1.

Introduction
1.1 Schiff Base
A Schiff Base, named after Hugo Schiff, is a compound with a functional group that contains a
carbon-nitrogen double bond with the nitrogen atom connected to an aryl or alkyl group, not
hydrogen. Schiff bases in a broad sense have the general formula R 1R2C=NR3, where R is an
organic side chain. In this definition, Schiff bases are synonymous with azomethine. Some
restrict the term to the secondary aldimines (azomethine where the carbon is connected to a
hydrogen atom), thus with general formula RCH=NR1

The chain of the nitrogen makes the Schiff base a stable imine. A Schiff base derived from
aniline, where R3 is a phenyl or a substituted phenyl, can be called an anil.

R1

C
R H

Figure 1.1: General structure Of Schiff base.

R3

C
R1 R2

Figure 1.2: General structure of azomethine

Schiff base forms an important class of the most widely used organic compounds and has a
wide variety of applications in many fields including analytical, biological, and inorganic
chemistry. Schiff bases have gained importance in medicinal and pharmaceutical fields due to a
broad spectrum of biological activities like anti-inflammatory [1-4], analgesic [5–8],
antimicrobial [9, 10], anticonvulsant [11], antitubercular [12], anticancer [13, 14], antioxidant
[15], anthelmintic [16], and so forth. The nitrogen atom of azomethine may be involved in the
formation of a hydrogen bond with the active centers of cell constituents and interferes in

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normal cell processes [17, 18]. Apart from biological activities, Schiff bases are also used as
catalysts, intermediates in organic synthesis, dyes, pigments, polymer stabilizers [3], and
corrosion inhibitors [19]. Studies enlightened that metal complexes show greater biological
activity than free organic compounds [20]. Augmentation of biological activity was reported by
implementation of transition metals into Schiff bases [21]. Schiff bases played an influencing
role in development of coordination chemistry and were involved as key point in the
development of inorganic biochemistry and optical materials [22].

1.2 Historical Background

Schiff bases have been known since middle of nineteenth century. First of all Ettling in 1840
isolated Schiff base complexes of copper. But the systematic synthetic study of Schiff base
complexes started with the work of Pfeiffer and coworkers in 1931. Jencks has shown the
formation of carbinolamine as an intermediate product which loses a water molecule to yield a
Schiff base.

R1

OH H
+ O C
H2N R
H R1 C N R

R1

C NR + H2O

Scheme 1.1: Systematic route for synthesis of Schiff base

Mourea and Mignonac have also synthesized the Schiff bases by the reaction of Grignard’s
reagent with aryl cyanide followed by careful hydrolysis of the intermediate product.

R H2O Ar

NMgBr C NH
RMgBr Ar C
ArCN +
R

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1.3 Metal Complex Of Schiff Base
One of the most important properties of metallic elements is their ability to act as Lewis acids
that form complexes with a variety of Lewis bases. A metal complex consists of a central metal
atom or ion that is bonded to one or more ligand (from the Latin ligare, meaning “to bind”),
which are ions or molecules that contain one or more pairs of electrons that can be shared with
the metal. Metal complexes of Schiff bases have occupied a central role in the development of
coordination chemistry. This situation is manifested by the huge number of publications. In
general, metal complexes of Schiff bases were prepared by one of the following general
method:

Metal Salt + Schif f Bases Complex

MX + SB MSB X

Where, X=NO3-,Cl-,CH3COO-,S042-
M=Lanthanides/ Transition metal ions

Schiff base-metal complexes were formed by nearly all the metals of the periodic table.
Although the number of known complexing agents is very large, the donor atoms, which
undergo combination with the metal, were restricted to the strongly non-metallic elements of
group 15 and 16.

1.4. S-substituted dithiocarbazate

Schiff base ligand formed from dithiocarbazates are a class of particularly important Schiff bases
which have been of immense interest owing to their potentially beneficial pharmacological
properties and their wide variety of bonding modes and stereochemistry. Dithiocarbazate easily
form an interesting series of ligands whose properties can be modified by introducing different
organic substituents to form stable complexes with a wide variety of metal ions. In 1974, Ali
and Livingstone first reviewed the chemistry of nitrogen-sulfur chelating ligands since then,
much has been published about metal complexes with dithiocarbazate. Most of the work has

3
focused upon S-methyl and S-benzyl dithiocarbazate Schiff bases and complexes, while other S-
substituted derivatives have been studied recently.

R1
NH2
S N
H

S-substituted dithiocarbazate

CH3- H2C H2C H2C

N
Methyl 2- 2-methylbenzyl benzyl
picolyl

CH2

H2C N

quinoline-2yl-methyl napthylmethyl

C
H2
allyl
Figure 1.3: Various S-substituents at position R1 in dithiocarbazate.

