?
and only V–O appears at 597 cm . Also, VO is a hard
acid, so it is expected to prefer bonding through the two
oxygen atoms of the hydroxyl groups of the Schiff-base
after deprotonation forming five-membered ring which
may be more stable than forming six-membered ring
through the nitrogen atoms [33].
anisotropy (Fig. 1) with g = 1.95 and g? = 1.99. The
k
spectrum shows two sets of eight-line pattern, characteristic
of an unpaired electron being coupled to the vanadium
nuclear spin (I = 7/2). The anisotropic hyperfine parameters
Magnetic and UV–Vis spectra
-
1
were calculated (A = 180 and A? = 66 cm ). The com-
k
plexes 3, 4 and 5 in polycrystalline state at room temperature
are axial with g = 1.968, 1.977 and 1.96 and g = 1.986,
Allthepreparedcomplexesareparamagneticinthe solidstate
1
with the electronic configuration [Ar]3d . Vanadium(IV) has
k
?
.985 and 1.988 and anisotropic hyperfine parameters
1
one unpaired electron with spin-only formula predicting a
magnetic moment of 1.73 B.M. The experimental values are
in the range 1.79–1.72 B.M. for the vanadyl complexes
-
4
-1
A = 178, 177.9 and 173 9 10 cm and A? = 67.9,
k
8.8 and 63.2 9 10 cm . The isotropic EPR parameters
-
4
-1
6
giso and Aiso can be determined from the anisotropic
(
Table 3). These values are in the range recorded for some
parameters, using the relations giso = 1/3(2 g? ? g ) and
monomeric pentacoordinated vanadyl Schiff-bases com-
plexes [8–11] and are consistent with square pyramidal
geometry around the central metal ion [34].
k
Aiso = 1/3(2 A? ? Ak). The measured value of gk, g?, Ak
and A? are in a good agreement for a square pyramidal
structure [40] and are reported in Table 5. The g values are
Electronic absorption spectral data of the oxovana-
dium(IV) complexes in DMSO solutions along with their
assignments are given in Table 3. The transitions that
attributed to p ? p* and n ? p* in the 316–257 and
generally lower than the free electron value, g = 2.002.
e
This lowering can be related to the spin–orbit interaction of
the ground state, dxy level, with the low-lying excited states
[41]. ESR spectra of the complexes 1 and 6 exhibit isotropic
spectra with giso values of 1.983 and 1.982.
3
65–312 nm region in the UV spectra of the complexes are
1
blueshifted compared to HL spectrum, indicating coordi-
nation of the imine nitrogen to the vanadyl ion [19].
Generally, vanadyl complexes have molecular orbital
scheme (based on VOSO .5H O spectrum, C symmetry)
Structure of the complexes
4
2
4v
1
,6
which give rise to three d–d bands [35]. They are assigned
2
According to the above-mentioned data, the ligands HL
2-4
2
as xy ? xz, yz (band I), xy ? x - y (band II) and
and H
2
L
behave as a dibasic tridentate ligands where
2
xy ? z (band III) in order of decreasing energy [36]. The
the vanadyl ion has a square pyramidal structure with the
123

M. A. Mahmoud et al.
Table 3 Electronic spectra and magnetic moments of the vanadyl complexes of the metformin Schiff-bases
Complex number
Band/nm
Assignment
Proposed structure
*leff
B.M.
1
258, 261
p ? p*
Spy
1.72
1.74
1.79
3
8
24
70
n ? p*
xy ? xz, yz (band I)
p ? p*
2
3
257, 281
Spy
Spy
3
8
14
89
n ? p*
xy ? xz, yz (band I)
p ? p*
257, 286
3
4
8
23
25
47
n ? p*
2
xy ? z (band III)
xy ? xz, yz (band I)
p ? p*
4
5
263
Spy
Spy
1.72
1.75
3
8
12
90
n ? p*
xy ? xz, yz (band I)
p ? p*
259, 268
3
5
8
20
19
58
n ? p*
2
2
xy ? x - y (band II)
xy ? xz, yz (band I)
p ? p*
6
316
Spy
1.77
3
5
8
65
72
85
n ? p*
2
2
xy ? x - y (band II)
xy ? xz, yz (band I)
Spy = square pyramid
*
T = 298 °K
Table 4 Mass fragmentation pattern of the complexes 3 and 5
Complex number
m/z
Rel. Int.
Wt. loss
Lost species
Assignment
Calcd.
