Polyhedron 28 (2009) 3993–3998

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Polyhedron
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Synthesis, structural characterization, and anti-ulcerogenic activity of schiff

base ligands derived from tryptamine and 5-chloro, 5-nitro, 3,5-ditertiarybutyl
salicylaldehyde and their nickel(II), copper(II), and zinc(II) complexes
I. Mohamed Mustafa a,*, M.A. Hapipah a, Mahmood Ameen Abdulla b, T. Robinson Ward a
a
Department of Chemistry, Faculty of Science, University Malaya, 50603 Kuala Lumpur, Malaysia
b
Department of Molecular Medicine, Faculty of Medicine, University of Malaya, 50603 Kuala Lumpur, Malaysia

a r t i c l e i n f o a b s t r a c t

Article history: Ni(II), Cu(II), and Zn(II) complexes with bidentate Schiff bases derived from the condensation reaction of
Received 31 August 2009 5-chlorosalicylaldehyde, 5-nitrosalicylaldehyde, and 3,5 ditertiarybutyl-2-hydroxy benzaldehyde with
Accepted 1 October 2009 tryptamine, have been reported. The ligands and complexes were characterized by elemental analysis,
Available online 6 October 2009
IR, 1H NMR and UV–Vis spectroscopy as well as single crystal X-ray structure analysis whenever possible.
The complexes were found to have the general formula [M(L)2]. Spectral studies reveal that these Schiff
Keywords: bases were acting as bidentate ligands and co-ordinating to the metal center through deprotonated phe-
Tryptamine
nolate oxygen and azomethine nitrogen atoms. The Zn(II) complexes establish a tetrahedral geometry in
Metal complexes
Anti-ulcerogenic activity
a 1:2 metal to ligand stoichiometry, whereas a square planar geometry was proposed for the nickel and
Crystal structure copper complexes, slightly distorted in the case of the latter.
The antiulcer activity of 5-chlorosalicylaldehyde derivative and its nickel and copper complexes were
evaluated in ethanol-induced gastric mucosal injury in rats. This Schiff base and its complexes promote
ulcer protection as ascertained by the comparative decrease in ulcer areas, and inhibition of edema and
leucocyte infiltration of the submucosal layer.
Ó 2009 Elsevier Ltd. All rights reserved.

1. Introduction Continuing this field of study, we describe here the preparation

Schiff bases are compounds containing an azomethine group
(–C@N–), have drawn attention for many years ago. Their metal
complexes have been studied, with a variety of transition metal
ions, since they frequently exhibit unusual structural properties
[1]. These properties have resulted in wide applications in the bio-
logical field [2–4]. Copper(II) complexes are known to be effective
against rheumatoid arthritis and they also show anti-ulcer activity
[5,6]. This is significant because gastrointestinal irritation often
precludes treatment by other antiarthritic drugs. This is in line
with the role of copper in generally preventing gastrointestinal
damage by acidic anti-inflammatory agents [6].
Some Schiff base complexes are also used as model molecules
for biological oxygen carrier systems [7–10] as well as having
applications in analytical fields [11].
There have been limited studies of metal complexes of the
Schiff base: 1H-indole-3-ethylenesalicyldamine and its derivatives
[12,13], and there are no data available regarding biological activ-
ities of these compounds.
* Corresponding author. Tel.: +60 3 79677155; fax: +60 3 79674193.
E-mail address: mohd_hashm4@hotmail.com (I.M. Mustafa).
of Schiff bases derived from the condensation reaction of trypt-
amine with 5-chlorosalicylaldehyde (TCS), 5-nitrosalicylaldehyde,
(TNS) and 3,5 di-tert-butyl-2-hydroxybenzaldehyde (TTET), and
their metal complexes with Ni(II), Cu(II), and Zn(II) together with
the evaluation of anti-ulcerogenic properties of TCS and its nickel
and copper complexes.
2. Experimental
2.1. Materials
Chemicals were purchased from Sigma–Aldrich and used with-
out further purification, ethanol was redistilled before use. Dry
dimethylsulfoxide and dimethylformamide were utilized for
recrystallization purposes.
2.2. Physical measurements
IR spectra were recorded with a Perkin–Elmer FT-IR spectro-
photometer model Spectrum 2000 using KBr pellets as support in
the range 4000–370 cm1. 1H NMR spectra were recorded at room
temperature on a JEOL ECA-400 spectrometer, operating with a fre-
quency of 400 MHz, using DMSO-d6 as solvent. Electronic spectra,

