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Journal of Coordination Chemistry

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Metal-based antibacterial agents:

synthesis, characterization, and
in vitro biological evaluation of
cefixime-derived Schiff bases and their
complexes with Zn(II), Cu(II), Ni(II), and
Co(II)
a a a
M. Arif , M.M.R. Qurashi & M.A. Shad
a
Department of Chemistry, Bahauddin Zakariya University, Multan
60800, Pakistan

Available online: 25 May 2011

To cite this article: M. Arif, M.M.R. Qurashi & M.A. Shad (2011): Metal-based antibacterial agents:
synthesis, characterization, and in vitro biological evaluation of cefixime-derived Schiff bases
and their complexes with Zn(II), Cu(II), Ni(II), and Co(II), Journal of Coordination Chemistry, 64:11,
1914-1930

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 Journal of Coordination Chemistry
Vol. 64, No. 11, 10 June 2011, 1914–1930

Metal-based antibacterial agents: synthesis, characterization,

and in vitro biological evaluation of cefixime-derived Schiff
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bases and their complexes with Zn(II), Cu(II), Ni(II), and Co(II)
M. ARIF*, M.M.R. QURASHI and M.A. SHAD

Department of Chemistry, Bahauddin Zakariya University, Multan 60800, Pakistan

(Received 20 April 2010; in final form 18 March 2011)

The zinc(II), copper(II), nickel(II), and cobalt(II) complexes of Schiff bases, obtained by the
condensation of cefixime with furyl-2-carboxaldehyde, thiophene-2-carboxaldehyde, salicylal-
dehyde, pyrrol-2-carboxaldehyde, and 3-hydroxynaphthalene-2-carboxaldehyde, were synthe-
sized and characterized by their elemental analyses, molar conductances, magnetic moments,
IR, and electronic spectral measurements. Analytical data and electrical conductivity
measurements indicated the formation of M : L (1 : 2) complexes, [M(L)2(H2O)2] or
[M(L)2(H2O)2]Cl2 [where M ¼ Zn(II), Cu(II), Ni(II), and Co(II)] in which ligands are bidentate
via azomethine-N and deprotonated-O of salicyl and naphthyl, furanyl-O, thienyl-S, and
deprotonated pyrrolyl-N. The magnetic moments and electronic spectral data suggest
octahedral complexes. The synthesized ligands, along with their metal complexes, were
screened for their antibacterial activity against different bacterial strains. The studies show the
metal complexes to be more active against one or more species as compared to the uncomplexed
ligands.

Keywords: Metal-based; Schiff bases; Cefixime; Antibacterial

1. Introduction

Cephalosporins are important in the treatment of bacterial infections, exhibiting broad

antibacterial activities with little toxicity and are generally well tolerated [1]. Structural
modifications of the cephem nucleus have produced a variety of antimicrobial agents
with improved spectra of activity and -lactamase stability [2]. The antibiotic cefixime
belongs to the third generation cephalosporin. The third generation has somewhat
increased activity against Gram-negative microorganisms than the first and second
generation cephalosporins.
The metal chelates of different cephalosporins have been studied because of their
biological activity [3–5]. However, a survey of the literature reveals that metal chelates
with Schiff bases derived from cephalosporin have not been reported. In continuation
of earlier work [6, 7], we report a series of antibacterial Schiff bases derived by the
condensation of cefixime (a third generation cephalosporin) with different aldehydes
(L1–L5; figure 1) and their metal chelates (1–20; figures 2–4). The Schiff bases and their

*Corresponding author. Email: pdmarif@hotmail.com

Journal of Coordination Chemistry

ISSN 0095-8972 print/ISSN 1029-0389 online ß 2011 Taylor & Francis
DOI: 10.1080/00958972.2011.582867
 Cefixime-derived Schiff bases 1915
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Figure 1. Proposed structure of Schiff-base ligands.

metal chelates were screened for antibacterial activity against Escherichia coli,
Enterococcus faecalis, Staphylococcus aureus, Pseudomonas aeruginosa, Salmonella
enteritidis, and Klebsiella pneumoniae. The Schiff bases showed increased antibacterial
activity against certain strains and their activities were enhanced on chelation.

2. Experimental

2.1. Materials and methods

All chemicals, analytical grade, were purchased from Aldrich & Sigma and used as
received. The solvents were redistilled by standard techniques before use. The metal
contents of the complexes were determined by atomic absorption spectroscopy after
decomposition with acid.
Elemental analyses were carried out on a Thermo Finnegan CHN MA 5200
elemental analyzer. FT-IR spectra were recorded with a Hitachi spectrometer using
KBr disks. Magnetic moments were determined with a Gouy balance using
Hg[Co(NCS)4] as the calibrant. Diamagnetic corrections were calculated from
Pascal’s constants [8]. Electronic absorption spectra of all the complexes were recorded
on a Shimadzu spectrophotometer. Conductance measurements were done in DMSO
(103 mol L1) using an electroconductivity bridge. 1H and 13C NMR spectra were
recorded on a Bruker Spectrospin Avance DPX-400 spectrometer using TMS as
internal standard and DMSO(d6) as solvent. Electron impact mass spectra (EIMS) were
recorded on a JEOL MS Route instrument.
 1916 M. Arif et al.

2.2. Preparation of Schiff bases (L1–L5)

A stirred solution of cefixime (4.53 g, 10 mmol) in methanol (30 mL) was mixed
with salicylaldehyde (1.3 g, 10 mmol) dissolved in methanol (25 mL). To this
KOH (0.1% in methanol) was added to adjust the pH of the solution at 7–8 and the
mixture was refluxed for 30 min. A clear colored solution was obtained. The
completion of reaction was monitored through TLC. After completion of the reaction,
a few drops of dilute acetic acid were added to adjust the pH to 7. The volume was
reduced to about one-third on a rotary evaporator and cooled to afford a solid product.
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The solid residue was filtered, washed with ethanol, then with ether, and dried.
Crystallization from a mixture of ethanol–propanol (60 : 40) afforded the desired Schiff
bases. The same method was applied for the preparation of all other ligands by using
the corresponding aldehydes, working in the same conditions with their respective
molar ratio.