Found
3
[VOHL H
3
368.21
–
–
54
20
54
4
–
36
18
45
186
8
–
2H
2
O]Á2H
2
O
3
[VOL H
-1
332.94
314.94
269.24
331.2
314.2
269.2
83.1
2
O
2
O]
3
[VOL ]
3
[VO(0.8L )]
H
2
O
HN(CH
3
0.8L
3
)
2
8
2.94
6.94
[VO
2
]
6
63.4
10
79
10
98
68
57
5
‘O
2
[VO]
5
[VOL (H
5
[VOL (H
5
386.21
386.1
368.1
333.1
288.1
270.1
83.05
63.5
–
–
2
O)
O)
2
]Á2H
]Á H
2
O
368.21
332.21
287.21
269.21
18
36
45
18
202
8
H
2
O
2
2
2
O
5
[VOL H
?1
2H
2
O
2
O]
5
?1
HN(CH
3
)
2
2
[VO(0.8L )H O]
5
?1
H
2
O
[VO(0.8L )]
[VO
[VO]
5
8
2.94
6.94
0.8L
‘O
2
]
6
64
2
oxo-ligand in the axial position. In the equatorial plane,
2
and the ionized C=NH group of the metformin (Struc-
ture 2). This ionization process was observed and dis-
cussed with other complexes of MF with transition metals
?
VO
is coordinated to the Schiff-bases through the
azomethine nitrogen, phenolic oxygen after deprotonation
1
23

Synthesis, spectral, thermal and insulin-enhancing properties of oxovanadium(IV) complexes of…
Table 5 ESR parameters of the vanadyl complexes of the metformin Schiff-bases
Complex number
ESR parameters (298 °K)
-
4
g
g?
giso=av
A
A?10 cm
Aiso=av
k
k
2
3
4
5
1.95
1.99
1.976
1.98
180
178
177
173
66
68
69
63
104
103
105
100
1.968
1.977
1.96
1.986
1.985
1.988
1.982
1.978
CH3
OH2
O
O
N
X
N
C
V
N
CH3
N
1000
H
C
C
H
NH
Complexes 1-4 where : X = H (1), 3-OH (2), 4-OH (3), 5-OH (4)
O
OH2
0
OH2
V
O
NH
C
NH
C
O
CH3
HN
–1000
N
C
3000
4000
H C
H
3
[
G]
HN
Complex (5)
Fig. 1 Solid-state ESR spectrum of the complex (2)
Structure 2 Complexes 1–5
5
14, 16, 20, 42, 43]. H L behave as dibasic bidentate
Thermal analysis
[
2
ligand by deprotonation of the phenolic hydroxyl groups,
2
?
Thermal behavior of the analytically characterized vanadyl
complexes of the metformin Schiff-bases has been studied
through TG, DTG and DTA (Fig. 2 is an example). The
phenomenological aspects are given in Tables 6 and 7.
and the VO forms covalent bond with the oxygen ions in
O chromophore in the equatorial plane using two H O
4
2
molecules.
Fig. 2 TG, DTG and DTA of
the complex (2)
DTA,
TG,
Dr TG
1
00
60
2
0
2
4
0
20
0
–
2
0
–
20
4
73
673
Temperature/K
873
123

M. A. Mahmoud et al.
Table 6 TG and DTG of the vanadyl complexes of the metformin Schiff-bases
Complex
number
Temp.
range/°C
DTG/ Mass loss %
°C
Process
Expected product/s
Residue % and
type
Found (Calcd.) %
Found Calcd.
