International Journal of Pharmaceutical Science and Health Care Issue 3, Vol 5.

October 2013
Available online on http://www.rspublication.com/ijphc/index.html ISSN 2249 – 5738

PHARMACOLOGICAL PROPERTIES OF SCHIFF BASE METAL COMPLEXES

DERIVED FROM SUBSITUTED PYRIDINE AND AROMATIC AMINE
– A REVIEW
M. Usharani, E. Akila, R. Ashokan and R. Rajavel*
Department of Chemistry, Periyar University, Periyar palkalai Nagar, Salem,
Tamil Nadu, India
___________________________________________________________________________
ABSTRACT
Schiff bases are aldehyde or ketone like compounds in which the carbonyl group is
replaced by an imine or azomethine group. They are widely used for industrial purposes and
also exhibit a broad range of biological activities. Aromatic aldehydes and aliphatic or
aromatic ketone gives stable azomethine moiety. So far, modifications of the Schiff bases
have proven highly efficient with improved potency and lesser toxicity. Schiff base metal(II)
complexes of various donor atom of Substituted pyridine and aromatic amine based ligands
posses anti-tumor and anti-viral, anti -malarial, anti -fungal and anti microbial activities. This
review focuses on pharmacological properties of Schiff base metal(II) complexes derived
from Substituted pyridine and aromatic amine.
KEYWORDS: Pyridine, aldehyde, amine, antimicrobial, antipyretic, antioxidant
___________________________________________________________________________

INTRODUCTION
Schiff bases are some of the most widely used organic compounds. They are used as
pigments and dyes, catalysts, intermediates in organic synthesis and as polymer stabilizers.
Schiff bases have also been shown to exhibit a broad range of biological activities, including
antifungal, antibacterial, antimalarial, antiproliferative, anti-inflammatory, antiviral, and
antipyretic properties.
Current literature reveals that these pyridine compounds possess a variety of
biological activities, such as vasodilator, bronchodilator, antiatherosclerotic, geroprotective,
hepatoprotective, antidiabetic, antimalarial, anti-inflammatory, antiasthamatic, antibacterial,
and tyrosine kinase inhibiting agents. Example: 4-Substituted 1,4-dihydropyridines (1,4-
DHPs) are an important class of drugs for the treatment of cardiovascular diseases,
Alzheimer’s disease and used as chemo sensitizer in tumor therapy. They can cure the
disordered heart ratio as the chain-cutting agent and also have the antagonist modulation
activities. Therefore, their synthesis has been the focus of much interest for organic and
medicinal researchers. These promising results are encouraging further research in this field,
for future applications.
We also highlight the most significant examples of substituted pyridine and aromatic
amine compounds belonging to this class, which exhibit analgesic, anti- inflammatory, and
other pharmacological activities to have been reported in the literature.
PHARMACOLOGICAL ACTIVITIES OF SCHIFF BASES

Antimicrobial, Anticonvulsant, Antitumor, Cytotoxic, Anti-inflammatory, Antioxidant and

analgesic Properties etc.

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International Journal of Pharmaceutical Science and Health Care Issue 3, Vol 5. October 2013
Available online on http://www.rspublication.com/ijphc/index.html ISSN 2249 – 5738

Farzana Nazir et al1 presented the synthesis, characterization and biological

evaluation of Zn(II), Cu(II), Ni(II), Co(II), Mn(II), Cr(II) and Cd(II) transition metal
complexes of Schiff bases salicylidene gemifloxacin derived from Gemifloxacin and
Salicylaldehyde. In these complexes amino group available in the drug substances was
allowed to react with Salicylaldehyde, to obtain Schiff bases which were, subsequently,
allowed to react with Zn(CH3COO)2.2H2O, Cu(CH3COO)2.H2O, NiCl2.6H2O, CoCl2.6H2O,
MnCl2.4H2O, CrCl3.6H2O and CdCl2.5 H2O separately to form Schiff base metal complexes.
The antibacterial activity of the prepared complexes showed the following trend: Metal
complexes > Schiff base ligands> Parent drugs.

Sankar and Nandi2 synthesised Schiff bases from the 4-aminopyridine and toluene or
acetic acid by using Dean Stark apparatus. After synthesis, the docking studies were done to
estimate their antitubercular effect and compared it with standard drug isoniazid. From
docking studies it was concluded that compounds formed in this process were effective as
anti-tubercular agent.