0277-5387/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.poly.2009.10.004
3994 I.M. Mustafa et al. / Polyhedron 28 (2009) 3993–3998

in DMSO solution, were obtained using a Varian 50 Conc UV–visi-
ble spectrophotometer over the wavelength range 200–800 nm.
Magnetic susceptibility data were obtained from powdered sam-
ples using a Sherwood Scientific magnetic susceptibility balance.
The effective magnetic moments were calculated from the expres-
pffiffiffi
sion (leff = 2.83 vM T) BM, where vM is the molar susceptibility
corrected using Pascal’s constants for diamagnetism of all atoms
in the compounds.
2.3. Preparation of the ligands
2.4.4. TNS nickel complex
Percentage yield (76%). The compound is insoluble in most or-
ganic solvents, but soluble in DMSO and DMF. Anal. Calc. for
C34H28N6O6Ni: C, 60.41; H, 4.14; N, 12.43. Found: C, 60.32; H,
4.24; N, 12.21%.
2.4.5. TNS copper complex
Percentage yield (76%). The compound is soluble in THF, DMSO,
and DMF. Anal. Calc. for C34H28N6O6Cu: C, 59.98; H, 4.11; N, 12.35.
Found: C, 59.62; H, 4.32; N, 12.17%.

2.3.1. Preparation of TCS 2.4.6. TTET zinc and nickel complexes

A solution of tryptamine (0.3 g, 1.9 mmol) in 50 ml of acidified
ethanol (pH 4.5) was added to a boiling solution of 5-chlorosalicyl-
aldehyde (0.29 g, 1.8 mmol) in 50 ml of acidified ethanol (pH 4.5).
The mixture was refluxed for 2 h. The solid product that had
formed was filtered off, and recrystallized from ethanol. Yield
79%. The compound was soluble in ethanol, methanol, acetone,
THF, and DMSO, but insoluble in water. Anal. Calc. for C17H15N2OCl:
C, 68.34; H, 5.06; N, 9.38. Found: C, 68.26; H, 4.96; N, 9.16%.
For the zinc complex the percentage yield is (72%). The com-
pound is sparingly soluble in ethanol and methanol but dissolves
in acetone, THF, and DMSO. Anal. Calc. for C50H62N4O2Zn: C,
73.48; H, 7.59; N, 6.85. Found: C, 73.24; H, 7.35; N, 6.80%.
For the nickel complex the percentage yield is (53%). The com-
pound is soluble in acetone, THF, and DMSO. Anal. Calc. for
C50H62N4O2Ni: C, 74.09; H, 7.65; N, 6.91. Found: C, 74.15; H,
7.56; N, 6.78%.

