Synthesis, characterization and antibacterial activities of Zn(II) and Cd(II) complexes of a 3-amino-2-phenylquinazolin-4(3H )- -one Schiff base

Article abstract of DOI:10.2298/JSC140130093B

Zn(II) and Cd(II) complexes of a Schiff base derived from 3-amino-2-phenylquinazolin-4(3H)-one and 2-(2-formylphenoxy) acetic acid were prepared and characterized by elemental and different spectroscopic (IR, UV-Vis and NMR) analyses. The elemental analys

Full text of DOI:10.2298/JSC140130093B

J. Serb. Chem. Soc. 79 (12) 1505–1513 (2014)
JSCS–4683
UDC 546.472’482+547.856:542.9+
547.571+547.551:615.281–188
Original scientific paper
Synthesis, characterization and antibacterial activities of Zn(II)
and Cd(II) complexes of a 3-amino-2-phenylquinazolin-4(3H)-
-one Schiff base
*
DHIRAJ BRAHMAN and BISWAJIT SINHA
Department of Chemistry, University of North Bengal, Darjeeling-734013, India
(Received 30 January, revised 18 June, accepted 11 September 2014)
Abstract: Zn(II) and Cd(II) complexes of a Schiff base derived from 3-amino-
2-phenylquinazolin-4(3H)-one and 2-(2-formylphenoxy) acetic acid were pre-
pared and characterized by elemental and different spectroscopic (IR, UV–Vis
and NMR) analyses. The elemental analysis indicated the formation of the
complexes: [ML(AcO)]·H2O, where M stands for Zn(II) or Cd(II) and L stands
for the Schiff base. The molar conductivities of the prepared complexes
revealed their non-electrolytic nature. The complexes were also investigated for
their antimicrobial activities using the turbidimetric assay method.
Keywords: Zn(II); Cd(II); quinazolin-4(3H)-one Schiff base; 2-(2-formylphen-
oxy) acetic acid; antibacterial activities.
INTRODUCTION
Schiff bases derived from an amine and aldehydes are an important class of
1–3
ligands that co-ordinate to metal ions through the azomethine nitrogen.
Among the wide variety of nitrogen-containing heterocycles explored for the
development of pharmaceutically important molecules, quinazoline is an impor-
tant compound in medicinal chemistry and subsequently have emerged as an
4
important pharmacophore. The quinazoline moiety has O and N donor atoms
and can act, therefore, as a good chelating agent. Quinazolin-4(3H)-one and its
derivatives are versatile nitrogen-containing heterocyclic compounds that have
5
long been known as a promising class of biologically active compounds. Com-
pounds containing 4(3H)-quinazolinone ring system were reported to possess
varied biological activities, such as antibacterial, antifungal, antitubercular,
antiviral, anticancer and anticonvulsant activities, depending on the substituents
6–9
in the ring system.
*Corresponding author. E-mail: biswachem@gmail.com
doi: 10.2298/JSC140130093B
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1506
BRAHMAN and SINHA
The aldehydic precursor 2-(2-formylphenoxy) acetic acid plays an important
role in reducing the toxicity of the parent drug and acts as a part of a pro-drug
10,11
12–19
called aconiazide.
A survey of the literature
revealed that the reaction
of quinazoline hydrazide 2 and 2-(2-formylphenoxy) acetic acid has hitherto
remained unattended. Therefore, it was thought worthwhile to synthesize a novel
quinazoline Schiff base and its complexes with transition metals. Hence, in this
work, the synthesis and characterization of the Schiff base ligand derived from
quinazolin-4-(3H)-one and 2-(2-formylphenoxy) acetic acid and its mononuclear
complexes with Zn(II) and Cd(II) ions are reported.