Hearn et al3 developed Schiff base derivatives from the isoniazid and carbonyl
precursors, which provides increase in lipophilicity to the drug and made it more effective
against tuberculosis.

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International Journal of Pharmaceutical Science and Health Care Issue 3, Vol 5. October 2013
Available online on http://www.rspublication.com/ijphc/index.html ISSN 2249 – 5738

Two new Schiff base ligands (L1, L2) have been prepared from the reaction of 2,6-
diacetylpyridine and 2-pyridinecarboxyaldehyde with 4-amino-2,3-dimethyl-1-phenyl-3-
pyrozolin-5-on, and their Co(II), Cu(II), Ni(II), Mn(II), and Cr(III) metal complexes have
also been prepared. The Schiff base ligands and all complexes were evaluated for their in
vitro antibacterial and antifungal activities by the disc diffusion method4.

L1 L2

Kulkarni et al5 reported the synthesis of Cu(II), Ni(II), Co(II), Fe(III), Zn(II) and
Mn(II) complexes from Schiff bases derived from 2-amino pyridine. The synthesized Schiff
bases and their transition metal complexes have been screened for their antimicrobial activity
against E. coli, S. typhi, S. aureus, B. subtilis and against various fungi like P. chrysogenum,
A. niger, F. moniliformae, and A. Flavus by agar diffusion method at various concentrations
such as 20, 50 and 100 μg /ml. The complexes show enhanced activity than their
corresponding ligands.

Shailendra Pandey et al6 have reporetd a series of new Schiff bases of 2-

aminopyridine were synthesized through the condensation reaction between 2-aminopyridine
with different aldehydes / ketones and cyclic ketones. The compounds were evaluated for
anticonvulsant properties against seizures induced by maximal electroshock (MES), and
chemically induced seizures in mice. The acute adverse effects profiles were assessed with
respect to impairments of motor co-ordination by rotorod test in mice. These Schiff bases
shows better anticonvulsant potency against MES and Sc.-PTZ induced seizures while found
moderately active against Sc.-STY induced seizure screen. The compound I6, II2 and VII
shows better ED50 values (6.16, 3.07, and 9.62) with PI >10, against MES induced seizures
than that of reference drug (Phenytoin and Phenobarbital). Compound I 5, I6 and II1 in Sc.-

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 International Journal of Pharmaceutical Science and Health Care Issue 3, Vol 5. October 2013
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PTZ shows promising ED50 while in Sc.-STY induced seizures only I2 shows good ED50.

R1

N N C

R2

Compounds R1 R2 Compounds R1 R2
Cl
I1 H I5 H

HO OCH3
I2 H I6 H
OH

O2N CH3
I3 H I7 H
CH3

OCH3

I4 H NO2
I8 H
OCH3

OCH3

Compounds R1 R2 Compounds R1 R2
NH2
II1 H III2 CH3
O

II2 H IV1

N
H
OH
II3 H IV2

III1 CH3 VII -

A new tetradentate Schiff base ligand 2,2'-(1E,1'E)-1,1'-(6-chloropyrimidine-2,4-

diyl)bis(azan-1-yl-1- ylidene)bis(ethan-1-yl-1-ylidene)diphenol (L) was synthesized by the
reaction of 2-hydroxy acetophenone and 4- chloro-2,6-diaminopyrimidine. The Schiff base
ligand and its metal complexes (Cu(II), Co(II), Ni(II) and Mn(II) were tested against four
pathogenic bacteria (Staphylococcus aureus, Bacillus substilis) as Gram-positive bacteria,
and (Escherichia coli, Klebsiella pneumonia) as Gram-negative bacteria. All the metal
complexes exhibit higher antibacterial activity than the free ligand. Cobalt(II) complexes
have higher bacterial activity and Nickel(II) than the other complexes 7.