2.2.1. 8-(2-Carboxymethoxyimino-2-{2-[(2-hydroxy-benzylidene)-amino]-thiazol-4-yl}-
acetylamino)-7-oxo-4-vinyl-2-thia-bicyclo[4.2.0]oct-4-ene-5-carboxylic acid (L1). Yield
85%; m.p. 154–156 C; (dark yellow), IR (KBr, cm1): 3435 (OH), 1610 (–HC ¼ N),
1766 (C ¼ O -lactam), 1665 (C ¼ O amide), 1595 (COO), 1320, 1480 (C–N); 1H NMR
(DMSO-d6, , ppm): 7.3–7.75 (m, 4H, –phenyl), 10.23 (s, 1H, –OH), 8.7 (s, 1H,
HC ¼ N), 11.0 (s, 1H, –COOH), 7.6 (s, 1H, thiozole), 9.1 (s, 1H, –NH–CO–), 6.1 (d, 1H,
J ¼ 7.2, -lactam), 6.3 (d, 1H, J ¼ 7.4, -lactam), 2.1 (s, 2H, six-membered thiozole
ring), 5.6 (t, 1H, vinyl), 4.47 (d, 2H, vinyl), 2.7 (s, 2H, –OCH2–COOH); 13C NMR
(DMSO-d6, , ppm): 176.31 (C13–COOH), 170.45 (C15, five-membered thiazole ring),
168.39 (C11, –C ¼ N), 163.62 (C17, –CH ¼ N), 163.43 (C10, –HN–CO), 163.02
(C2, –lactam), 161.50 (C7, –COOH), 157.82 (C19, –OH–ph), 142.61 (C5), 136.09
(C8, C ¼ CH2), 132.24, 130.46, 121.25, 118.45, 115.82 (C18, C20–C23 phenyl), 58.12 (C3,
-lactam ring), 57.33 (C1, -lactam); Anal. Calcd for C23H19N5O8S2 (557.56) (%): C,
49.55; H, 3.41; N, 12.57. Found (%): C, 49.88; H, 3.42; N, 12.54. Mass spectrum (ESI)
[M]þ ¼ 557.10. 1H NMR of Zn(II) complex (DMSO-d6, , ppm): 4.67 (d, 2H, CH2),
7.48–7.87 (m, 4H, Ph), 8.32 (s, 1H, azomethine), 11.20 (s, 1H, COOH); 13C NMR
(DMSO-d6, , ppm): 115.82, 118.45, 121.25, 130.46, 132.24, 157.82 (PhOH), 164.42
(–CH ¼ N), 176.34 (COOH).

2.2.2. 8-(2-Carboxymethoxyimino-2-{2-[(2-hydroxy-naphthalen-2-ylmethylene)-amino]
thiazol-4-yl}-acetylamino)-7-oxo-4-vinyl-2-thia-bicyclo[4.2.0]oct-4-ene-5-carboxylic acid
(L2). Yield 80%; m.p. 153–155 C; (dark yellow); IR (KBr, cm1): 3445 (OH), 1610
(–HC¼N), 1770 (C¼O -lactam), 1668 (C¼O amide), 1595 (COO), 1315, 1485 (C–N);
1
H NMR (DMSO-d6, , ppm): 7.35–7.81 (m, 6H, Naph), 8.11 (s, 1H, azomethine), 9.83
(s, 1H, OH), 11.10 (s, 1H, COOH), 7.5 (s, 1H, thiozole), 9.2 (s, 1H, –NH–CO–), 6.3 (d,
1H, J ¼ 7.2, -lactam), 6.4 (d, 1H, J ¼ 7.8, -lactam), 2.2 (s, 2H, six-membered thiozole
ring), 5.8 (t, 1H, vinyl group), 4.47 (d, 2H, vinyl), 2.9 (s, 2H, –OCH2–COOH);
13
C NMR (DMSO-d6, , ppm): 176.38 (C13–COOH), 170.42 (C15, five-membered
thiazole ring), 168.45 (C11, –C¼N), 163.65 (C17, –CH¼N), 163.21 (C10, –HN–CO),
163.02 (C2, -lactam), 161.50 (C7, –COOH), 142.61 (C5), 136.09 (C8, C¼CH2), 111.4–
152.8 (nephthyl), 58.7 (C3, -lactam ring), 57.01 (C1, -lactam). Anal. Calcd for
C27H21N5O8S2 (607.61) (%): C, 53.38; H, 3.46; N, 11.53. Found (%): C, 53.82; H, 3.40;
 Cefixime-derived Schiff bases 1917

N, 11.34. Mass spectrum (ESI) [M]þ ¼ 607.10. 1H NMR of Zn(II) complex (DMSO-d6,
, ppm): 4.63 (d, 2H, CH2), 7.38–7.89 (m, 6H, Naph), 8.31 (s, 1H, azomethine), 11.23
(s, 1H, COOH). 13C NMR (DMSO-d6, , ppm): 111.8–153.85 (NaphO), 164.21
(–CH ¼ N), 176.38 (COOH).