2.4.7. TTET copper complex

2.3.2. Preparation of TNS
TNS was obtained, following the same procedure as for TCS, by
adding relevant amounts of tryptamine and 5-nitrosalisylaldehyde.
The product was recrystallized from THF (Yield 54%) and is soluble
in acetone, THF, and DMSO, but not soluble in either ethanol or
water. Anal. Calc. for C17H15N3O3: C, 66.01; H, 4.89; N, 13.58.
Found: C, 65.97; H, 4.79; N, 13.63%.
2.3.3. Preparation of TTET
TTET was also obtained by the same procedure using stoichiom-
etric amounts of tryptamine and 3,5-ditertiarybutyl-2-hydroxy-
benzaldehyde. The product was recrystallized from ethanol (Yield
74.4%). The compound is readily soluble in ethanol, methanol,
and most organic solvents, but insoluble in n-hexane. Anal. Calc.
for C25H32N2O: C, 79.75; H, 8.57; N, 7.44. Found: C, 79.58; H,
8.72; N, 7.22%.
Percentage yield (70%). The compound is soluble in acetone,
THF, and DMSO. Anal. Calc. for C50H62N4O2Cu: C, 73.65; H, 7.61;
N, 6.87. Found: C, 73.38; H, 7.88; N, 6.90%.
2.5. Crystallographic measurement
Pale yellow crystals for the complex were obtained from DMSO.
The unit cell constants and crystal orientation matrix for the com-
plex were defined by a least squares fit to the angular positions of
6794 accurately located reflections in the range 4.8 < 2h < 53.2.
Intensity data for the complex were collected at 100 K, using the
x-scan technique, up to 2h = 60° and an APEX-2 area detector dif-
fractometer. A total of 7854 independent reflections were collected
using Mo Ka X-radiation. Unique reflections (5138) having I > 2r(I)
were used in the refinement of the crystal structure. The structure
was solved by direct methods [14]. Hydrogen atoms were included

2.4. General method of preparation of the complexes Table 1

Crystal data and structure refinement details for: Zn(TTET)2 complex.
To solutions of nickel acetate tetrahydrate, copper acetate Chemical formula C54H74N4O4S2Zn
monohydrate or zinc acetate dehydrate (1 mmol) in absolute eth- Formula weight 972.66
anol (50 ml), were added solutions of the appropriate Schiff base Temperature 100(2) K
Wavelength 0.71073 Å
(2 mmol) in the same solvent (20 ml), followed by a few drops of
Crystal system orthorhombic
triethylamine. The mixtures were heated under reflux for 5 h. Space group Pbcn
The product that had formed was filtered off, washed with absolute
Unit cell dimensions
ethanol and dried over anhydrous silica gel. a (Å) 19.9694(4)
b (Å) 8.1019(2)
c (Å) 32.7530(6)
2.4.1. TCS nickel complex Volume (Å3) 5299.11(19)
Percentage yield (70%). The compound is soluble in THF, DMSO, Z 8
and DMF. Anal. Calc. for C34H28N4O2Cl2Ni: C, 62.36; H, 4.28; N, 8.56. Calculated density (mg/m3) 1.219
Found: C, 62.55; H, 4.37; N, 8.24%. Absorption coefficient (l) (mm1) 0.589
F(0 0 0) 2080
Crystal size (mm) 0.40  0.07  0.03
2.4.2. TCS copper complex h Range for data collection 2.04–30.51°
Reflections collected/unique 55274/7854 [Rint = 0.0793]
Percentage yield (85%). The compound is insoluble in most or-
Completeness to h = 25.00 100.0%
ganic solvents, but soluble in DMSO. Anal. Calc. for C34H28N4O2Cl2- Absorption correction Semi-empirical from
Cu: C, 61.90; H, 4.25; N, 8.49%. Found: C, 61.78; H, 4.32; N, 8.52%. equivalents
Max. and min. transmission 0.9826 and 0.7986
Refinement method Full-matrix least-squares on F2
2.4.3. TNS zinc complex Data/restraints/parameters 7854/78/336
Percentage yield (59%). The compound is insoluble in ethanol, Goodness-of-fit on F2 1.019
methanol, or acetone, but dissolves in THF and DMSO. Anal. Calc. Final R indices [I > 2r(I)] R1 = 0.0541, wR2 = 0.1271
R indices (all data) R1 = 0.0996, wR2 = 0.1485
for C34H28N6O6Zn: C, 59.82; H, 4.10; N, 12.31. Found: C, 59.67; H,
Largest difference in peak and hole (e A3) 0.803 and 0.606
4.32; N, 12.65%.
 I.M. Mustafa et al. / Polyhedron 28 (2009) 3993–3998 3995