EXPERIMENTAL
Materials and measurements
Pyridine, benzoyl chloride, anthranilic acid, hydrazine hydrate, salicylaldehyde, mono-
chloroacetic acid, cadmium acetate dihydrate and zinc acetate dihydrate were procured from
S. D. Fine Chemicals, India. Except monochloroacetic acid (purity 98 %) and hydrazine
hydrate (purity 80 %), all the chemicals were of 99 % purity. The spectroscopic grade solvents
were also purchased from S. D. Fine Chemicals, India and used without further purification.
2-(2-Formylphenoxy) acetic acid and quinazolin-4(3H)-one were prepared by following rep-
orted procedures.20,21
The FT-IR spectra of the ligand and metal complexes were recorded in KBr discs in the
1
range 400–4000 cm-1 using a Shimadzu FTIR 8300 spectrophotometer. H- and 13C-NMR
spectra were recorded on an FT-NMR Bruker Advance II 400 MHz spectrometer with TMS as
the internal standard. Mass spectrum of the ligand was recorded employing a ZQMAA225
mass spectrometer using acetonitrile as a solvent. Due to the poor solubility of the synthesized
metal complexes in common solvents, their masses were not recorded. The UV–Vis spectra
were measured in DMF with a JascoV-530 spectrophotometer. Elemental microanalyses were
realized using a CHNOS elemental analyzer (Model 550 Carlo-Erba). The molar conduct-
ances of the complexes (1×10-3 mol dm-3) were measured in DMF with a Systronic-308
conductivity bridge at 25 °C under atmospheric pressure. The melting points of the ligand and
the complexes were determined using the open capillary method.
Synthesis of the ligand
The syntheses of 3-amino-2-phenylquinazolin-4(3H)-one was reported earlier.21 The
synthesis of 3-amino-2-phenylquinazolin-4(3H)-one is shown in Scheme 1. A mixture of
2-phenyl-4H-3,1-benzoxazin-4-one (2.23 g, 0.01 mol), 1, and hydrazine hydrate (0.5 mL, 0.01
mol) in ethanol was refluxed for 8 h. The excess of solvent was then evaporated and the
Scheme 1. The synthesis of the ligand (LH): 1, 2-phenyl-4H-3,1-benzoxazin-4-one;
2, 3-amino-2-phenylquinazolin-4(3H)-one; 3, the ligand (LH).
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Zn(II) AND Cd(II) COMPLEXES OF A QUINAZOLIN-4(3H)-ONE SCHIFF BASE
1507
resulting solid 3-amino-2-phenylquinazolin-4(3H)-one 2 was filtered off, dried under vacuum
and recrystallized from ethanol. Its melting point was 142 °C and its yield was 72 %.
Next, a mixture of 3-amino-2-phenylquinazolin-4(3H)-one and 2-(2-formylphenoxy)
acetic acid in equimolar amount (5 mmol each: 1.18 and 0.90 g, respectively) in absolute
ethanol was refluxed for about 5 h. The solution was then cooled and poured into ice-cold
water. The resulting white product, 2-{2-[((4-oxo-2-phenyl-3(4H)-quinazolinyl)imino)-
methyl]phenoxy}acetic acid 3 was filtered off, washed with dried ethanol and recrystallized
from ethanol.
Synthesis of complexes
A solution of 0.5 mmol of metal acetate dihydrate [Zn(II) and Cd(II)]: 0.109 and 0.134 g,
respectively) in 15 mL ethanol was added to 0.5 mmol, 0.200 g of the ligand dissolved in 20
mL absolute ethanol. The solution was heated under reflux for about 2 h. The resulting
precipitate was filtered off washed with cold dried ethanol and dried under vacuum over fused
CaCl2.
