Synthesis, spectral and biological studies of novel schiff base metal complexes derived from cephalexin and sugars

Article abstract of DOI:10.14233/ajchem.2013.13005

Fe(II), Co(II) and Ni(II) metal complexes of novel Schiff bases derived from cephalexin and sugars (D-glucose, D-xylose) were synthesized and characterized by physio-chemical (elemental analysis, magnetic susceptibility and electrolytic conductance) and s

Full text of DOI:10.14233/ajchem.2013.13005

Asian Journal of Chemistry; Vol. 25, No. 1 (2013), 297-300
http://dx.doi.org/10.14233/ajchem.2013.13005
Synthesis, Spectral and Biological Studies of Novel Schiff Base
Metal Complexes Derived from Cephalexin and Sugars
*
NARJIS NAZ , ZUBI SADIQ and MUHAMMAD ZAFAR IQBAL
Department of Chemistry, Lahore College for Women University, Lahore-54000, Pakistan
*Corresponding author: E-mail: narjis107@gmail.com
(Received: 3 November 2011;
Accepted: 23 July 2012)
AJC-11866
Fe(II), Co(II) and Ni(II) metal complexes of novel Schiff bases derived from cephalexin and sugars (D-glucose, D-xylose) were synthesized
and characterized by physio-chemical (elemental analysis, magnetic susceptibility and electrolytic conductance) and spectral techniques.
It has been found that Schiff bases behave as bidentate ligands forming complexes with 1:2 (metal:ligand) stoichiometry. Thermal behaviour
of complexes has been investigated using thermogravimetric techniques. The biological activities of complexes have been evaluated
against two gram negative (Escherichia coli and Pseudomonas aeruginosa) and two gram positive (Bacillus subtilis and
Staphylococcus aureus) bacteria by Agar diffusion disc method. It has been found that the complexes have higher activity as compared to
the pure cephalexin against the bacteria.
Key Words: Schiff base complexes, Cephalexin, Sugars.
INTRODUCTION
The widely use of the antibiotics leads to the serious
O
O
O
KOH
H2N
S
N
medical problem of drugs resistance and public health
concern1-4. Studies of new synthetic derivatives of antibiotics
with novel mechanism of action has become an important
chore to deal with drugs resistance dilemma5-7.
N
S
N
H
R
HN
CH3
CH3OH
HN
CH3
R
COOH
COOH
O
O
where, R = C5H11O5 or C4H9O4
Literature suggests that some antibiotics showed improved
activity when administered as metal complex rather than as
simple organic molecule8-11 and that the coordinating possi-
bility of antibiotics has been improved by condensing with a
variety of carbonyl compounds to make chemotherapeutic
Schiff base metal complexes12,13. Schiff bases are distinctive
class of chelating ligands in coordination chemistry14-16 and
have diversity of applications in different fields17,18 owing to
its greater pick, sensitivity and synthetic flexibility to coordi-
Scheme-I: Systematic approach of Schiff base ligand
The electronic spectra of the Schiff base and their metals
complexes were obtained in DMSO on a Hitachi 220 S spectro-
photometer in the range 900-200 nm. Elemental analysis (C,
H, N, S) was performed using a Carlo Erba 1106 elemental
analyzer. The FTIR spectra in the range 4000-200 cm-1 were
obtained using KBr discs on a Michaelson Bomen series
spectrophotometer. Magnetic measurements were carried out
by the Gouy's method using Hg[Co(SCN)4] as a calibrant.
Molar conductance of the Schiff base metal complexes was
determined in DMSO at room temperature using Wescan-212
conductometer. Metal contents in complexes were determined
by Hitachi Z-8000 atomic absorption spectrophotometer after
undertaking proper acid digestion. Thermal Analysis was
performed on Netzsch simultaneous thermal analyzer.
nate with different transition metal ions19,20
.
In continuance21,22 of our research work, we reported the
synthesis, spectroscopic and biological studies of new schiff
base derivatives of cephalexin with sugars and their Fe(II),
Co(II) and Ni(II) metal complexes (Scheme-I).
EXPERIMENTAL
All the solvents and regents used for this study were of
analytical grade and obtained from E. Merck. The Cephalexin
was obtained from Remington Pharmaceutical Industries Pvt.
Ltd.
Preparation of Schiff base metal complexes: A
methanolic solution (50 mL) of cephalexin (1 mmol) was
mixed with sugar (1 mmol) dissolved in methanol (50 mL)
under constant stirring. Solution of KOH (0.1 % in methanol)

298 Naz et al.
Asian J. Chem.