in calculated positions. Scattering factors were taken from interna-
tional tables [15]. The structure refinement converged to a final
conventional R1 factor = 0.054. Crystal data and structure refine-
ment details are given in Table 1.
2.6. Experimental animal
Adult male Sprague-Dawley rats were obtained from the Ani-
mal House, Faculty of Medicine, University of Malaya, Kuala Lum-
pur (Ethics No. PM 28/9/2007 MAA (R)). The rats weighed between
200 and 220 g. They were fasted for 48 h before the experiment
[16], but were allowed free access to drinking water till two hours
before the experiment. During the fasting period, the rats were
placed in four cages, with wide-mesh wire bottoms to prevent cop-
rophagia, each cage contains six randomly selected rats.
Gastric ulcer was induced according to the method described by
Robert et al. [17] with some modification in adult male Sprague-
Dawley rats. Group 1 rats were negative controls that received
10 ml/kg of 10% Tween-20 orally by orogastric intubations;
whereas Group 2 rats received oral doses of 50 mg/kg Cimetidine
(10 ml/kg) as positive controls. Group 3 and 4 rats received oral
high dose (250 mg/kg) and low dose (62.5 mg/kg) of different syn-
thesized Schiff bases and complexes, respectively. One hour after
this pre-treatment, rats were gavaged with absolute ethanol
(5 ml/kg) in order to induce gastric ulcers. The rats were eutha-
nized 60 min later [18] by overdoses of diethyl ether and their
stomachs were immediately excised. Each stomach was opened
along the greater curvature, washed with distilled water and fixed
in 10% buffered formalin for 15 min.
The stomachs were removed and the gastric juice was obtained
from each stomach. The surface area (mm2) covered by each lesion
was measured [19], and the sum of erosion areas per rat stomach
was estimated by using a microscope at magnification 1.8. Per-
centage ulcerated surface (US), was calculated as: US (mm2) = (to-
tal area covered by ulcers/total corpus mucosal surface)  100. The
ulcer index (UI) for each animal was then calculated as the mean
ulcer score. Percentage inhibition (%I) was determined as [(UI in
controlUI in test group)/UI in control group]  100 [20].
After the stomach contents were collected, they were centri-
fuged and gastric juice was separated from the mucus. The mucus
content was weighed and expressed in terms of grams [21] and the
pH of the stomach juice was recorded.
The acute toxicity study was used to determine a safe dose for
the compounds TCS, (TCS)2Ni, and (TCS)2Cu. Thirty six ICR mice
(18 males and 18 females) were assigned equally into 3 groups la-
beled as vehicle 10% Tween-20 (5 ml/kg); 2 g/kg, and 5 g/kg for
each of the compounds in 10% Tween-20 preparation. These ani-
mals were subjected to overnight fasting (food but not water) prior
to dosing. Food was withheld for a further 3–4 h after dosing. The
animals were observed for 30 min and 2, 4, 24, and 48 h after the
administration for the onset of clinical or toxicological symptoms.
Mortality, if any was observed over a period of 2 weeks.
3. Results and discussion
3.1. Characterization of ligands and complexes
3.1.1. Infrared spectroscopy
The IR spectra of the ligands and complexes have been summa-
rized in Table 2. It can be clearly shown that the absence of the
characteristic aldehydic carbonyl stretching bands, and the appear-
ance of the azomethine –C@N– bands, at 1630 cm1, 1647 cm1,
and 1633 cm1 for TCS, TNS, and TTET, respectively indicates the
formation of the Schiff base. The broad band at 3054–2948 could
be attributed to the intra-molecular hydrogen-bonded O–H group
[22]. This band was absent in the spectra of complexes due to
deprotonation upon complexation. The metal ion is coordinated
through the oxygen atom of the hydroxyl group. The azomethine
–C@N– bands have been shifted to lower frequencies in all com-
plexes due to the withdrawal of electron density from the nitrogen
atom owing to co-ordination [22]. A similar effect was observed in
the stretching vibration of the Schiff base phenolic C–O group, with
respect to the same group in the complexes where it was shifted to
higher frequency, confirming oxygen co-ordination to the metal
[12]. In TNS the band at 1541 cm1 could be ascribed to the vibra-
tions of the nitro group [22]. New bands in the region 588–

Table 2
IR spectra of the ligands and complexes.