Antibacterial activity
The antibacterial activities of the ligand and its complexes were assayed against the
Gram-negative bacteria Escherichia coli (K12MTCC302) by the turbidimetric method. The
test compounds were dissolved in DMSO (SRL, Extra-pure, India) to prepare stock solutions,
which were aseptically filtered through a bacterial membrane. The required volumes of filtrate
were transferred to tubes containing a defined volume of nutrient broth to achieve the desired
concentration of the compounds. The concentrations of the tested compounds were 25, 50,
100, 200, 300, 400, 600, 800 and 1000 μg mL-1 and the standard drug for comparison was
ampicillin. A loop full of bacteria from a 24 h-old slant culture were transferred to 10 mL of
nutrient broth (Himedia M 502) and incubated at 37 °C for 6 h. The tubes in duplicate
containing 5 mL nutrient broth were incubated with 0.1 mL of a 6-h liquid culture. The tubes
containing the nutrient broth were incubated at 37 °C for 18 h and the relative growths in the
tubes were determined turbidimetrically by spectrophotometry.
RESULTS AND DISCUSSION
All the isolated compounds were found to be air-stable and were character-
ized based on elemental and different spectroscopic analyses, the results of which
are given in the Supplementary material to this paper. The metal complexes were
insoluble in common organic solvents except in DMF and DMSO.
Molar conductivity
The molar conductivity (Λ ) of the synthesized complexes were measured
M
at 25 °C and under atmospheric pressure in DMF. The molar conductivities of the
–3
–3
complexes (1×10 mol dm ) indicated that the complexes behave as non-elec-
trolytes in DMF, which suggests that no anion was present outside the coordi-
nation sphere as a counter anion of the central metal ion.
Infrared spectra of the Schiff base ligand and its complexes
The comparative IR spectral study of ligand and its complexes revealed the
coordination mode of the synthesized ligand during the complex formations. The
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1508
BRAHMAN and SINHA
–1
–1
weak broad bands at 3084 cm and 3230–3294 cm in the spectrum of the free
ligand may be attributed to the –NH stretching and the hydrogen bonded –OH of
the carboxylic moiety, respectively. In the complexes the disappearance of these
–1
bands followed by a shift of acid carbonyl from 1734.6 to 1684–1690 cm
implied deprotonation and subsequent coordination of the oxygen of carbonyl
2+
(C=O) group to the metal ions (M ). In the spectra of the free ligand and the
–1
complexes, the band at 1653.8–1654.8 cm was due to the amide C=O and this
band did not change, supporting the fact that the carbonyl oxygen of the amide
–1
did not participate in the metallation. The azomethine band at 1602.7 cm in the
spectrum of the free ligand shifted towards lower frequency range 1590–1597.9
–1
cm , which indicated coordination of the N-atom of the azomethine group to
2+
M . This fact was further supported by concomitant increase in the ν
N–N
–1
–1
stretching frequency from 930 cm towards the range 963–960 cm for free
ligand and the complexes, respectively.
ethereal oxygen (>C–O–C<) to M was confirmed by the observed frequency
increase of the 1215.1 cm band towards the range 1232–1256 cm on com-
22,23
In addition, the coordination of the
2+
–1
–1
–1
plexation. The medium intensity broad bands at 3435 and 3420 cm for the
Zn(II) and Cd(II) complexes, respectively, are due to the presence of water mole-
24
cules in the coordinating sphere. Assignment of the proposed coordination sites
was further supported by the appearance of medium bands at 592.1 and 594.1
–1
25,26
cm attributed to ν
for the Zn(II) and Cd(II) complexes, respectively.