2.2.3. 8-(2-Carboxymethoxyimino-2-{2-[(furan-2-ylmethylene)-amino]-thiazol-4-yl}-
acetylamino)-7-oxo-4-vinyl-2-thia-bicyclo[4.2.0]oct-4-ene-5-carboxylic acid (L3). Yield
80%; m.p. 155–158 C; (dark orange), IR (KBr, cm1): 3245 (OH), 1615 (–HC¼N),
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1768 (C¼O -lactam), 1667 (C¼O amide), 1590 (COOH), 1310, 1255 (C–O); 1H NMR
(DMSO-d6, , ppm): 7.4 (d, 1H, J ¼ 1.81 Hz, furanyl C5–H), 6.35 (dd, 1H, J ¼ 3.62,
1.81 Hz, furanyl C4–H), 6.95 (d, 1H, J ¼ 3.62 Hz, furanyl C3–H), 7.5 (s, 1H, HC¼N), 7.3
(s, 1H, thiozole), 9.3 (s, 1H, –NH–CO–), 6.2 (d, 1H, J ¼ 7.1, -lactam), 6.3 (d, 1H,
J ¼ 7.4, -lactam), 11.15 (s, 1H, COOH), 2.2 (s, 2H, six-membered thiozole ring),
5.8 (t, 1H, vinyl group), 4.45 (d, 2H, vinyl), 2.9 (s, 2H, –OCH2–COOH); 13C NMR
(DMSO-d6, , ppm): 170.31 (C13–COOH), 170.05 (C15, five-membered thiazole ring),
168.32 (C11, –C¼N), 163.71 (C17, –CH¼N), 163.42 (C10, –HN–CO), 163.05 (C2,
-lactam), 161.25 (C7, –COOH), 143.7 (C19, furanyl), 141.56 (C22, furanyl), 141.91 (C5),
138.6 (C8, C¼CH2), 112.7 (C21, furanyl), 110.4 (C20, furanyl), 58.39 (C3, -lactam ring),
57.71 (C1, -lactam); Anal. Calcd for C21H17N5O8S2 (531.45) (%): C, 47.46; H, 3.20; N,
13.18. Found (%): C, 47.68; H, 3.40; N, 13.34. Mass spectrum (ESI) [M]þ ¼ 531.08.
1
H NMR of Zn(II) complex (DMSO-d6, , ppm): 4.67 (d, 2H, CH2), 6.38–7.45 (m, 3H,
furanyl), 7.73 (s, 1H, azomethine), 11.21 (s, 1H, COOH); 13C NMR (DMSO-d6, ,
ppm): 110.8–143.80 (furanyl), 164.20 (–CH¼N), 170.38 (COOH).

2.2.4. 8-(2-Carboxymethoxyimino-2-{2-[(thiophene-2-ylmethylene)-amino]-thiazol-4-yl}-
acetylamino)-7-oxo-4-vinyl-2-thia-bicyclo[4.2.0]oct-4-ene-5-carboxylic acid (L4). Yield
78%; m.p. 170–172 C; (yellowish orange), IR (KBr, cm1): 3250 (OH), 1620 (–HC¼
N), 1765 (C¼O -lactam), 1670 (C¼O amide), 1585 (COO), 755 (C–S); 1H NMR
(DMSO-d6, , ppm): 7.11 (d, 1H, J ¼ 4.78 Hz, thienyl, C5–H), 7.0 (dd, 1H, J ¼ 4.78,
3.85 Hz, thienyl, C4–H), 7.21 (d, 1H, J ¼ 3.85 Hz, thienyl, C3–H), 7.55 (s, 1H, HC¼N),
7.7 (s, 1H, thiozole), 9.2 (s, 1H, –NH–CO–), 6.7 (d, 1H, J ¼ 7.3, -lactam), 6.7 (d, 1H,
J ¼ 7.4, -lactam), 11.10 (1H, –COOH), 2.5 (s, 2H, six-membered thiozole ring), 5.9
(t, 1H, vinyl group), 4.45 (d, 2H, vinyl), 4.47 (s, 2H, –OCH2–COOH); 13C NMR
(DMSO-d6, , ppm): 170.21 (C13–COOH), 170.12 (C15, five-membered thiazole
ring), 168.37 (C11, –C¼N), 163.70 (C17, –CH¼N), 163.53 (C10, –HN–CO), 163.09
(C2– -lactam), 161.28 (C7, –COOH), 144.6 (C19, thienyl), 141.95 (C5), 138.6
(C8, C¼CH2), 127.80 (C22, thienyl), 127.48 (C21, thienyl), 126.4 (C20, thienyl), 58.39
(C3, -lactam ring), 57.71 (C1, -lactam); Anal. Calcd for C21H17N5O7S3 (547.56)
(%): C, 46.07; H, 3.11; N, 12.80. Found (%): C, 47.65; H, 3.45; N, 12.34. Mass
spectrum (ESI) [M]þ ¼ 547.07. 1H NMR of Zn(II) complex (DMSO-d6, , ppm): 4.57
(d, 2H, CH2), 7.23–7.45 (m, 3H, thienyl), 7.85 (s, 1H, azomethine), 11.20 (s, 1H,
COOH); 13C NMR (DMSO-d6, , ppm): 126.8–127.80 (thienyl), 164.25 (–CH¼N),
170.58 (COOH).

2.2.5. 8-(2-Carboxymethoxyimino-2-{2-[(1H-pyrrol-2-ylmethylene)-amino]-thiazol-4-yl}-
acetylamino)-7-oxo-4-vinyl-2-thia-bicyclo[4.2.0]oct-4-ene-5-carboxylic acid (L5). Yield
 1918 M. Arif et al.

78%; m.p. 170 C; IR (KBr, cm1): 3310 (NH), 3250 (OH), 1610 (–HC¼N), 1765,
(C¼O -lactam), 1660 (C¼O amide), 1590 (COO), 1H NMR (DMSO-d6, , ppm): 6.43
(d, 1H, J ¼ 2.87 Hz pyrrolyl, C5–H), 6.2 (dd, 1H, J ¼ 3.95, 2.87 Hz, pyrrolyl, C4–H),
6.61 (d, 1H, J ¼ 3.95 Hz, pyrrolyl, C3–H), 9.7 (s, 1H, pyrrolyl, NH), 7.5 (s, 1H, HC¼N),
7.3 (s, 1H, thiozole), 9.2 (s, 1H, NH–CO–), 6.3 (d, 1H, J ¼ 7.4, -lactam), 6.5 (d, 1H,
J ¼ 7.1, -lactam), 11.10 (s, 1H, COOH), 2.3 (s, 2H, six-membered thiozole ring), 5.9
(t, 1H, vinyl), 4.47 (d, 2H, vinyl), 2.6 (s, 2H, OCH2–COOH); 13C NMR (DMSO-d6, ,
ppm): 170.60 (C13–COOH), 170.23 (C15, five-membered thiazole ring), 168.31 (C11,
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–C¼N), 163.75 (C17, –CH¼N), 163.57 (C10, –HN–CO), 163.17 (C2, -lactam), 161.22
(C7, –COOH), 141.95 (C5), 134.5 (C19, pyrrolyl), 128.75 (C8, C¼CH2), 118.70 (C22,
pyrrolyl), 108.4 (C21, pyrrolyl), 126.4 (C20, pyrrolyl), 59.2 (C3, -lactam ring), 54.4 (C1,
-lactam); Anal. Calcd for C21H18N6O7S2 (530.63) (%): C, 47.55; H, 3.40; N, 15.85.
Found (%): C, 47.60; H, 3.45; N, 15.54. Mass spectrum (ESI) [M]þ ¼ 530.08. 1H NMR
of Zn(II) complex (DMSO-d6, , ppm): 4.50 (d, 2H, CH2), 6.23–6.65 (m, 3H, pyrrolyl),
7.90 (s, 1H, azomethine), 11.15 (s, 1H, COOH). 13C NMR (DMSO-d6, , ppm): 108.8–
118.85 (pyrrolyl), 164.35 (–CH¼N), 170.60 (COOH).