Compound N–H O–H C–H aliphatic C@N C–O C–H aromatic bend M–O M–N
TCS 3433 3054 2948 1630 1280 746 – –
Ni(TCS)2 3431 – 2917 1617 1326 739 463 420
Cu(TCS)2 3431 – 2912 1620 1324 739 452 420
TNS 3360 – 1647 1296 741 - -
Zn(TNS)2 3414 – 2925 1635 1316 739 518 425
Ni(TNS)2 3346 – 2951 1613 1315 740 481
Cu(TNS)2 3399 – 2913 1619 1301 739 588 419
TTET 3400 overlap 2953 1633 1248 750 – –
Zn(TTET)2 3402 – 2958 1618 1254 743 540 486
Ni(TTET)2 3404 – 2958 1613 1255 742 542 485
Cu(TTET)2 3427 – 2954 1618 1257 745 539 476

Table 3
1
H NMR spectra of ligands and complexes.

Cpd Ha Hb Hc Hd He Hf Hg Haromatic
1
H NMR chemical shifts in ppm
TCS 10.80(s) 3.04(t) 3.85(t) 8.41(s) 12.80(s) – – 6.82–7.42(m)
TNS 10.89(s) 3.12(t) 3.92(t) 8.59(s) 12.89(s) – – 6.54–7.98(m)
Zn(TNS)2 10.77(s) 2.94(t) 3.86(t) 8.52(s) – – – 6.68–8.29(m)
TTET 10.81(s) 3.05(t) 3.85(t) 8.49(s) 12.82(s) 1.30(s) 1.27(s) 6.93–7.62(m)
Zn(TTET)2 10.77(d) 3.03(t) 3.81(t) 8.49(s) – 1.34(s) 1.24(s) 6.68–7.36(m)

Key: t = triplet, s = singlet, d = doublet, m = multiplet.