M–N
1
13
H- and C-NMR spectra
1
13
The H- and C-NMR spectra of the ligand and the Cd(II) complex were
recorded in DMSO-d . The 2D-NMR spectrum for the ligand was also recorded
6
in order to distinguish the different protons on the phenyl ring of the quinazoline
1
moiety. The H-NMR spectrum of the ligand showed the following signals (δ /
/ ppm): 4.79 (s), 6.99–8.56 (m), 8.87 (s) and 11.99–12.24 (s); these signals may
be assigned to the protons in –O–CH –, the aromatic moiety, the azomethine
2
(HC=N) group, –OH (carboxylic proton hydrogen bonded with –N= group) and
1
the free –OH (carboxylic) group, respectively. Since the H-NMR spectrum of
the synthesized ligand showed close signals in the δ range 6.99–8.87 ppm, its 2D
spectra were recorded. In the 2D spectrum of the ligand, three sets of correl-
ations: the quinazoline protons (H –H ), the arylidene protons (H ″–H ″) and the
5
8
3
6
phenyl protons of the 2-phenyl group (H ′–H ′), were observed. In the total
2
4
correlated spectroscopy (TOCSY) spectrum, a distinct set of four cross-peaks
was observed, indicating four consecutive protons with δ values of 8.56, 7.95,
7.62 and 6.99 ppm. The atom numbering of the ligand is shown in Fig. 1A. An
1
1
analysis of the cross-peaks of H– H correlation spectroscopy (COSY) spectra
(Fig. 1B) revealed the nearest member of each proton. Since the proton at the ortho-
-position to the amidic group was assumed to be most deshielded (marked as H ),
5
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Zn(II) AND Cd(II) COMPLEXES OF A QUINAZOLIN-4(3H)-ONE SCHIFF BASE
1509
Fig. 1. A) Atom numbering of the ligand structure; B) 1H–1H COSY spectra of the ligand;
C) 1H–13C COSY spectra of the ligand.
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1510
BRAHMAN and SINHA
all other protons were assigned with respect to this proton (H ). The sequential
5
assignments were thus at δ values: 8.56 (H ), 7.61 (H ), 7.65 (H ) and 7.27 ppm
5
6
7
(H ). The arylidene protons (H ″–H ″) and the 2-phenyl protons (H ′–H ′) were
8
3
6
2
4
also assigned in similar fashions. The arylidene protons were assigned the fol-
lowing δ values: 7.04 (H ″), 7.56 (H ″), 6.99 (H ″) and 7.40 ppm (H ″), and
3
4
5
6
2-phenyl protons were assigned the δ values: 7.95 (H ′), 7.91 (H ′) and 7.93 ppm
2
3
1
1
13
(H ′). After the assignment of the entire H-spectrum of the ligand, the H– C
COSY spectrum was further analyzed to assign the eleven H– C peaks (Fig. 1C).
4
1
13
1
In the H-NMR spectrum of the Cd(II) complex the signal due to carboxylic
proton had disappeared, which confirmed the involvement of the carboxylic
group in the coordination. The shifts in the signal assigned to the azomethine pro-
ton and the methylene proton at 8.73 and 4.53 ppm in the complex were indi-
cations of the coordination of the nitrogen of the azomethine linkage and ethereal
oxygen of the –O–CH – linkage to the metal ion. A signal at around 2.45–2.50
2
ppm was also observed and assigned to methyl protons of the acetate group coor-
dinated to the metal ion. This fact clearly indicated that during complex form-
ation, one proton (carboxylic) of the free ligand was deprotonated and it behaved
as a monobasic tridentate ligand. Unfortunately, it was not possible to perform
NMR studies on the Zn(II) complex due to its poor solubility in DMSO-d .
6
Electronic spectra
The electronic spectra of the ligand and its Zn(II) and Cd(II) complexes,
recorded in DMF, are shown in Fig. 2. In the electronic spectra, the n→π* trans-
ition associated with the azomethine group of the ligand was found at 332 nm but
was shifted to longer wavelengths for Cd(II) and Zn(II) complexes. These results
indicated that the nitrogen atom of azomethine group remained coordinated to the
metal ions in the complexes. From the electronic and other spectral data, it could
Fig. 2. UV–Vis spectra of
the ligand and its Zn(II) and
Cd(II) complexes. 1, LH; 2,
Cd(II) complex; 3, Zn(II)
complex.
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Zn(II) AND Cd(II) COMPLEXES OF A QUINAZOLIN-4(3H)-ONE SCHIFF BASE
1511
thus be concluded that both the complexes had tetrahedral geometry. The prob-
able structure of the metal complexes is shown in Fig. 3.