1
HL [24]
160–293
258
351
503
19.17 19.29 Partial decomposition
30.14 30.44 Ligand decomposition
30.25 30.32 Final decomposition
HN(CH
3
)
2
20.1
2
4
94–422
23–600
HN(C=NH)
0.13L
2
(19.29)
Carbonaceous
material
1
2
3
4
5
58–125
26–200
01–378
79–522
66
152
364
415
7.91
12.45 13.11 Partial decomposition
5.28 5.24 Coordinated water
52.85 53.91 Ligand decomposition
7.86 Dehydration
1‘H
2
O
VO
1
2
3
NH(CH
3
3
3
3
)
)
)
)
2
2
2
2
20.87
(19.50)
2
H O
0.8L
4
67
62–173
74–272
73–343
43–371
82–565
50–175
76–258
59–348
48–375
96–543
56–193
94–256
57–344
44–372
49–551
41–115
16–174
75–274
139
218
302
352
527
141
219
303
352
523
138
216
307
356
507
68
9.68
12.89 12.22 Partial decomposition
5.25 4.89 Coordinated water
53.89 54.39 Ligand decomposition
9.77 Dehydration
2H
2
O
V
1
2
3
4
NH(CH
13.88
(13.83)
2
H O
0.8L
‘O
2H
NH(CH
4.17
9.65
4.34 Reduction
2
9.77 Dehydration
2
O
V
1
2
3
4
12.83 12.22 Partial decomposition
5.21 4.89 Coordinated water
53.89 54.39 Ligand decomposition
13.50
(13.83)
2
H O
0.8L
‘O
2H
NH(CH
4.50
9.69
4.34 Reduction
2
9.77 Dehydration
2
O
V
1
2
2
4
12.10 12.22 Partial decomposition
5.18 4.89 Coordinated water
54.89 54.39 Ligand decomposition
13.44
(13.83)
2
H O
0.8L
‘O
4.42
4.17
4.23
4.34 Reduction
4.66 Dehydration
4.66 Dehydration
2
H
H
2
O
V
1
1
133
225
2
O
12.86
(13.19)
15.77 16.31 Partial
decomposition ? Coordinated
water
HN(CH
3
)
2
H O
2
2
75–374
318
22.95 23.04 Coordinated water ? Ligand
decomposition
2
H O HN(CH=NH)
2
3
75–530
31–559
44–163
64–243
43–333
34–472
477
539
137
205
278
375
32.27 32.36 Final decomposition
C
6
H
6
? H O ? HN=CH
2
5
6.10
8.33
6.21 Reduction
’O
2H
HN(CH
2
6
8.95 Dehydration
2
O
V
1
2
3
11.19 11.16 Partial decomposition
4.48 4.41 Coordinated water
3
)
2
12.51
(12.66)
2
H O
58.61 58.74 Ligand decomposition
Final decomposition
0.84L
4
41
4
72–567
516
4.17
3.97 Reduction
‘O
2
The first decomposition step involves dehydration which
74 °C and the other one at 139 °C with mass loss of 4.17 and
4.23/4.66%. These data show that the complex dehydrate in
two well-separated steps due to the presence of a loosely
takes place at 66, 139, 141, 138and 137 °C for the complexes
–4 and 6. Mass losses recorded during this step are
found/calc.): 7.91/7.86%, 9.69–9.65/9.77% and 8.33/8.95%
1
-
1
(
bound lattice water molecule (DH = ?88 J g ) and more
-
1
associated with endothermic DTA peaks at 72, 142, 146, 144
strongly bound one (DH = ?259 J g ). The complexes
2–6 have melting points at 193, 190, 180, 189 and 198 °C as
shown by their endothermic DTA changes.
and 143 °C, respectively. On the other hand, the complex 5
dehydrate in two steps with evolution of 1 mol of H O at
2
1
23

Synthesis, spectral, thermal and insulin-enhancing properties of oxovanadium(IV) complexes of…
Table 7 DTA of the vanadyl complexes of the metformin Schiff-bases
-
1
Complex number
Temp. range/°C
DTA temp./°C
DH/J g
Process
1
HL [24]
160–213
195 endo.
255 endo.
343 exo.
530 exo.
72 endo.
155 endo.
347 endo.
?89
–
Melting
2
3
5
38–284
13–365
00–530
Partial decomposition
Partial decomposition
Final decomposition
Dehydration
–190
–210
?441
?194
?116
1
2
58–125
1
3
25–200
12–420
Partial decomposition
Coordinated water
Ligand decomposition
Final decomposition
Dehydration
4
07 exo.
4
20–522
479 exo.
142 endo.
193 endo.
–508
?451
–
107–173
1
80–234
Melting
2
24 endo.
Partial decomposition
Coordinated water
Ligand decomposition
Final decomposition
Reduction
2
3
4
4
72–343
43–371
28–482
82–565
308 endo.
356 endo.
465 exo.
529 exo.
146 endo.
190 endo.
218 exo.
309 endo.
358 endo.
525 exo.
144 endo.
180 exo.
236 endo.
314 endo.
357 endo.
506 exo.
74 endo.
139 endo.
189 endo.
237 endo.
?170
–
-103
-381
?373
–
3
4
5
114–175
Dehydration
1
2
2
3
4
75–203
03–232
60–348
48–375
96–543
Melting
-174
?323
–
Partial decomposition
Coordinated water
Ligand decomposition
Reduction
-142
?370
–
123–168
Dehydration
1
1
2
3
4
68–193
93–236
88–344
44–372
49–551
Melting
–
Partial decomposition
Coordinated water
Ligand decomposition
Reduction
?199
–
-446
?88
?259
–
41–115
Dehydration
1
1
2
15–174
74–207
52–300
Dehydration
Melting
?107
Partial decomposition?