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International Journal of Pharmaceutical Science and Health Care Issue 3, Vol 5. October 2013
Available online on http://www.rspublication.com/ijphc/index.html ISSN 2249 – 5738

Ayen et al8 investigated antibacterial activities of Schiff base ligands derived from 2-
((4-benzyloxy-benzylidene)amino)phenol (L1) derived from 4-benzyloxybenzaldehyde and 2-
aminophenol, (4-benzyloxy-benzylidene)pyridine-2-yl-amine(L2) derived from 4-benzyloxy-
benzaldehyde and 2-aminopyridine. The Schiff bases were screened for in-vitro antibacterial
activities by disc diffusion and broth micro dilution techniques. Cephazoline was used as
standard and DMSO was used as control. The minimum inhibitory concentration (MIC)
values were calculated by microplate reader at 620 nm. The compounds inhibited both the
gram-positive and gram-negative bacteria with MIC between 62.5 and 250 µg/mL. It was
found compounds showed mild to moderate antibacterial activity by disc diffusion technique.
OH

N N O N O

L1 L2

Hegazy et al9 reported the synthesis of asymmetric 1,1`-disubstituted ferrocene-

derived Schiff-bases which is used in the preparation of their novel Pd(II) and Pt(IV) metal
chelates. These have also been used for screening against B. subtilis, S. aureus, E. coli, S.
typhi (bacteria), C. albicans (yeast), A. niger and F. solani (fungi). The antimicrobial results
indicated that the chelates prepared are more active than the ligand and have been found to be
a novel class of organometallic-based antimicrobials. The Schiff-base ligands and their Pd(II)
and Pt(IV) chelates showed valuable activity against the screened strains. In comparison with
the ligands, the metal chelates are more antimicrobial active and can considered as novel
class of organometallic-based antimicrobials.

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International Journal of Pharmaceutical Science and Health Care Issue 3, Vol 5. October 2013
Available online on http://www.rspublication.com/ijphc/index.html ISSN 2249 – 5738

A rapid, efficient, clean and environmentally benign exclusive synthesis of Schiff

bases as new ligands has been developed using condensation of 2-aminonicotinic acid with
salicyldehyde, 5- nitrosalicyldehyde, 5-bromosalicyldehyde and 5-methoxysalicyldehyde
efficiently in a water suspension medium using acid catalyst with excellent yields under
microwaves. The synthesized Schiff bases and their transition metal complexes were
evaluated for their in vitro antibacterial activity against four gram-negative and two gram-
positive bacterial stains by the agar-well diffusion method. Schiff bases were found to exhibit
either no or low to moderate activity but all the complexes exhibited varied vigorous activity
against different bacteria. Schiff bases which were inactive before complexation became
active and less active became more active upon coordination with mentioned bivalent
transition metal ions. The compound L3H was found to be active against all the Gram-
positive and Gram-negative bacteria. The compound L4H was found to be inactive against
the Gram-negative species, Escherichia coli, Pseudomonas aeruginosa & Salmonella typhi
and the Gram-positive species, Bacillus subtilis. The compound L1H showed no inhibitory
action against the Gram-negative species, Salmonella typhi & Shigella flexneri, and the
Gram-positive species, Bacillus subtilis. The Schiff base, L2H was found to be inactive
against the Gram-negative species, Pseudomonas aeruginosa & Shigella flexneri. In contrast,
the growth of all the Gram-negative and Gram-positive species was inhibited by all the metal
complexes under investigation10.

Singha et al11 showed a condensation reaction of 2,6-diaminopyridine with isatin in

the presence of divalent metal ions results in the formation of the macrocyclic complexes of
the type [M(C26H16N8)X2], where M= Co(II), Ni(II), Cu(II), Zn(II), Cd(II) and X= Cl−, NO3
−, CH3COO−. The complexes were tested for their in vitro antibacterial activity. Some of the
complexes showed good antibacterial activities against some selected bacterial strains.

Where M= Co(II), Ni(II), Cu(II), Zn(II), Cd(II); X= Cl−, NO3−, CH3COO−

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International Journal of Pharmaceutical Science and Health Care Issue 3, Vol 5. October 2013
Available online on http://www.rspublication.com/ijphc/index.html ISSN 2249 – 5738

Nirmal et al12 reported the synthesis of novel Schiff bases analogues of 3-(4-amino)
Phenylimino) 5-fluoroindolin-2-one. Among the Schiff bases compound N-3 exhibited
significant analgesic activity. Among the title compounds studied some exhibited significant
anti- inflammatory activity comparable to reference standard diclofenac sodium. The test
compounds showed only mild ulcerogenic side effect when compared to aspirin.