1.5 Antimicrobial Agents

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An antimicrobial is any substance of natural, semisynthetic or synthetic origin that kills or
inhibits the growth of microorganisms while hopefully causing minimal damage to the host. 
Antimicrobials can be used as therapy for bacteria (antibacterial), viruses (antiviral), fungi
(antifungal) or protozoa (antiprotozoal). The production and use of the antibiotic penicillin in
the early 1940s became the basis for the era of modern antimicrobial
therapy. Streptomycin was discovered in 1944, and since then many other antibiotics and other
types of antimicrobials have been found and put into use. A major discovery following the
introduction of these agents into medicine was the finding that their basic structure could be
modified chemically to improve their characteristics. Thus, antimicrobial agents that are used in
the treatment of disease include synthetic chemicals as well as chemical substances or
metabolic products made by microorganisms and chemical substances derived from plants.

Antibacterial Agents: An antibacterial is an agent that inhibits bacterial growth or kills bacteria.

Antibacterial are classified in several ways, including:

1. Spectrum of activity.

2. Effect on bacteria.

3. Mode of action.

Spectrum of activity: Depending on the range of bacterial species susceptible to these agent,
antibacterial agents are classified as-

(1) Broad Spectrum Antibacterial: are active against both gram-positive and gram-negative
organism.

(2) Narrow Spectrum Antibacterial: have limited activity and are primarily only useful against
particular species of microorganism.

Effect on bacteria: Because of differences in the mechanisms by which antibiotics affect

bacteria, the clinical use of antibacterial may have very different  effects on bacterial agents,
leading to an endpoint of either inactivation or actual death of the bacteria.

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1. Bactericidal drugs: are those that kill target organisms.  Examples of bactericidal drugs
include aminoglycosides, cephalosporins, penicillins, and quinolones .

2. Bacteriostatic drugs: inhibit or delay bacterial growth and replication. Examples of such

include tetracyclines, sulfonamides, and macrolides. 

Mode of action: Different antibiotics have different modes of action, owing to the nature of
their structure and degree of affinity to certain target sites within bacterial cells.  

1. Inhibitors of cell wall synthesis. While the cells of humans and animals do not have cell
walls, this structure is critical for the life and survival of bacterial species.  A drug that
targets cell walls can therefore selectively kill or inhibit bacterial organisms.  Examples:
penicillin’s, cephalosporins, bacitracin and vancomycin.

2. Inhibitors of cell membrane function. Cell membranes are important barriers that
segregate and regulate the intra- and extracellular flow of substances. A disruption or
damage to this structure could result in leakage of important solutes essential for the
cell’s survival.  Because this structure is found in both eukaryotic and prokaryotic cells,
the action of this class of antibiotic are often poorly selective and can often be toxic for
systemic use in the mammalian host.  Most clinical usage is therefore limited to topical
applications. Examples: Polymyxin B and colistin.

3. Inhibitors of protein synthesis. Enzymes and cellular structures are primarily made of
proteins. Protein synthesis is an essential process necessary for the multiplication and
survival of all bacterial cells.  Several types of antibacterial agents target bacterial protein
synthesis by binding to either the 30S or 50S subunits of the intracellular ribosomes. This
activity then results in the disruption of the normal cellular metabolism of the bacteria,
and consequently leads to the death of the organism or the inhibition of its growth and
multiplication.  Examples: Aminoglycosides, macrolides, lincosamides, streptogramins,
chloramphenicol, tetracyclines.

4. Inhibitors of nucleic acid synthesis. DNA and RNA are keys to the replication of all living
forms, including bacteria. Some antibiotics work by binding to components involved in

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 the process of DNA or RNA synthesis, which causes interference of the normal cellular
processes which will ultimately compromise bacterial multiplication and survival. 
Examples: quinolones, metronidazole, and rifampin.

5. Inhibitors of other metabolic processes. Other antibiotics act on selected cellular

processes essential for the survival of the bacterial pathogens.    For example, both
sulfonamides and trimethoprim disrupt the folic acid pathway, which is a necessary step
for bacteria to produce precursors important for DNA synthesis.  Sulfonamides target and
bind to dihydropteroate synthase, trimethophrim inhibit dihydrofolate reductase; both of
these enzymes are essential for the production of folic acid, a vitamin synthesized by
bacteria, but not humans.

Figure 1.4: Mechanism of action of antibacterial agents.

Schiff base [23] derived from furyglyoxal and p-toluidine show antibacterial activity against
Escherichia coli, Staphylococcus aureus, Bacillus subtilis and Proteus vulgaris. Complexes of
thallium with benzothiazolines [24] show antibacterial activity against pathogenic bacteria.
Various metal complexes in II and IV oxidation state derived with aniline [25-28] show different

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behavior with different types of bacteria. Metal complexes [29] of Mo and Mn with ligands
hydrazine carboxamide and hydrazine carbothiamide show antibacterial activity against S.
aureus and Xanthomonas compestris. Tridentate Schiff bases [30-33] and their metal complexes
show antibacterial activity against E.coli, S.aureus.
Br

O
O
H Ph
N S N
Ph N
M N Ph
N S N
Ph H
O
O

Br

Figure 1.5: Metal complexes of Schiff base derived from pyrimidine where M=Cu.