Coordinated water
Coordinated water
Ligand decomposition
Reduction
3
4
00–374
15–589
336 endo.
473 exo.
–
-2540
5
36 exo.
6
111–163
143 endo
198 endo.
230 endo.
279 endo.
?535
?75
–
Dehydration
1
2
2
63–225
25–254
55–337
Melting
Partial decomposition
Coordinated water ?
Ligand decomposition
Final decomposition
Reduction
?237
3
4
56–389
26–567
376 endo.
480 exo.
?105
-1750
5
10 exo.
1
Comparing with TG of HL [24], the second decom-
position stage concerns with evolution of NH(CH ) spe-
218, 219, 216 and 205 °C which bring weight loss of
(found/calc.): 12.45/13.11%, 12.89/12.22%, 12.83/12.22%,
12.1/12.22% and 11.19/11.16%, respectively. Endothermic
3
2
cies for the complexes 1–4 and 6. It has DTG peaks at 152,
123

M. A. Mahmoud et al.
complex 1 shows the final decomposition step at 467 °C
(exothermic DTA = 479 °C) with the formation of VO as
a final residue. Note that the molar masses of the removed
and remaining species in every step for the complexes 3
and 5 were found to match with mass spectral fragments of
the same value (Table 4), which indicates the reliability of
the decomposition scheme proposed.
160 °C
The complexes 2–6 have V metal as a final product. This
may be due to reduction of the VO—formed as a final
product—to V which takes place at 527, 523, 507, 539 and
5
16 °C with loss of ‘ - ’ O associated with exothermic
2
DTA maxima at 529, 525, 506, 536 and 510 °C, respec-
tively. The reduction is completed due to the presence of
carbonaceous material resulting from the ligand decom-
position [44].
Generally, the final decomposition of the Schiff-base in
the complexes 2–4 (0.8L) takes place in one step at 352 and
480 °C
356 °C, which may reflect similarity in the coordination
sphere. On the other hand, final decomposition in the
complexes 1 and 6 takes place at higher temperature and in
two steps at 415,467 and 375,441 °C, respectively. This
probably indicates a different bonding in coordination
sphere compared to the other series of complexes as shown
above.
3
000
2000
1000
Wavenumber/cm–1
Fig. 3 IR spectrum of the complex (1) at different temperatures
DTA peaks taking place at 155, 224, 218, 236 and 230 °C,
respectively, confirm this decomposition. It is noticed that
this step takes place at the lowest temperature for the
complexes 1 and 6. This may be due to the stronger
interaction between V ion and –C=N group of the met-
formin species of the Schiff-base through covalent bond
formation which leads to weakening of the C–N bond of
the group C–N(CH ) resulting in its rupture at low tem-
Mechanism of thermal decomposition
The IR spectrum of the complex 1 heated at 100, 160, 370,
4
20 and 480 °C is shown in Fig. 3. It shows that the IR
spectrum changes shape, intensity and position of some
3
2
characteristic bands. Heating the complex at 100 °C, its IR
spectrum shows the disappearance of the broad band at
-1
perature. The third stage is a broad one in the 201–378,
73–343, 259–348, 257–344 and 243–333 °C range with
2
3
414 cm
indicating dehydration [30]. Also, medium
-1
broad band shown at 3432 cm may be due to coordinated
DTG maxima at 364, 302, 303 and 307, 278 °C, respec-
tively, which represents decomposition of coordinated
water for the above-mentioned complexes which is con-
firmed by endothermic DTA peaks at 347, 308, 309, 314
and 279 °C, respectively. This shows that the coordinated
water in the complex 1 evaporates at the higher tempera-
ture in the above series of the complexes. It reflects the
strong bonding in the coordination sphere of the complex 1
due to the formation of covalent bond where deprotonation
of the metformin C=NH group takes place.
water. The t(NH) bands are shifted to 3317 and 3263;
-1
besides, t(C=N) appears as a sharp band at 1616 cm
.
Heating the complex at 160 °C, distinct bands of t(CH ) at
3
-1
3084 and 2977 cm
were not observed, indicating
cleavage of the ligand and evolution of NH(CH ) species.