2.3. Preparation of Schiff-base metal complexes (1–20)

The Schiff base (L1) (2.23 g, 2 mmol) dissolved in methanol (25 mL) was mixed with
CuCl2  2H2O (0.171 g, 1 mmol) dissolved in methanol (25 mL). The reaction mixture
was refluxed for 3–4 h. The volume was reduced to about one-third on a rotary
evaporator and then cooled to room temperature. On cooling a solid product
precipitated, was filtered off, washed with methanol, then with ether, and dried under
vacuum. Crystallization from hot methanol gave the desired metal complex. The same
method was used for the preparation of all other complexes by using their respective
hydrated metal(II) chlorides.

2.4. Antibacterial activity

All the synthesized ligands (L1–L5) and their corresponding metal(II) complexes (1–20)
were screened in vitro for their antibacterial activity against E. coli, E. faecalis,
S. aureus, P. aeruginosa, S. enteritidis, and K. pneumonia bacterial strains using
agar-well diffusion method, as described previously [9]. Two- to eight-hour-old
bacterial inoculums containing approximately 104–106 colony forming units
(CFU) mL1 were used in these assays. Wells were dug in the media with a sterile
metallic borer with centers at least 24 mm. Recommended concentration of the test
sample in DMSO was introduced in the respective wells. Other wells supplemented with
DMSO and reference antibacterial drug served as negative and positive controls,
respectively. The plates were incubated at 37 C for 20 h. Activity was determined by
measuring the diameter of zones showing complete inhibition (mm). Growth inhibition
was compared with the standard drug [10]. In order to clarify any role of DMSO in the
biological screening, separate studies were carried out with DMSO alone, which showed
no activity against any bacterial strains.
 Cefixime-derived Schiff bases 1919

2.5. Minimum inhibitory concentration

The minimum inhibitory concentrations (MIC)s of selected compounds, which showed
significant activity against selected bacterial strains, were determined using the disk
diffusion method [11] by preparing disks containing 10, 25, 50, and 100 mg mL1 and
applying the reported protocol. MIC was the lowest concentration of an antimicrobial
compound at which the inhibition of growth occurred.
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3. Results and discussion

L1–L5 were prepared by refluxing the appropriate amount of cefixime with the
corresponding heteroaromatic (salicylaldehyde and 3-hydroxynaphthalene-2-carbox-
aldehyde) and heterocyclic (furyl-2-carboxaldehyde, thiophene-2-carboxaldehyde, and
pyrrole-2-carboxaldehyde) systems, respectively, in methanol. The structures of
synthesized Schiff-base ligands were established by IR, NMR, and microanalytical
data. The air and moisture stable metal complexes (1–20) of these ligands were prepared
by the stoichiometric reaction of the corresponding metal(II) chloride hydrate with the
ligand in a molar ratio M : L of 1 : 2. The synthesized colored complexes were
amorphous solids which decomposed without melting and were only soluble in DMSO.
Karl–Fischer titrations indicated the presence of water in all these complexes. Molar
conductance values (table 1) of the soluble complexes in DMSO (103 mol L1 solution
at 25 C) indicated that complexes with salicylaldehyde, 3-hydroxynaphthalene-
2-carboxaldehyde, and pyrrole-2-carboxaldehyde have low values
(20–25
1 cm2 mol1) indicating that they are non electrolytes, whereas complexes
with furyl-2-carboxaldehyde and thiophene-2-carboxaldehyde have high values
(120–125
1 cm2 mol1) indicating that they are electrolytic [12]. Elemental analyses
of the Schiff bases (reported in experimental) and their complexes (table 2) are
compatible with the structures shown in figure 1 and with that of formulae of the
complexes, [M(L)2(H2O)2] where [M ¼ Zn(II), Cu(II), Ni(II), or Co(II) and L ¼ L1, L2,
or L5] and [M(L)2(H2O)2]Cl2 where [M ¼ Zn(II), Cu(II), Ni(II), or Co(II) and L ¼ L3
or L4]. The suggested structures of the ligands and their complexes are shown in
figures 1–4.

3.1. IR spectra
IR spectra of the ligands showed the absence of bands at 1735 and 3420 cm1 due to
(C¼O) and (NH2) stretching vibrations and instead, a new band appeared at
1620 cm1 assigned [13] to azomethine (HC¼N). This suggested that amino and
aldehyde moieties of the starting reagents have been converted into the corresponding
Schiff bases (figure 1). The bonding of the synthesized Schiff bases to metal ions was
investigated by comparing FT-IR spectra of the complexes with those of the free
ligands. Some important absorption bands and their assignments are given in table 3.
The spectra of these complexes exhibited a broad band around 3445–3540 cm1,
assigned to water, (OH), associated with the complexes. In addition to these modes,
coordinated water exhibited r(H2O) rocking at 850–890 cm1 and w(H2O) wagging at
540–550 cm1 [13]. The spectra of all the ligands contained a band at 1610–1620 cm1,
(C¼N), which shifted to higher values (1615–1645 cm1) in the complexes suggesting
 1920 M. Arif et al.

that the ligands coordinate to the metal ion through azomethine [14]. The absence of
O–H and N–H stretching and bending vibrations, for salicyl-, naphthyl-, and pyrrolyl-,
from the spectra of the complexes indicate the deprotonation of O–H and/or N–H,
confirming formation of a bond to metal. A medium sharp band due to (C–O) and
(C–S) is found at 1140–1150 and 760–750 cm1, respectively, in the spectra of the
complexes which indicate the formation of a coordinate bond through these moieties
[15]. The absorption due to lactam (C¼O) and carboxylic groups did not change in
spectra of the complexes, indicating that these groups are not involved in coordination.
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New absorption bands (M–N), (M–O), and (M–S) appeared at 510–520, 420–430,
and 380–390 cm1, respectively, in the spectra of the complexes which indicate the
coordination of the ligands through nitrogen, oxygen, and sulfur [16].