TABLE-1
PHYSICAL PROPERTIES OF SCHIFF BASE METAL COMPLEXES (I-VI)
Elemental analysis (%): Calcd. (found)
Conductivity
Ω-1 cm2 mol-1
5.96
S.
No.
Yield
(%)
µeff
(BM)
λmax nm
(ε cm-1 mol-1)
Compounds Colour Empirical formula
(gluceph)2 Reddish (C22H26N3O9S)2 Fe
M
C
H
N
S
1
59
64
55
64
58
60
4.96
49.16
4.72
7.65
(7.83)
5.74
(5.96)
5.15
2.21
-
284 (41015),
338 (8011)
Fe
brown
(5.20) (49.24) (4.88)
5.33 49.05 4.73
(5.48) (49.10) (4.87)
5.42 48.98 4.76
(5.45) (49.11) (4.87)
5.35 49.70 4.74
(5.51) (49.79) (4.77)
5.76 49.52 4.72
(5.80) (49.63) (4.76)
5.72 49.59 4.71
(5.78) (49.65) (4.76)
(gluceph)2
Co
Dark (C22H26N3O9S)2 Co
brown
7.69
(7.81)
5.71
(5.95)
3.06
5.24
4.96
3.15
5.13
286 (41025),
335 (8024)
2
3
4
5
6
(gluceph)2 Light (C22H26N3O9S)2 Ni
Ni green
(xylceph)2 Reddish (C21H24N3O8S)2 Fe
7.73
(7.81)
5.76
(5.95)
280 (41011), 330
(8095) 480 (66)
8.22
(8.29)
6.09
(6.32)
5.12
2.24
-
285 (41006),
335 (7899)
Fe
brown
(xylceph)2
Co
Dark (C21H24N3O8S)2 Co
brown
8.18
(8.27)
6.13
(6.30)
288 (41024),
330 (8094)
(xylceph)2 Light (C21H24N3O8S)2 Ni
Ni breen
*Theoretical values are given in brackets
8.22
(8.27)
6.11
(6.30)
282 (41012), 330
(8000), 482 (69)
was gradually added to the above reaction mixture and
refluxed for ca. 0.5 h. A yellow solution of Schiff base was
formed. The coloured solution, thus obtained was mixed with
the solution of metal salt (4 mmol) in methanol and refluxed.
The refluxing was continued for ca. 2 h. The coloured solid
(depends upon the metal salt used) formed was isolated by
filtration and washed with distilled water, ethanol and methanol
and dried in vacuum over CaCl2.
The electronic absorption data of the complexes dissolved
in DMSO is given in Table-1. In the spectra of complexes the
band in the 288-280 nm range is assigned to phenyl ring π-π*
transition31. The bands appear in the range 338-330 nm are
attributed to π-π* transition originating in the C=N chromo-
phore group32. The band for chromophore group is usually
present in range 348-390 nm. During the formation of the
complexes this band is shifted to the lower wavelength
suggesting that nitrogen atom of the azomethine is coordinated
to metal ion33. The lower energy bands in range of 482-480
nm are due to d-d transition. The magnetic susceptibilities of
the iron (II) complexes under investigation are in the range of
5.15-5.12 BM, tetrahedral geometry is proposed for these
complexes34. Schiff base complexes of cobalt(II) are usually
low spin with magnetic moments in the range of 2.24-2.21
BM35 and possess square planar geometry.
Biological activity: In vitro biological screening effect
of the investigated compounds have been screened against
bacteria byAgar diffusion disc method23,24. Two gram negative
(Escherichia coli and Pseudomonas aeruginosa) and two gram
positive (Staphylococcus aureus and Bacillus subtilis) bacteria
were grown in nutrient agar medium at 37 ºC for 24 h25,26. The
sterile (5 mm) diameter sensitivity discs were prepared by
soaking the blank discs in the solution of appropriate concen-
tration (10 µg/10 µL in DMSO) of the complex to be tested.
Test discs and standard cephalexin (10 µg/10 µL) disc were
placed on the nutrient agar slightly pressing them on to the
medium. The plates were then incubated for 24 h at 37 ºC for
bacteria. The results were recorded by measuring the zone of
growth inhibition (mm) surrounding the discs.
Diamagnetic complexes of nickel are square planner36
where as paramagnetic complexes are tetrahedral, the nickel(II)
complexes under observation are diamagnetic so square planar
structure is proposed.