3
2
IR spectrum of heated sample at 370 °C showing new
medium broad band at 3440, 2923, 2854 and 1622 cm
-1
may be assigned to t(OH), t(CH ) and d(OH). Also, t(NH)
2
frequency completely disappeared, referring to cleavage of
The second and third decomposition steps for the com-
plex 5 include vaporization of H O ? NH(CH ) and H
the metformin part in the Schiff-base. Appearance of new
-1
bands at 3480 and 1626 cm in the IR spectrum of heated
2
3 2
2-
O ? NH(CH=NH) at 225 and 318 °C accompanied with
2
sample at 420 °C refers to the formation of a mixture of
aqua-hydroxo species [45]. IR bands characteristic for the
presence of vanadium oxide is shown as strong broad band
endothermic DTA peaks at 237 and 336 °C. This decom-
position mode reinforces the presence of two coordinated
water molecules in two different positions in the complex
structure. Final decomposition of this complex is obtained
at 477 °C with loss of the species C H ? H O ? NH=CH
-1
-1
at 533 cm and medium split band at 1009 and 988 cm
46]. Proposed mechanism of thermal decomposition of the
complex 1 is shown as follows:
[
6
6
2
associated with endothermic DTA peak at 473 °C. The
1
23

Synthesis, spectral, thermal and insulin-enhancing properties of oxovanadium(IV) complexes of…
Table 8 Effect of metformin (20 and 40 mg/kg) and the complexes 1 and 4 on survival %, blood glucose, total cholesterol and serum ALT and
AST activities in the experimental groups
-1
-1
-1
-1
Groups
Survival %
Blood glucose/mg dL
Total cholesterol/mg dL
ALT/U L
AST/U/L
Vehicle
100
79.99 ± 6.66
401.67 ± 35.87
212.3 ± 34.95*
188.5 ± 1.8*
69 ± 10.4
126 ± 11*
129 ± 13*
121 ± 29*
24.5 ± 4
76.8 ± 3
65.9 ± 7
Diabetic
83.33
100
44.5 ± 5*
56.5 ± 5*
52.3 ± 5*
56.5 ± 6*
51.7 ± 5*
49.3 ± 5*
47 ± 5*
D
D
Metformin (20 mg/kg)
Metformin (40 mg/kg)
Complex 1 (20 mg/kg)
Complex 1 (40 mg/kg)
Complex 4 (20 mg/kg)
Complex 4 (40 mg/kg)
126.4 ± 20*
128 ± 20*
100
M
DM
83.33
83.33
100
163.4 ± 17.9*
144.25 ± 47.67*
165.5 ± 13.64*
126 ± 31*
88.18 ± 14
M
DM
100 ± 41*
97.39 ± 21*
DM
85.81 ± 4
DM
72 ± 17
M
DM
DM
100
101.2 ± 8.08*
55 ± 6
101.5 ± 6*
Results are expressed as mean ± SEM and analyzed using one-way ANOVA followed by Bonferroni’s post hoc test
ALT alanine aminotransferase, AST aspartate aminotransferase
*
D
P \ 0.05 compared to vehicle group
P \ 0.05 compared to diabetic group
M
P \ 0.05 compared to corresponding metformin group
2
1
1
0
6
2
8
4
0
Complex 1
Vehicle
Complex 4
Diabetic
Fig. 5 Mean diameter for pancreatic islets in the experimental groups
therapeutic period (14 days), mice treated with metformin
showed blood glucose levels lower than that measured in
diabetic control group (P \ 0.05, Table 8) by 47.14
-
1
-1
(
20 mg kg ) and 53.07% (40 mg kg ). Similarly, mice
treated with the complexes 1 and 4 showed also lower
-1
blood glucose values of 59.31, 58.79 (20 mg kg ) and
Fig. 4 Sections from the pancreas stained with hematoxylin and
eosin
-
4.98, 74.8% (40 mg kg ). These results suggested that
1
6
these complexes have a potential blood glucose-lowering
effect equivalent to previous complexes [8–12]. The dia-
betic control mice showed 83.33% survival, while mice
treated with vanadium complexes showed 83.33–100%
survival, indicating appropriate degree of safety.
Insulin-enhancing studies
In the current study, injection of mice using alloxan
-
1
150 mg kg ) produced hyperglycemia that was con-
(
firmed one week after injection and those with fasting
blood glucose greater than 200 mg/dL were considered
diabetic. The cytotoxic effects of alloxan are due to its
active damaging insulin-secreting b-pancreatic cells, lead-
ing to increased blood sugar level [47]. At the end of the
Measuring serum total cholesterol highlighted that treat-
ment with metformin did not significantly modify the total
cholesterol level compared to diabetic control. Mice treated
-
1
with the complex 1 (40 mg kg ) showed lower serum
cholesterol compared to mice treated with metformin. On the
123

M. A. Mahmoud et al.
other hand, mice treated with the complex 4 (20 or
4
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1
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