3996 I.M. Mustafa et al. / Polyhedron 28 (2009) 3993–3998

420 cm1 were assigned to vibrations associated with M–N and M– lengths and intensity. For Ni complexes, the charge transfer bands
O bonds, respectively [23,24]. at 384–410 nm are more intense with respect to the same band in
related compounds reported in the literature [25]. The rest of the
3.1.2. Proton NMR spectra bands at 273 nm and 226 nm are associated with the p–p* transi-
1
H NMR spectra of ligands and complexes are given in Table 3. tions of the ligand. Ni(TCS)2 is diamagnetic, which is consistent
The spectra of the Schiff bases were consistent with the structures with a tetra coordinated planar complex [28,29]. It has also been
proposed (Fig. 1). Eight aromatic protons were observed in the re- reported that nickel(II) complexes, with salicylaldimine ligands
gion of d 6.82–7.42 ppm as a multiplet in the case of TCS and in the
region of d 6.54–7.98 ppm in the case of TNS, but only 7 protons in
Table 4
the range of d 6.93–7.62 ppm for TTET. Additional singlets are also UV spectra of ligands and complexes.
observed for TTET at d 1.30 and 1.27 ppm due to the tertiary butyl
protons (f) and (g) (Fig. 2). It is important to mention here that no Compound Conc. e (mol1 cm1) kmax Assignment
(mol/L) (nm)
clear NMR spectrum can be reported for Ni and Cu complexes due
to paramagnetic effects in these complexes. TCS 4.01  104 684.7 419.5 n–p*
7.72  103 265 p–p* chelate ring
Ni(TCS)2 4.20  105 1.06  104 384.5 CT
3.1.3. UV–Vis spectroscopy and magnetic measurements 2.83  104 273.5 p–p* ligand
The electronic spectra of the compounds with their assignments 620 d–d transition
are given in Table 4 Cu(TCS)2 4.17  105 9.73  103 373 CT, n–p*
2.23  104 260 p–p* ligand
The UV–Vis spectra of the ligands looks closely similar to the
685 d–d transition
spectra of Sal–Tpa reported by Martin Reyes et al. [12] with some TNS 9.70  105 1.40  104 420 n–p*
shifts in the position of the bands. The bands between 284.9 and 1.20  104 260 p–p* chelate ring
400 nm were assigned to p–p* transitions of the chelate ring Zn(TNS)2 5.50  105 3.01  104 377.5 CT, n–p*
[25]. There is no large shift for these bands, with respect to the nat- 2.22  104 260 p–p* indole group
Ni(TNS)2 3.70  105 5.87  104 410 CT
ure of the substituent in the fifth position, in comparison with the 2.84  104 283 p–p* ligand
unsubstituted ligand Sal–Tpa reported in the literature [12]. The Cu(TNS)2 3.67  105 4.25  104 383 CT, n–p*
bands between 205 and 270 nm in the ligands could be assigned 4.03  104 261 p–p* ligand
to the indole group p–p* transitions, while the bands between 630 d–d transition
TTET 3.45  104 376.5 417 n–p*
417 and 420 nm could be attributed to n–p*[26]. The double band
9.77  103 267 p–p* chelate ring
in the region 260–267 nm is characteristic of hydrogen-bonded p– Zn(TTET)2 1.60  104 9.32  104 381.5 CT, n–p*
p* transitions, indicating an equilibrium between ketoic and enolic 1.93  104 283 p–p* ligand
forms [27]. The spectra of the complexes generally show the char- Ni(TTET)2 1.50  104 7.65  103 385 CT
acteristic bands of the free ligand with some changes both in wave 2.67  104 281 p–p* ligand
Cu(TTET)2 1.60  104 1.09  104 377 CT, n–p*
1.07  104 325 p–p* ligand

R
b
H H
Table 5
N C Selected bond lengths (Å) and bond angles (°) for Zn(TTET)2 complex.
H
Zn–O(1) 1.9121(15)
d
Zn–N(1) 1.993(2)
H H N(1)–C(7) 1.281(3)
c HO N(1)–C(8) 1.468(3)
e O(1)–C(1) 1.315(3)
N C(1)–C(6) 1.427(3)
C(1)–C(2) 1.433(3)
C(2)–C(3) 1.385(3)
H
C(2)–C(20) 1.540(3)
a
C(3)–C(4) 1.409(3)
C(4)–C(5) 1.371(3)
p R = Cl , NO2 C(14)–C(15) 1.399(5)
C(15)–C(16) 1.369(5)
Fig. 1. Different kinds of protons for TCS and TNS. C(16)–C(17) 1.395(4)
C(20)–C(22) 1.526(4)
C(20)–C(23) 1.528(4)
C(20)–C(21) 1.538(4)
C(CH3)3
b Bond angles
g
H H O(1)–Zn–O(10 ) 116.04(10)
O(1)–Zn–N(1) 95.89(7)
N C N(1)–Zn–N(10 ) 105.87(12)
H C(7)–N(1)–C(8) 117.5(2)
d C(7)–N(1)–Zn 120.34(16)
H H C(8)–N(1)–Zn 122.07(16)
c HO C(CH3)3 C(1)–O(1)–Zn 125.73(14)
e C(13)–C(12)–C(11) 133.9(2)
f
N C(17)–C(12)–C(11) 107.0(2)
C(14)–C(13)–H(13) 121.0
C(12)–C(13)–H(13) 121.0
H C(13)–C(14)–C(15) 121.7(3)
a C(13)–C(14)–H(14) 119.2
C(15)–C(14)–H(14) 119.2
Fig. 2. Different kinds of protons for TTET.
 I.M. Mustafa et al. / Polyhedron 28 (2009) 3993–3998 3997