3.2. 1H-NMR spectra

1
H-NMR spectra of the Schiff bases (L1–L5) displayed the azomethine [17] proton
(–CH¼N) at  7.5–8.7 as a singlet. Multiplets at 6.9–7.75 ppm due to phenyl protons
were also present with a hydroxyl proton as a singlet at  10.23 and 10.85. Similarly in
1
H-NMR spectra of L2 six protons in naphthalene moiety C3–8–H appear as a multiplet
at  6.7–7.5 and the hydroxyl proton as a singlet at  9.83 due to its attachment with
naphthalene. 1H-NMR spectra of L1–L5 doublets from CO–CH and N–CH on the
-lactam ring and NH appear at 6.1–6.6 and 9.1–9.3 ppm, respectively [18]. In 1H NMR
spectrum of Schiff bases single peaks attributed to –CH2–COOH appear at 2.9 and
11.10 ppm, respectively. In all the ligands, a singlet appeared at  2.3–2.6 due to 2H of
the six-membered thiazole ring while a singlet also appeared at  7.5–7.7 due to 1H of
the five-membered thiazole.

13
3.3. C NMR spectra
The l3C NMR spectra of free ligands and their diamagnetic Zn(II) complexes were
recorded in CD l3C/DMSO-d6 and reported along with possible assignments in
the experimental section. Comparison of chemical shifts of the ligands with those of the
complexes shows that the signal due to phenolic proton (L1–L2) and pyrrolyl-NH were
absent in the complexes, suggesting coordination after deprotonation [19]. The
azomethine proton (CH¼N–) undergoes a significant shift, indicating coordination
of the azomethine nitrogen. More detailed information about the structure of the
ligands was provided by 13C NMR spectra. All the carbon atoms due to heteroatomic
and/or aromatic groups were found in their expected region [20, 21]. In the spectra of
diamagnetic Zn(II) chelates, these signals shifted downfield due to the increased
conjugation and coordination to the metal ions. The number of protons and carbons
calculated from the integration curves agreed with those obtained from the values of the
CHN analysis.

3.4. Magnetic and electronic absorption spectral studies

The Co(II) complexes exhibited well-resolved bands around 17,560–17,650 cm1 and
a strong high-energy band at 21,767–21,790 cm1 (table 1), which were assigned to
 Cefixime-derived Schiff bases 1921

4
T1g(F) ! 4T2g(F) and 4T1g(F) ! 4T1g(P), respectively, for a high-spin octahedral
geometry. The magnetic susceptibility measurements (4.7–4.9 BM) for the solid Co(II)
complexes are also indicative of three unpaired electrons per Co(II) ion consistent with
their octahedral environment [22]. The electronic absorption spectrum of the Cu(II)
complex showed a single low-intensity broad band at 15,256–15,320 cm1, typical for an
octahedral configuration. The magnetic moment (1.7–1.9 BM) suggested one unpaired
electron per Cu(II) consistent with their octahedral environment [23]. The spectrum of
the Ni(II) complex showed d–d bands at 12,978–13,020, 16,565–16,630, and 24,385–
24,440 cm1, assigned to the spin-allowed transitions 3A2g(F) ! 3T2g(F),
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3
A2g(F) ! 3T1g(F), and 3A2g(F) ! 3T1g(P), respectively, consistent with octahedral
configuration. The magnetic moment of 3.1–3.4 BM suggested two unpaired electrons
per Ni(II) also consistent with octahedral geometry. The spectrum of the Zn(II)
complex exhibited only a high-intensity band at 28,370–28,405 cm1, which was
assigned to a ligand-to-metal charge transfer [24, 25].

3.5. Thermogravimetric analysis

Thermogravimetric analyses (TGA) for the complexes were carried out from room
temperature to 700 C. Coordinated waters are usually eliminated at higher tempera-
tures than those of hydration [26, 27], usually in the temperature range 100–350 C. The
ligand together with the anions (Cl) in the complexes may decompose in more than
two steps with the formation of intermediates [28, 29]; calculated and estimated mass
losses are comparable.
The TGA curve of Schiff-base metal complexes from L1, L2, and L5 have two stages
of mass loss, at 135–223 C and at 223–595 C. At 82–109 C, the estimated mass loss of
5.47–5.67% may be due to the loss of two Cl atoms in complexes of L3 and L4. Weight
loss in the range 102–227 C with estimated mass loss of 2.65–3.05% in all the complexes
indicates the loss of two coordinated waters. From 210 C to 595 C, a sharp decrease in
weight indicated the loss of one Schiff base from the complexes with estimated mass loss
of 42.85–46.35% for all the complexes, respectively. The data are given in table 4.
In general, the stages of thermal decomposition of the metal complexes may be
summarized by the following equations.
First decomposition step is represented as

80110 C
½MðLÞ2 ð2H2 OÞCl2 ! ½MðLÞ2 ð2H2 OÞ þ Cl2
102227 C
½MðLÞ2 ð2H2 OÞ ! ½MðLÞ2  þ 2H2 O,
Dehydration

where M ¼ Cu, Ni, Co, and Zn.

In the second step of decomposition, the loss of ligand occurs

227595 C
½MðLÞ2  ! ML þ L:
final decomp:

The molecular masses determined mass spectrometrically (table 1) also confirmed the
ML2 composition. Based upon experimental evidence thus obtained, the complexes
were characterized as six coordinates with the two positions occupied by water. The
 1922 M. Arif et al.
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Figure 2. Proposed structure of metal complexes of L1 and L2, where R ¼ H and phenyl; M ¼ Zn(II), Cu(II),
Ni(II), and Co(II).