In vitro evaluated thiazolyl and benzothiazolyl Schiff bases for screening anti-
degenerative activity on nasal pig cartilage and cultures treated with interleukin 1beta, (IL-
1beta). The results suggested that thiazolyl and benzothiazolyl Schiff bases in general, and
particularly the Schiff base with bromine and methoxyl group in position three would protect
cartilage matrix from degenerative factors induced by IL-1beta. These studied exhibited that
these compounds have anti-inflammatory activities. Many human diseases are associated
with the overproduction of oxygen free radicals that inflict cell damage. A manganese (II)
complex with bis (cyclohexylpyridine)- substituted macrocyclic ligand has designed as a
functional mimic of the superoxide dismutase (SOD) enzymes that normally remove these
radicals13.

Cezar Spinu et al14 have reported a metal complexes, ML2Cl2, where M is Fe(II),
Co(II), Ni(II), Cu(II), Zn(II), or Cd(II), and L is the Schiff base formed by condensation of 2-
thiophenecarboxaldehyde with 2-aminopyridine, N-(2-thienylmethylidene)-2-aminopyridine
(TNAPY). The Schiff base and its metal chelates have been screened for their in vitro
antibacterial activity against Escherichia coli, Staphylococcus aureus, and Pseudomonas
aeruginosa. The metal chelates were shown to possess more antibacterial activity than the
uncomplexed Schiff-base. The activity of the Schiff base complexes became more
pronounced when coordinated with the metal ions. The biological activity of the complexes
follow the order: Co(II) = Fe(II) > Ni(II) = Zn(II) = Cu(II) >Cd(II).

a [M(MNAPY)2Cl2], M = FeII, CoII, NiII, and CuII.

b [M(MNAPY)2]Cl2, M = ZnII, and CdII .

Noureen et al15 evaluated and reported the synthesis of Schiff base esters, by two
synthetic routes using variably substituted hydroxy benzaldehydes with para amino phenol in
appreciable yields. All the synthesized compounds were subjected to potato disc antitumor
assay, and carrageen an induced edema test in rat hind paw. All the synthesized compounds
showed significant tumor inhibitory activities. Compound [N-4′-methoxybenzylidene-4-(3″-
phenyl) butyroyloxyaniline] showed best tumor inhibition activity (IC50 value 0.15 and 8.03

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International Journal of Pharmaceutical Science and Health Care Issue 3, Vol 5. October 2013
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μg/ml respectively) in potatodisc antitumor assay. Compound [N-4′-methoxy benzylidene-4-

[2″-{4″′-(2″″-methylpropyl)phenyl} propanoyloxyaniline] was found to be most active
compound in the early phase of inflammation (88.86 % inhibition) and compound [N-
benzylidene-4-naphthoyloxyaniline] was found to have the highest activity in the late phase
of inflammation, i.e. 90.35 %.

New tridentate Schiff base were prepared by condensing S-2-picolyldithiocarbazate

with pyridine-2-carboxaldehyde, 2-acetylpyrrole and 2-acetylthiophene while a bidentate
Schiff base was prepared by condensing the S-2-picolyldithiocarbazate with 2-acetylfuran.
Synthesized Schiff base were evaluated for cytotoxic and antimicrobial activities. Bidentate
Schiff base and the Schiff base prepared from 2-acetylthiophene showed activity against a
number of bacteria while Schiff base prepared from pyridine-2-carboxaldehyde were evolved
as a cytotoxic agent against human cell T-lymphoblastic leukemia and human colon
adrenocarcinoma cell. Further, all the Schiff base were complexed with Ni (II). None of the
complexes showed activity against Human cell T-lymphoblastic leukemia16.