The most pertinent FTIR spectral bands of complexes and
their assignments are presented in Table-2. The assignments
are made in comparison with the spectrum of pure cephalexin.
The bands present in the 3278-3276 cm-1 region in spectra of
the complexes exclude the involvement of NH group in coordi-
nating with metal ions37. The new band at 1602-1598 cm-1
region in the spectra of complexes is assigned to the azomethine
group coordinated to the metal ion. The spectrum of pure
cephalexin shows stretching vibration at 2610 cm-1 due to NH2
group38,39. The stretching vibrations at 2610 cm-1 due to NH2
group of cephalexin and at 2840 cm-l due to free CO group of
aldehyde were absent in the FTIR spectra of these complexes.
This indicates that NH2 group of Cephalexin and aldehyde
group of sugar condensed to produce the -CH=N- group. The
absorption band for the azomethine group is generally
observed at 1650-1630 cm-1 40. The observed low value of this
band confirms the coordination through the azomethine
nitrogen41,42. The spectra of these complexes exhibited a strong
bands around 1775-1773 cm-1 and 1695-1690 cm-1, which are
assigned to β-lactam ν(C=O) and amide ν(C=O) respec-
tively38,39. The invariance of the frequencies of β-lactam
ν(C=O) and amide ν(C=O) groups relative to the spectra of
RESULTS AND DISCUSSION
New Schiff base derivatives of cephalexin were prepared
by refluxing it with sugars i.e., D-glucose and D-xylose.Amino
group available in Cephalexin was allowed to react with the
aldehydic group of sugars (aldoses) to obtain Schiff bases.
Formation of Schiff base ligands was indicated by yellowing
of solution and development of an absorption band with a
maximum at 400 nm27 in the visible region. It is known that
Schiff bases obtained from aliphatic carbonyl compounds are
readily hydrolyzed28. However these Schiff bases are isolated
as metal chelates. The newly synthesized Schiff base metal
complexes are coloured, non-hygroscopic and stable at room
temperature. They are soluble in DMF and DMSO. The
analytical data of the complexes with some physical properties
are presented in Table-1. The analytical data reveals that these
have metal:ligand stoichiometry of 1:2 corresponding to the
general formula of M(L)2 where M is metal and L is ligand.
The lower conductance values of the complexes support their
non electrolytes nature29,30
.

Vol. 25, No. 1 (2013)
Studies of Novel Schiff Base Metal Complexes Derived from Cephalexin and Sugars 299
TABLE-2
ASSIGNMENT OF MORE SIGNIFICANT ABSORPTION BANDS (cm-1) of SCHIFF BASE TRANSITION METAL COMPLEXES (1-6)
Compound
No
ν(C=O)
β-lactam
1760
ν(NH)
(amide)
ν(C=O)
(amide)
νas(COO)
ν(C=N-) νs(COO)
∆v
ν(CN)
ν(CS)
ν(M-N)
ν(M-O)
1
2
3
4
5
6
3276
3278
3273
3276
3276
3278
1695
1692
1690
1692
1692
1692
1626
1622
1626
1626
1624
1626
1598
1600
1600
1600
1602
1600
1385
1382
1385
1385
1385
1382
241
240
241
241
238
244
1017
1021
1020
1017
1022
1022
580
580
580
584
584
584
406
408
400
406
402
398
369
360
358
369
362
362
1758
1758
1760
1760
1758
30
Cephalexin
Complex 1
Complex 2
Complex 3
Complex 4
Complex 5
Complex 6
pure cephalexin (at 1758 and 1688) ruled out the involvement
of β-lactam ν(C=O) and amide ν(C=O) in coordination. Coor-
dination of the Sulphur atom can be excluded on the basis of
the absorption band at 582-580 cm-1, which is at almost at
25
20
15
10
5
same region as in the spectrum of free Cephalexin38,39
.
0
Free carboxylate (COO) in pure cephalexin shows absor-
ption band at 1582 cm-1 and 1400 cm-1 region for asymmetric
and symmetric vibrations38,39. In all the complexes the
carboxylate ν(COO)asy were shifted towards higher wave
numbers at 1626-1622 cm-1 while ν(COO)sy were shifted
towards lower wave numbers at 1385-1382 cm-1. This experi-
mental finding evidently indicates that carboxylate is involved
in coordination in all complexes43. The ∆v value [∆v= ν(COO)sy-
ν(COO)asy] is equal to 182 for pure cephalexin. The ∆v values
in all the complexes increased, which are characteristic of
monodentate carboxylate ion in coordination with metal44. New
absorption bands for ν(MN) and ν(MO) appeared at 408-398
cm-1 and 369-358 cm-1 respectively45. The FTIR spectral data
indicate that coordinating groups are C=N- and -COO present
in the Schiff base ligands.