adopt square planar co-ordination geometries. Thus, square planar
geometry is proposed for this complex as well [28]. The Ni(TTET)2
complex appears amorphous in the solid state, and could be an oli-
gomer between the planar and tetrahedral coordination forms
with a magnetic moment of 2.87 BM [30]. Ni(TNS)2 has an excep-
tionally low magnetic moment of 1.40 BM at room temperature.
For copper complexes, the electronic spectra show bands be-
tween 260 and 261 nm, which can be attributed to p–p* transitions
of the ligands. The bands between 373 and 383 nm are attributable
to charge transfer between the metal and the ligand. The magnetic
moment of Cu(TCS)2 is 1.86 BM at room temperature. This behav-
ior is in agreement with the presence of isolated trans-planar para-
magnetic species [25], whereas the Cu(TNS)2 complex shows a
magnetic moment of 2.1 BM at room temperature which is in a
good agreement with analogous copper(II) complexes with
pseudotetrahedral geometry around the copper ion [31,32].
For nickel, and copper complexes, the bands appear at 620 nm
for Ni(TCS)2, 685 nm for Cu(TCS)2, and 630 nm for Cu(TNS)2 are
assignable to d–d transitions and are similar to those observed
for related complexes with planar co-ordination geometries [28].
3.1.4. The crystal structure of Zn(TTET)2
Only the X-ray crystal structure analysis of the Zn(TTET)2 com-
plex will be described here. An X-ray structure analysis of TNS has
been described previously in the literature [33].
Selected bond lengths and bond angles are summarized in Table
5. A perspective view of the complex is given in Fig. 3. Because the
zinc atom lies on a crystallographic 2-fold rotational axis of
symmetry, it must be coordinated to two Schiff base ligand mole-
cules. Bonding is through the deprotonated phenolate oxygen atom
O1 and the azomethine nitrogen atom N1. Zinc coordination is only
approximately tetrahedral, since the angles O1–Zn–O10 16.04(10)),
O1–Zn–N1 (95.89(7)) and N1–Zn–N10 (105.87(12)) differ signifi-
cantly from the normal tetrahedral angle. The tertiary butyl group,
connected to C4 of the salicylaldehyde moiety, is rotationally dis-
ordered around C4–C40 bond. Both this molecule and one solvate
DMSO molecule are disordered in the crystal structure. The DMSO
disorder is complex, but both are adequately modeled. In a similar
compound [34], the angle N1–Zn–N10 which is 105.87(12) Å here,
is larger than the corresponding angle (99.56(8)) in bis{4-chloro-
2-[2-(1H-indol-3-yl)ethyliminomethyl] phenolato-j2 N,O} zinc(II).
This may be due to the steric effects exerted by the bulky tertiary
butyl groups in the salicylaldehyde moiety.
3.2. Anti-ulcerogenic activity
The administration of ethanol to rats produces gastric mucosal
lesions and erosions similar to those occurring in gastric ulcers.
These lesions are produced because ethanol can affect the protec-
tive defense mechanisms at the mucus [35].
The administration of salicylaldimine Schiff bases and com-
plexes 30 min before the administration of absolute ethanol leads
to good prevention results in reducing or eliminating the lesions.

Fig. 3. Perspective view of Zn(TTET)2 drawn at the 50% probability level. Hydrogen atoms are shown as spheres of arbitrary radii.

Table 6
Observed mucus weight, pH, ulcer area, and inhibition percentage in rats.