Bu N N

Cu

HO N O

Bu
OH

Figure 1.6: Cu complex derived from Schiff base ligands and 1,10-phenanthroline

Antifungal Agents: Antifungal drugs interfere with biosynthesis or integrity of ergosterol, the
major sterol in the fungal cell membrane. Others cause disruption of the fungal cell wall. Based
on their mechanism of action, the major agents can be grouped into five classes: polyenes;
azoles; allylamines; echinocandins; and other agents, including griseofulvin and flucytosine. The
synthesis of ergosterol is inhibited by allylamines drugs and by azole derivatives. Amphotericin

8
B and other polyenes antibiotics bind to ergosterol in fungal cell membranes and increase
membrane permeability. Ciclopirox increases membrane permeability by another mechanism
(not shown). Flucytosine is accumulated by fungal cells and converted to 5-fluorouracil (5-FU).
When 5-FU is incorporated into fungal RNA, protein synthesis is inhibited. Griseofulvin
interferes with microtubule function and blocks mitosis (not shown). Caspofungin inhibits
fungal cell wall synthesis.

Figure 1.7: Mechanism of action of antifungal agents.

Thiazole and benzothiazole Schiff bases show effective antifungal activity [34]. Pyrandione
Schiff bases [35] show activity against A.niger. Some Schiff bases of quinazolinones [36] show
antifungal activity against Candida albicans, A.niger and Micoporum gypseum. Furfurglidene
nictoinamide Schiff base [37] show antifungal activity against A.niger, Alternaria solani.
Ruthenium (II) complexes with Schiff base salicyladmine [38], copper (II) complexes of

9
benzoylpyridine Schiff base [39] and thallium (I) complexes with benzothiazolines [40] show
antifungal activities.

SCH3
X
HN

N N
O

H N M N H

O N
N

NH
X
H3CS

Figure 1.8: Metal complex of triazole Schiff base where M=Ni, Cu, Zn

N O
V
CH3
N O
N O
H

Figure 1.9: Tridentate Schiff Base Ligands with Pyrazolone Moiety and Their Metal

Complexes

Antiviral Agent: Antiviral drugs are a class of medication used specifically for treating viral

infections rather than bacterial ones. Most antivirals are used for specific viral infections, while
a broad-spectrum antiviral is effective against a wide range of viruses. Unlike most antibiotics,
antiviral drugs do not destroy their target pathogen; instead they inhibit their development.
Antiviral agents are nucleoside or nucleotide analogues whose mechanism of action is inhibition
of virus nucleic acid synthesis.

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 Figure 1.10: Mechanism of action of antiviral agents

Schiff bases of gossypol [41] show high antiviral activity. Silver complexes [42] in oxidation state
+1 show inhibition against Cucumber mosaic virus. Glycine salicylaldehyde Schiff base [43] gave
effective result against mosaic virus.

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 N

N
Ag N

SCH3

N
SH
CH3 H H CH3
M
O C N O
N C

N S

SCH3
Figure 2.1: Metal complexes of Schiff base having antiviral activity

Anti-Tumor and Cytotoxic Activities: Cytotoxic agents are substances used in the treatment of
malignant and other diseases.  They are designed to destroy rapidly growing cancer cells. They
have been shown to be mutagenic, carcinogenic and/or teratogenicity, either in treatment
doses or animal and bacterial assays. Cytotoxic agents compete for the folate binding site of the
enzyme dihydrofolate reductase. Folic acid must be reduced to tetra hydro folic acid for DNA
synthesis and replication to occur. Competitive inhibition of the enzyme leads to obstruction of
tetrahydrofolate synthesis, depletion of precursor nucleotides, and inhibition of DNA, RNA and
protein synthesis.

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 Figure 2.2: Mechanism of action of anticancer agents

Schiff bases and their metal complexes [44] containing Cu, Ni, Zn and Co synthesized from
salicylaldehyde, 2,4-dihydroxy benzaldehyde show anti-tumor activities and their order of
reactivity with metal complexes is Ni>Cu>Zn>Co. Amino Schiff bases [45] derived with aromatic
and heterocyclic amine possess high activity against human tumor cell lines. Aryl-azo Schiff
bases [46] exhibit anticancer activity. Schiff base of indole-2-caboxaldehydes [47] show inhibitor
activities to K B cell lines.

Cl

O
O N
V

N
S N
N

NH2

13
 NO2
Br

Br O
O
Co
N
N
N

Figure 2.3: Metal complex of Schiff base having cytotoxic activities

1.6. Contribution of metal complexes to the improvement of antimicrobial

agents:

The rich coordination geometry of metals offers an exciting platform for the discovery of new
and potent metallodrugs with novel mechanism of action. These attributes may allow
antimicrobial metal complexes to be less likely to induce resistance in bacteria or at least to
delay development of resistance. The different geometric arrangement of ligands in metal
complexes, which vary according to the number and types of ligands bound to the metal center
and to the coordination preference of the metal, affect their bioactivity. The past few decades
have witnessed the development and evolution of potential antibacterial agents derived from
metal-based compounds although their mechanism of action are not still very well understood.

O O

N N

M=Mn,Co and Ni

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 N O
O
H M
H
O
O N

M=Cu

Figure 2.4: Metal complexes of Schiff base having biological

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