S. aureus
B. subtilis
E. coli
P. aeruginosa
Fig. 1. Antibacterial activity data of metal complexes
It is known that chelation tends to make simple organic
molecule a more powerful and potent bactericidal agent48. All
the complexes show more antibacterial activities as compared
to the pure cephalexin. The antibacterial activities of Schiff
base metal complexes were found in the order:
Co(II) > Ni(II) > Fe(II)
S
N
CONH
O
N
O
The thermal behaviour of the complexes has been investi-
gated using thermogravimetric technique. The decomposition
temperature and weight loss of the complexes were calculated
from TGA data listed in Table-3. These complexes do not
possess sharp melting points but decompose when heated
above 200 ºC. Thermal analysis indicates that these complexes
are anhydrous as there was no weight loss for coordination or
lattice water when heated between 100-180 ºC46. The thermal
behaviour of all the complexes is same and they undergo comp-
lete decomposition in single step to the corresponding metal
oxides47.
R
CH3
O
N
M
O
O
O
N
R
H3C
NHOC
S
where, M = Fe, Co and Ni
Proposed structure of Schiff base metal complex
TABLE-3
THERMAL DECOMPOSITION OF THE METAL COMPLEXES
ACKNOWLEDGEMENTS
Decomposition
temperature
range
Weight loss (%)
calculated
(found)
Residue (%)
calculated
(found)
Compounds
number
The authors are thankful to the Remington Pharmaceutical
Company Pvt. and Kundian Chemical Plant I Pakistan for
providing assistance in this work.
I
215-725
220-723
218-722
220-725
222-722
218-723
93.52 (93.48)
93.26 (93.20)
93.28 (93.23)
93.52 (93.75)
93.26 (93.18)
93.28 (93.25)
6.70 (6.66)
6.96 (6.90)
6.94 (6.91)
7.09 (6.98)
7.38 (7.22)
7.35 (7.28)
II
III
IV
V
REFERENCES
1. K. Singh, M.S. Barwa and P. Tyagi, Eur. J. Med. Chem., 42, 394 (2007).
2. J.G. Lara, M. Masalha and S.J. Foster, Drug Discovery Today, 10, 643
(2005).
VI
3. S. Tehranchian, T. Akbarzadeh, M.R. Fazeli, H. Jamalifar and A.
Shafiee, Bioorg. Med. Lett., 5, 1023 (2005).
Antimicrobial activities: The antimicrobial activities of
all the Schiff base transition metal complexes derived from
cephalexin, sugars and metals such as Fe(II), Co(II), Ni(II)
against four bacteria: Escherichia coli, Staphylococcus aureus,
Pseudomonas aeruginosa and Bacillus subtilis in comparison
of pure cephalexin were recorded in Fig. 1.
4. N. Gumrukcouglu, M. Serdar, E. Celik, A. Sevim and N. Demirbas,
Turk. J. Chem., 31, 335 (2007).
5. M.S. Iqbal, I.H. Bukhari and M. Arif, Appl. Organomet. Chem., 19,
864 (2005).
6. G.B. Bagihalli, P.G. Avaji, S.A. Patil and P.S. Badami, Eur. J. Med.
Chem., 43, 2639 (2008).

300 Naz et al.
Asian J. Chem.
7. N. Raman, J.D. Raja and A. Sakthivel, J. Chem. Sci., 119, 303 (2007).
8. M.S. Iqbal,A.R.Ahmad, M. Sabir and S.M.Asad, J. Pharm. Pharmacol.,
51, 371 (1999).
28. M.S. Iqbal, S.J. Khurshid and M.Z. Iqbal, Can. J. Chem., 71, 629 (1993).
29. S.M.E. Khalil, S.L. Stefan and K.A. Bashir, Synth. React. Inorg. Met.-
Org. Chem., 29, 1685 (1999).
9. Z.H. Chohan and M.F. Jaffery, Metal Based Drugs, 7, 265 (2000).
10. R. Di Stefano, M. Scopelliti, C. Pellerito, T. Fiore, R. Vitturi, M.S.
Colomba, P. Gianguzza, G.C. Stoccoa, M. Consiglioa and L. Pelleritoa,
J. Inorg. Biochem., 89, 279 (2002).
30. M. Sekerci and E. Tas, Heteroatom Chem., 11, 254 (2000).
31. B. Bosnich, J. Am. Chem. Soc., 90, 627 (1968).
32. R.S. Downing and F.L. Urbach, J. Am. Chem. Soc., 91, 5977 (1969).
33. M. Sonmez and M. Sekerci, Polish J. Chem., 76, 907 (2002).
34. F.A. Cotton and G. Wilkinson, Advance Inorganic Chemistry, Academic
Press, New York, edn. 4, p. 790 (1980).