Animal group Pre-treatment Mucus weight (g) pH of gastric content Ulcer area (mm)2 (mean ± SEM) Inhibition (%)
a a
1 Tween-20 (ve control) 0.58 ± 0.03 7.00 ± 0.11 1438 ± 56.56 –
2 Cimetidine (+ve control) 0.61 ± 0.02ab 7.00 ± 0.19 168 ± 4.93bg 88.32
3 TCS (LD) 1.22 ± 0.09c 3.68 ± 0.09 0.00 ± 0.00cf 100
4 TCS (HD) 1.10 ± 0.05c 7.00 ± 0.13 262.8 ± 0.83db 81.72
5 Ni(TCS)2 (LD) 1.18 ± 0.04c 4.02 ± 0.05 117.6 ± 1.05eg 91.82
6 Ni(TCS)2 (HD) 1.58 ± 0.03d 7.00 ± 0.12 38.4 ± 0.18fe 97.33
7 Cu(TCS)2 (LD) 2.03 ± 0.04e 2.80 ± 0.13 4.80 ± 0.40h 99.66
8 Cu(TCS)2 (HD) 2.84 ± 0.06e 2.35 ± 0.09 2.4 ± 0.34h 99.83

All values are expressed as mean ± standard error mean. Means with different superscripts are significantly different. The mean difference is significant at the p < 0.05 level.
LD = low dose (62.5 mg/kg), HD = high dose (250 mg/kg).
3998 I.M. Mustafa et al. / Polyhedron 28 (2009) 3993–3998
During this study, we concentrate our attention to TCS and its
nickel and copper complexes in comparison with Cimetidine (Table
6). It was observed that protection of gastric mucosa was more
prominent in rats pre-treated with low dose of TCS ligand
(62.5 mg/kg). Flattening of the mucosal folds was observed which
suggests that the gastro protective effect of the complex might
be due to a decrease in gastric motility. It is reported that the
changes in the gastric motility may play a role in the development
and prevention of experimental gastric lesions [36,37]. Relaxation
of circular muscles may protect the gastric mucosa through flatten-
ing of the folds. This will increase the mucosal area exposed to nec-
rotizing agents and reduce the volume of the gastric irritants on
rugal crest [38]. Ethanol produces a marked contraction of the cir-
cular muscles of rat fundic strip, and such a contraction can lead to
mucosal compression at the site of the greatest mechanical stress,
at the crests of mucosal folds leading to necrosis and ulceration
[39]. Metals like Fe, Mn, and Zn have been shown to be concerned
with the synthesis of procollagin, proelastin, or mucopolysaccha-
ride, which are necessary for healing following tissue damage,
and this study proved that nickel and copper may also have similar
effects [40]. The acute toxicity profile of the compounds could be
considered favorable judging from the high oral LD50 value ob-
tained and the absence of adverse clinical manifestations in exper-
imental animals after two week of observation. It is concluded that
acute toxicity study with a dose of 2 g/kg did not manifest any tox-
icological signs in mice and that the oral lethal dose for male and
female mice is in excess of 2 g/kg. Based on these acute toxicity
tests, the compounds were found safe. This implies a high thera-
peutic index, which is ideal for any drug. Further studies are rec-
ommended, in particular, to detail the mechanism of action of
these bioactive compounds.
4. Conclusion
Schiff base ligands derived from tryptamine and substituted sal-
icylaldehydes, have been synthesised and characterized, and the
anti-ulcerogenic activities of TCS and its nickel and copper com-
plexes have been evaluated. The compounds could significantly
protect the gastric mucosa against ethanol-induced injury. Such
protection was ascertained by the reduction of gastric ulcer areas
and by the production of mucus. Further studies are required to en-
hance the aqueous solubility of these compounds, for instance,
through inclusion complexes or salt formation and to determine
the active ingredients, and the mechanism responsible for the anti-
ulcer activity.
Supplementary data
CCDC 742572 contains the supplementary crystallographic data
for Zn(TTET)2. These data can be obtained free of charge via http://
www.ccdc.cam.ac.uk/conts/retrieving.html, or from 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.
Acknowledgement
The authors thankfully acknowledge support from University
Malaya IPPP Grant No. PS145/2007B for financial assistance. We
also convey acknowledgement to UM colleagues for CHN analysis.
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