H3C S CH2
C N N C
N
SH

NH

The new complex formed by Cd(II) and the 1:2 Schiff-base-type ligand 2,6-bis[1-(4-
amino-1,2,3,6- tetrahydro-1,3- dimethyl-2,6- dioxopyrimidin-5-yl) imino] ethylpyridine
(DAPDAAU) has been evaluated for DNA interactions. The interaction of the Cd(II)
complex (compound I) with calf-thymus DNA as observed by circular dichroism
spectroscopy suggests the initial unwinding of the DNA double helix strongly depends on
increasing incubation times and metal-to-nucleic acid molar ratios. Electrophoretic
experiments indicate that the cadmium complex induces cleavage of the plasmid pBR322
DNA to give ulterior nicking and shortening of this molecule, as a result of the complex
binding to DNA, resulting in the conclusion that compound I behaves as a chemical nuclease.
Cytotoxic activity of the Cd(II) complex against selected different human cancer cell lines
also shows specific and increases with increasing concentration of the metal compound; this
fact indicates the potential antitumor character of the complex17.

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International Journal of Pharmaceutical Science and Health Care Issue 3, Vol 5. October 2013
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Arora et al18 synthesized 5- aminosalicylic acids or mesalamine with molecular

formula C7H7NO3. It is proved to a useful drug in an effective treatment of inflammatory
bowel disease. It possesses both anti-inflammatory and analgesic activity by targeting COX,
prostaglandins and lipoxygenase enzyme. The positive control, 5- aminosalicylic acid and
test compounds significantly inhibited the Paw edema response in comparison to control
group. 5 aminosalicylic acids showed an inhibition of 54.1% after 3 hours. Compound 3b
showed almost comparable activity with standard with an inhibition of 50.45% and
compound 3a showed minimum activity with an inhibition of 41.7 % after 3 hours.

Alam et al19 synthesized 4-Aminoantipyrine (4-amino-1,5-dimethyl-2-

phenylpyrazole-3-one) and its analogues have been found to be compounds of interest for
their anti-inflammatory, analgesic, antiviral, antipyretic, antirheumatic and antimicrobial
activities. The IC (50) values for two compounds were found to be 0.44 and 0.93 μM,
respectively, comparable to that of ascorbic acid (IC (50) 0.41 μM), a standard antioxidant
agent. From the comparisons between the hydroxylated and methoxylated compounds, the
rank order of antioxidant activity for the products resulting from benzylidene phenyl ring
substitution was 2,4,6-OH>3,4-OH>3-OMe-4-OH>3,5-OMe-4-OH>2,4-OH>3-Me-4-
OMe>3,4-OMe>4-OMe>4-OH. The position and nature of the substituted group on the
benzylidene phenyl ring of the Schiff base analogues of 4-aminoantipyrine play an important
role in their antioxidant activity. The anti-inflammatory activity of a compound which also
exhibited excellent antioxidant activity was evaluated in terms of its inhibition of NO
production, an inflammatory modulator, in LPS pretreated RAW 264.7 cells using the Griess
method. It was observed that compound significantly reduced NO production and inhibited
LPS-stimulated iNOS and COX-2 mRNA levels in a dose-dependent manner. Overall, that
compound showed promising antioxidant and anti-inflammatory activities and may be used
as the lead compound in a future study.

Bhosale et al20 reported the synthesis of new 4-(4- substituted phenyl )- N – ( 4-

substituted – benzylidene )- thiazol – 2 – amine derivatives and evaluated for their anti-
inflammatory and analgesic activities at a dose of 50 mg /kg p.o. The most active compounds
4-(4- chloro phenyl)- N – ( 4- methoxy – benzylidene )- thiazol – 2 – amine. 4-(4- bromo
benzylidene )- 4 – ( 4- chlorophenyl) - thiazol – 2 – amine have been subjected to acute
ulcerogenesis study at a dose of 150 mg/kg.

Conclusion

This review reveals that the Schiff base complexes derived from substituted pyridine
and aromatic amines are most commonly used as antimicrobial agent than other
pharmacological agents. Hence we conclude that the Schiff base and its complexes may serve
as antifungal, antibacterial, antimalarial, antiproliferative, anti-inflammatory, antiviral,
antitumor and antipyretic agents.

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International Journal of Pharmaceutical Science and Health Care Issue 3, Vol 5. October 2013
Available online on http://www.rspublication.com/ijphc/index.html ISSN 2249 – 5738

Acknowledgement

Financial support from DST INSPIRE Fellowship, New Delhi, is gratefully

acknowledged. We are also thankful to our supervisor and professors of department of
chemistry, Periyar University - Salem for further support.
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