Figure 3. Proposed structure of metal complexes of L3 and L4, where X ¼ O and S; M ¼ Zn(II), Cu(II),
Ni(II), and Co(II).

hydrated complexes have significant importance in the enzymatic systems, as the

substrates can bind to metal by substituting the coordinated water. The proposed
structures of the complexes under investigation, on the basis of above experimental
evidence, are shown in figures 2–4. Unsuccessful attempts to isolate crystals suitable for
X-ray analysis prevented further structure elucidation.
 Cefixime-derived Schiff bases 1923
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Figure 4. Proposed structure of metal complexes of L5, where M ¼ Zn(II), Cu(II), Ni(II), and Co(II).

Table 1. Physical and spectral data of the metal(II) complexes (1–20).

Metal chelates Molar conductance (

1 cm2 mol1) m (BM) max (cm1 mol1)

1 (Mþ: 1210 m/e) 20 Dia –

2 (Mþ: 1211 m/e) 24 1.8 15,256
3 (Mþ: 1206 m/e) 22 3.2 12,978; 16,570; 24,390
4 (Mþ: 1206 m/e) 20 4.7 17,560; 21,780
5 (Mþ: 1310 m/e) 25 Dia –
6 (Mþ: 1311 m/e) 20 1.7 15,320
7 (Mþ: 1306 m/e) 21 3.4 13,020; 16,565; 24,385
8 (Mþ: 1306 m/e) 24 4.9 17,620; 21,767
9 (Mþ: 1231 m/e) 120 Dia –
10 (Mþ: 1232 m/e) 124 1.9 15,280
11 (Mþ: 1227 m/e) 122 3.1 13,010; 16,630; 24,430
12 (Mþ: 1227 m/e) 125 4.9 17,650; 21,780
13 (Mþ: 1263 m/e) 123 Dia –
14 (Mþ: 1264 m/e) 124 1.8 15,275
15 (Mþ: 1259 m/e) 121 3.3 12.980; 16,590; 24,440
16 (Mþ: 1259 m/e) 125 4.8 17,590; 21,790
17 (Mþ: 1156 m/e) 20 Dia –
18 (Mþ: 1157 m/e) 23 1.7 15,310
19 (Mþ: 1152 m/e) 22 3.2 12,980; 16,610; 24,425
20 (Mþ: 1152 m/e) 25 4.7 17,625; 21,785

3.6. Biological activity

All compounds were tested against E. coli, E. faecalis, S. aureus, P. aeruginosa,
S. enteritidis, and K. pneumonia bacterial strains (table 5) according to literature
protocol [10]. The ligands were active against one or more bacterial strains. Cobalt(II),
copper(II), nickel(II), and zinc(II) metal complexes of these synthesized ligands (L1–L5)
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Table 2. Physical and analytical data of the metal(II) complexes (1–20).

1924

Calculated (Found) %

No. Metal chelates (mol. wt.) Color m.p. ( C) Yield (%) C H N M

1 [Zn(L1)2(H2O)2] [1211.39] Pale yellow 230 70 45.57 3.30 11.56 5.23

C46H40N10O18S4Zn (45.50) (3.70) (11.20) (5.40)
2 [Cu(L1)2(H2O)2] [1211.54] Dark green 235 75 45.56 3.30 11.56 5.24
C46H40N10O18S4Cu (45.62) (3.60) (11.31) (5.25)
3 [Ni(L1)2(H2O)2] [1206.69] Light green 232 72 45.74 3.31 11.60 4.86
C46H40N10O18S4Ni (45.79) (3.72) (11.10) (4.80)
4 [Co(L1)2(H2O)2] [1206.93] Pink 237 73 45.74 3.31 11.60 4.88
C46H40N10O18S4Co (45.89) (3.75) (11.32) (4.81)
5 [Zn(L2)2(H2O)2] [1311.39] Pale yellow 245 69 49.41 3.36 10.68 4.83
C54H44N10O18S4Zn (49.01) (3.53) (10.47) (4.90)
6 [Cu(L2)2(H2O)2] [1311.54] Green 242 73 49.41 3.35 10.67 4.84
C54H44N10O18S4Cu (49.12) (3.69) (10.68) (4.73)
7 [Ni(L2)2(H2O)2] [1306.69] Light green 240 75 49.59 3.37 10.71 4.49
C54H44N10O18S4Ni (49.32) (3.59) (10.67) (4.52)
8 [Co(L2)2(H2O)2] [1306.93] Pink 248 72 49.58 3.37 1.71 4.51
C54H44N10O18S4Co (49.16) (3.68) (10.68) (4.61)
M. Arif et al.

9 [Zn(L3)2(H2O)2]Cl2 [1232.39] Off white 236 71 40.90 3.08 11.36 5.14

C42H38N10O18S4Cl2Zn (41.01) (3.20) (11.15) (5.09)
10 [Cu(L3)2(H2O)2]Cl2 [1232.54] Dark green 232 75 40.89 3.08 11.36 5.16
C42H38N10O18S4Cl2Cu (40.99) (3.35) (11.18) (5.21)
11 [Ni(L3)2(H2O)2]Cl2 [1227.69] Sea green 238 72 41.05 3.10 11.40 4.78
C42H38N10O18S4Cl2Ni (41.01) (3.13) (11.19) (4.85)
12 [Co(L3)2(H2O)2]Cl2 [1227.93] Pink 240 70 41.04 3.09 11.40 4.80
C42H38N10O18S4Cl2Co (41.17) (3.31) (11.20) (4.75)
13 [Zn(L4)2(H2O)2]Cl2 [1264.39] Pale yellow 260 73 39.86 3.01 11.07 5.01
C42H38N10O16S6Cl2Zn (39.72) (3.21) (11.59) (4.99)
14 [Cu(L4)2(H2O)2]Cl2 [1264.54] Dark green 255 71 39.86 3.01 11.07 5.02
C42H38N10O16S6Cl2Cu (39.79) (3.17) (11.47) (5.08)
15 [Ni(L4)2(H2O)2]Cl2 [1259.69] Light green 256 74 40.01 3.02 11.11 4.66
C42H38N10O16S6Cl2Ni (40.03) (3.12) (11.48) (4.57)
16 [Co(L4)2(H2O)2]Cl2 [1259.93] Brown 255 73 40.00 3.02 11.11 4.68
C42H38N10O16S6Cl2Co (40.05) (3.21) (10.83) (4.69)

(Continued )
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Table 2. Continued.