11. R. Ramesh and M. Sivagamasundari, Synth. React. Inorg. Met.-Org.
Chem., 33, 809 (2003).
12. P. Singh, R.L. Goel and B.P. Singh, J. Indian Chem. Soc., 52, 958 (1975).
13. A.M. Mahindra, J.M. Fisher and Rabinovitz, Nature (London), 64, 303
(1983).
35. N.N. Green andA. Earnshaw, Chemistry of the Elements, Pergamon Press,
Oxford, U.K., p. 1315 (1984).
36. R.L. Duta and A. Syamal, Elements of Magnetochemistry, edn. 2 (1992).
37. R. Di Stefano, M. Scopelliti, C. Pellerito, G. Casella, T. Fiore, G.C. Stocco,
R. Vitturi, M. Colomba, L. Ronconi, I.D. Sciacca and L. Pellerito, J. Inorg.
Biochem. 98, 534 (2004).
14. M. Sonmez, Turk. J. Chem., 25, 181 (2001).
15. K.S. Abou-Melha and H. Faruk, J. Iran. Chem. Soc., 5, 122 (2008).
16. W. Radecka-Paryzek, V. Patroniak and J. Lisowski, Coord. Chem. Rev.,
249, 2156 (2005).
38. P.K. Bhattacharrya and W.M. Cort,Analytical Profiles of Drug Substances,
p. 28 (1978).
17. N. Raman, A. Kulandaisamy and K. Jeyasubramanian, Transition Met.
Chem., 26, 131 (2001).
39. E. Ivashikiv, Analytical Profiles of Drug Substances, p. 5 (1973).
40. K. Nakamoto, Infrared and Raman Spectra of Inorganic and Coordina-
tion Compounds, NewYork, NY: John Wiley Interscience, p. 59 (1997).
41. N. Raman, S. Ravichandran and A. Kulandaisamy, Asian J. Chem., 14,
1261 (2002).
18. M. Sonmez, Polish J. Chem., 77, 397 (2003).
19. C. Spinu and A. Kriza, Acta Chim. Slov., 47, 179 (2000).
20. S. Baluja, A. Aolanki and N. Kachhadia, J. Iran. Chem. Soc., 3, 312
(2006).
21. N. Naz and M.Z. Iqbal, J. Chem. Soc. Pak., 31, 440 (2009).
22. N. Naz and M.Z. Iqbal, Sci. Int., 23, 27 (2011).
23. Z.H. Chohan and S.K.A. Sheazi, Synth. React. Inorg. Met.-Org. Chem.,
29, 105 (1999).
42. R.K. Agarwal, D. Sharma, L. Singh and H. Agarwal, Bioinorg. Chem.
Appl., article 29234 (2006).
43. Z.H. Chohan, M. Arif, M.A. Akhtar and C.T. Supuran, Bioinorg. Chem.
Appl., article 83131 (2006).
24. A.K. Halve, D. Bhadauria, B. Bhaskar, R. Dubey and S. Vasudha, Indian
J. Pharm. Sci., 69, 680 (2007).
44. G.B. Deacon, F. Huber and R.J. Phillips, Inorg. Chim. Acta, 41, 104
(1985).
25. V.K. Tandon, D.B. Yadav, R.V. Singh, M. Vaish, A.K. Chaturvedi and
P.K. Shukla, Bioorg. Med. Chem., 15, 3463 (2007).
26. A.K. Sadana,Y. Miraza, K.R.Aneja and O. Prakash, Eur. J. Med. Chem.,
38, 533 (2003).
45. X. Tai, X. Yin, Q. Chen and M. Tan, Molecules, 8, 439 (2003).
46. N. Raman and S. Ravichandran, Polish J. Chem., 78 (2004).
47. E. Canpolat and M. Kaya, Russian J. Chem., 31, 415 (2005).
48. Z.H. Chohan, C.T. Supuran and A. Scozzafava, J. Enzyme Inhib. Med.
Chem., 19, 79 (2004).
27. D.E. Metzler, J. Am. Chem. Soc., 91, 627 (1968).