Fig. 3. Probable structure of the synthesized
metal complexes (M = Cd(II) or Zn(II)).
Antibacterial activities
The ligand and its Zn(II) complex did not show any antibacterial activity
–1
against E. coli up to 1000 μg mL , whereas the Cd(II) complex showed anti-
–1
bacterial activity at 100 μg mL . Thus, it could be concluded that the incorp-
oration of the 2-(2-formylphenoxy) acetic acid group in the quinazoline molecule
quenched the antibacterial activity of the parent quinazoline molecule.
CONCLUSIONS
In this paper, the syntheses and physicochemical characterization of a 3-
amino-2-phenylquinazolin-4(3H)-one Schiff base ligand and its Zn(II) and Cd(II)
complexes are described. The antibacterial activities of the synthesized com-
pounds are also described. The results of elemental analysis confirmed a 1:1 ratio
of ligand to metal binding. Based on the physical and spectral analyses (IR, UV–
–Vis and NMR), tetrahedral geometry was proposed for the complexes of quina-
zolin-4-(3H)-one Schiff base. In the complexes, the azomethine nitrogen, ethereal
oxygen and phenoxy oxygen occupied the three coordination sites. The fourth
coordination site was occupied by an acetate group and one water molecule of
crystallization was present in the complex, as confirmed by elemental analysis.
The Zn(II) complex did not show any antibacterial activity, whereas the Cd(II)
complex showed marked antibacterial activity. Again, it was found that the incor-
poration of the 2-(2-formylphenoxy) acetic acid group in the quinazoline mole-
cule quenched the antibacterial activity of the parent quinazoline molecule.
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1512
BRAHMAN and SINHA
SUPPLEMENTARY MATERIAL
Physical, analytical and spectral data for the ligand and its Zn and Cd complexes are
available electronically from http://www.shd.org.rs/JSCS/, or from the corresponding author
on request.
Acknowledgements. The authors are grateful to the Departmental Special Assistance
Scheme under the University Grants Commission, New Delhi (SAP-DRS-III, No.
540/12/DRS/2013) for financial support and to SAIF, NEHU for elemental analysis and NMR
studies. We also thankfully acknowledge the Department of Biotechnology, N. B. U for the
antibacterial analyses. One of the authors (D. B) is also thankful to UGC, India for granting
him UGC BSR Research Fellowship in Science [Ref. No: 4-1/2008 (BSR)].
И З В О Д
СИНТЕЗА, КАРАКТЕРИЗАЦИЈА И АНТИБАКТЕРИЈСКА АКТИВНОСТ КОМПЛЕКСА
Zn(II) И Cd(II) СА ШИФОВОМ БАЗОМ 3-АМИНО-2-ФЕНИЛХИНАЗОЛИН-4(3H)-ОНА
DHIRAJ BRAHMAN и BISWAJIT SINHA
Department of Chemistry, University of North Bengal, Darjeeling-734013, India
Описана је синтеза Zn(II) и Cd(II) комплекса са Шифовом базом 3-амино-2-хина-
золин-4(3H)-она и 2-(2-формилфенокси)-сирћетне киселине као лигандом. Комплекси
су окарактерисани помоћу елементалне микроанализе и различитих спектроскопских
метода (IR, UV–Vis и NMR). На основу елементалне микроанализе претпостављено је да
комплекси имају општу формулу: [ML(AcO)]·H2O, где је M Zn(II) или Cd(II), а L пред-
ставља Шифову базу као лиганд. На основу кондуктометријских мерења закључено је да
изоловани комплекси представљају неутралне комплексне врсте. Применом турбиди-
метријских метода испитивана је антимикробна активност изолованих комплекса.
(Примљено 30. јануара, ревидирано 18 јуна, прихваћено 11. септембра 2014)
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