Calculated (Found) %

No. Metal chelates (mol. wt.) Color m.p. ( C) Yield (%) C H N M

17 [Zn(L5)2(H2O)2] [1157.39] Off white 245 75 43.55 3.28 14.52 5.48

C42H38N12O16S4Zn (43.65) (3.45) (14.18) (5.42)
18 [Cu(L5)2(H2O)2] [1157.54] Greenish brown 243 72 43.54 3.28 14.51 5.49
C42H38N12O16S4Cu (43.62) (3.50) (14.07) (5.45)
19 [Ni(L5)2(H2O)2] [1152.69] Green 250 74 43.72 3.30 14.57 5.09
C42H38N12O16S4Ni (43.79) (3.41) (14.20) (5.12)
Cefixime-derived Schiff bases

20 [Co(L5)2(H2O)2] [1152.93] Dark pink 248 75 43.71 3.30 14.57 5.11

C42H38N12O16S4Co (43.89) (3.53) (14.61) (5.08)
1925
 1926 M. Arif et al.

Table 3. Observed IR frequencies (cm1) and assignments.

Metal chelates (OH) (C¼N) (CO)lact (COO) (MN) (MO) (MS)

1 3540 1630 1775 1590 510 419 –

2 3500 1625 1770 1595 512 420 –
3 3520 1635 1770 1590 520 425 –
4 3510 1625 1775 1595 511 430 –
5 3535 1630 1780 1592 514 430 –
6 3445 1630 1770 1591 519 427 –
7 3525 1625 1775 1592 516 426 –
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8 3505 1635 1780 1595 520 428 –

9 3530 1640 1780 1591 513 420 –
10 3505 1630 1775 1593 512 426 –
11 3530 1635 1770 1589 518 430 –
12 3520 1640 1770 1590 510 430 –
13 3530 1645 1780 1582 517 421 390
14 3495 1640 1770 1580 515 423 380
15 3525 1635 1775 1582 516 426 385
16 3515 1640 1780 1584 520 420 390
17 3535 1620 1770 1588 515 430 –
18 3500 1615 1770 1587 513 427 –
19 3530 1610 1775 1590 518 423 –
20 3510 1620 1775 1585 513 421 –

Table 4. Thermal analyses (TGA and DTA) results of cef-binary chelates.

Mass loss %
Complexes Temperature range ( C) Found (Calcd) Assignment

1 155–220 2.81 (2.97) Loss of 2H2O

220–590 45.65 (45.98) Loss of (L1) þ metallic residue
2 150–215 2.85 (2.97) Loss of 2H2O
215–592 45.58 (45.99) Loss of (L1) þ metallic residue
3 150–210 2.87 (2.98) Loss of 2H2O
210–585 46.03 (46.16) Loss of (L1) þ metallic residue
4 157–220 2.86 (2.98) Loss of 2H2O
220–595 46.05 (46.18) Loss of (L1) þ metallic residue
5 150–223 2.65 (2.74) Loss of 2H2O
223–584 46.11 (46.28) Loss of (L2) þ metallic residue
6 156–210 2.67 (2.73) Loss of 2H2O
210–590 46.15 (46.27) Loss of (L2) þ metallic residue
7 150–225 2.71 (2.75) Loss of 2H2O
225–590 46.35 (46.47) Loss of (L2) þ metallic residue
8 157–210 2.67 (2.74) Loss of 2H2O
210–593 46.35 (46.46) Loss of (L2) þ metallic residue
9 82–109 5.57 (5.67) Loss of 2Cl2
109–227 2.67 (2.73) Loss of 2H2O
227–559 42.95 (43.10) Loss of (L3) þ metallic residue
10 82–109 5.47 (5.65) Loss of 2Cl2
109–225 2.65(2.74) Loss of 2H2O
225–558 42.85 (43.09) Loss of (L3) þ metallic residue
11 80–110 5.67 (5.70) Loss of 2Cl2
110–225 2.87(2.93) Loss of 2H2O
225–590 43.15 (43.24) Loss of (L3) þ metallic residue
12 83–110 5.67 (5.70) Loss of 2Cl2
110–220 2.85 (2.93) Loss of 2H2O
220–593 43.17 (43.25) Loss of (L3) þ metallic residue
 Cefixime-derived Schiff bases 1927

13 83–110 5.47 (5.53) Loss of 2Cl2

110–227 2.75 (2.84) Loss of 2H2O
227–595 43.25 (43.27) Loss of (L4) þ metallic residue
14 75–105 5.51 (5.54) Loss of 2Cl2
105–225 2.76 (2.83) Loss of 2H2O
225–587 43.08 (43.25) Loss of (L4) þ metallic residue
15 70–102 5.52 (5.55) Loss of 2Cl2
102–217 2.81 (2.87) Loss of 2H2O
217–590 43.33 (43.41) Loss of (L4) þ metallic residue
16 77–105 5.48 (5.56) Loss of 2Cl2
105–210 2.79 (2.86) Loss of 2H2O
210–593 43.15 (43.40) Loss of (L4) þ metallic residue
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17 135–220 3.02 (3.11) Loss of 2H2O

220–574 45.75 (45.80) Loss of (L5) þ metallic residue
18 138–223 3.02 (3.10) Loss of 2H2O
223–587 45.68 (45.79) Loss of (L5) þ metallic residue
19 135–219 3.05 (3.13) Loss of 2H2O
219–585 45.85 (46.00) Loss of (L5) þ metallic residue
20 137–211 3.05 (3.12) Loss of 2H2O
211–590 45.78 (45.99) Loss of (L5) þ metallic residue

Table 5. Antibacterial activity of cefixime Schiff base and their metal complexes (zone of inhibition in mm)
(400 mg mL1).

No. Compounds (a) (b) (c) (d) (e) (f)

1 Cefixime 35 21 40 9 44 25
2 L1 37 23 42 10 46 26
3 L2 37 25 43 7 46 23
4 L3 39 23 42 10 47 26
5 L4 36 23 44 11 48 27
6 L5 36 25 42 10 46 26
7 [Zn(L1)2(H2O)2] 50 36 55 17 60 40
8 [Cu(L1)2(H2O)2] 46 32 50 15 57 38
9 [Ni(L1)2(H2O)2] 40 25 44 11 48 26
10 [Co(L1)2(H2O)2] 42 29 48 13 51 33
11 [Zn(L2)2(H2O)2] 50 38 55 15 61 38
12 [Cu(L2)2(H2O)2] 46 34 50 12 58 37
13 [Ni(L2)2(H2O)2] 39 28 45 10 48 25
14 [Co(L2)2(H2O)2] 42 30 48 11 51 30
15 [Zn(L3)2(H2O)2]Cl2 52 36 54 16 61 40
16 [Cu(L3)2(H2O)2]Cl2 48 32 52 15 58 38
17 [Ni(L3)2(H2O)2]Cl2 41 25 44 11 49 28
18 [Co(L3)2(H2O)2]Cl2 44 27 47 13 52 33
19 [Zn(L4)2(H2O)2]Cl2 49 35 57 17 62 41
20 [Cu(L4)2(H2O)2]Cl2 44 33 52 15 60 39
21 [Ni(L4)2(H2O)2]Cl2 39 26 45 11 49 28
22 [Co(L4)2(H2O)2]Cl2 40 28 49 13 53 34
23 [Zn(L5)2(H2O)2] 50 37 54 16 62 40
24 [Cu(L5)2(H2O)2] 45 33 50 15 58 38
25 [Ni(L5)2(H2O)2] 39 26 44 11 48 29
26 [Co(L5)2(H2O)2] 41 29 47 13 52 33

(a) ¼ Escherichia coli, (b) ¼ Enterococcus faecalis, (c) ¼ Staphylococcus aureus, (d) ¼ Pseudomonas aeruginosa, (e) ¼
Salmonella enteritidis, (f) ¼ Klebsiella pneumoniae.
 1928 M. Arif et al.

Table 6. MICs (mg mL1) of the cefixime Schiff-base ligands and their metal complexes (10, 25, 50,
100 mg mL1).

No. Compounds (a) (b) (c) (d) (e) (f)

1 Cefixime 15 4100 12.5 4100 510 50

2 L1 14 4100 12.2 4100 510 48
3 L2 14 100 12.1 4100 510 55
4 L3 13 4100 12.1 4100 510 48
5 L4 14.5 4100 12 4100 510 47
6 L5 14.5 100 12.2 4100 510 48
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7 [Zn(L1)2(H2O)2] 510 75 510 90 510 20

8 [Cu(L1)2(H2O)2] 10.5 85 10.2 100 510 25
9 [Ni(L1)2(H2O)2] 13.5 100 124 100 510 48
10 [Co(L1)2(H2O)2] 12 95 10.5 4100 510 35
11 [Zn(L2)2(H2O)2] 510 70 510 100 510 24
12 [Cu(L2)2(H2O)2] 10.5 80 10.2 4100 510 25
13 [Ni(L2)2(H2O)2] 13 95 11.5 4100 510 50
14 [Co(L2)2(H2O)2] 12 97 10.5 4100 510 40
15 [Zn(L3)2(H2O)2]Cl2 510 75 510 95 510 20
16 [Cu(L3)2(H2O)2]Cl2 10 87 10 100 510 25
17 [Ni(L3)2(H2O)2]Cl2 13.5 100 12 4100 510 44
18 [Co(L3)2(H2O)2]Cl2 11.5 93 10.5 4100 510 35
19 [Zn(L4)2(H2O)2]Cl2 510 75 510 90 510 21
20 [Cu(L4)2(H2O)2]Cl2 11.5 87 10 100 510 25
21 [Ni(L4)2(H2O)2]Cl2 13 100 11.5 4100 510 44
22 [Co(L4)2(H2O)2]Cl2 13.5 95 10.4 4100 510 36
23 [Zn(L5)2(H2O)2] 510 72 510 95 510 20
24 [Cu(L5)2(H2O)2] 11 90 10.2 100 510 25
25 [Ni(L5)2(H2O)2] 13 100 12 4100 510 46
26 [Co(L5)2(H2O)2] 12.5 95 10.6 4100 510 35

(a) ¼ Escherichia coli, (b) ¼ Enterococcus faecalis, (c) ¼ Staphylococcus aureus, (d) ¼ Pseudomonas aeruginosa, (e) ¼
Salmonella enteritidis, (f) ¼ Klebsiella pneumoniae.

Figure 5. Average antibacterial activity.

were also screened against the same bacterial strains. The potency of the uncoordinated
ligands was enhanced on coordination with metal.

3.7. Minimum inhibitory concentration

The MIC was determined using the disk diffusion method [11]. MIC was the lowest
concentration of a substance at which the inhibition of growth occurred. The MIC of
 Cefixime-derived Schiff bases 1929
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Figure 6. Comparison of antibacterial activity.

these compounds varied from 10 to 100 mg mL1. The results (table 6) indicated that
these compounds are most active by inhibiting the growth of the tested organisms at
10 mg mL1. Some of the compounds showed good antibacterial activity against some
bacterial species (figures 5 and 6). This enhancement in the activity is rationalized on the
basis of the structures of (L1–L5) by possessing an additional azomethine (C¼N)
linkage important in elucidating the mechanism of transamination and resamination
reactions in biological system [30]. It has also been suggested that ligands with nitrogen
and oxygen donors might inhibit enzyme production, because the enzymes which
require these groups for their activity appear to be more susceptible to deactivation by
the metal ions upon chelation.

4. Conclusion

The synthesized cefixime-derived Schiff bases showed antibacterial properties with

metal complexes more active against all bacterial strains. These observations, in line
with other studies, suggest that the metal-based drugs possess potential as therapeutics.

Acknowledgments

Our sincere thanks are to the Higher Education Commission of Pakistan for providing
financial support. We are grateful to University of Manchester, U.K., for providing us
with the elemental analysis, NMR, and mass spectra. We are also thankful to HEJ
Research Institute of Karachi, University of Karachi, Pakistan, where in the
antibacterial assays were performed.
 1930 M. Arif et al.

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