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1 P. Sathyadevi, 2011 Chapter I Introduction Earlier, chemistry, as a science discipline was divided into different subfields such as analytical, industrial, inorganic, organic, physical and polymer chemistry. Later, chemistry has become one of the very interesting inter disciplinary subjects owing to its role in other related science subjects. The field of coordination chemistry that had begun more than a century ago, has registered a phenomenal growth during last few decades. There has been a tremendous interest in the pursuit of coordination compounds from the days of Werner, whose coordination theory opened new avenues to think about the structure and reactions of coordination compounds. It is well known fact that precious metals have been used for medicinal purposes for atleast 3500 years. At that time, precious metals were believed to benefit health because of their rarity, but research has now well established the link between medicinal properties of inorganic drugs and specific biological properties. The elucidation of a drug mechanism is however complex and the activity of many drugs remain unknown. Many naturally occurring coordination compounds are proved to be vital for living organisms. The metabolic activity of biological compounds like vitamin B 12 , chlorophyll and hemoglobin had been a puzzle to all chemists and induced them to think seriously about the fundamental studies on the principles of coordination chemistry. Among the coordination compounds, transition metal complexes constitute a distinct class that are widely studied due to their interesting structural features and captivating application in diverse fields such as catalysis, molecular electronics and medicine. The chemistry of transition elements is being investigated for over several decades with so much of newer concepts and exciting results. During the past few decades, these elements and their compounds were proven to be a nearly ideal touchstone for many of the models that have been developed to understand the principles of structure and bonding in coordination compounds. Most of the first row transition metals are biologically essential, with a number of their complexes demonstrating potential

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1

P. Sathyadevi, 2011

Chapter I

Introduction

Earlier, chemistry, as a science discipline was divided into different subfields

such as analytical, industrial, inorganic, organic, physical and polymer chemistry. Later,

chemistry has become one of the very interesting inter disciplinary subjects owing to its

role in other related science subjects. The field of coordination chemistry that had begun

more than a century ago, has registered a phenomenal growth during last few decades.

There has been a tremendous interest in the pursuit of coordination compounds from the

days of Werner, whose coordination theory opened new avenues to think about the

structure and reactions of coordination compounds.

It is well known fact that precious metals have been used for medicinal purposes

for atleast 3500 years. At that time, precious metals were believed to benefit health

because of their rarity, but research has now well established the link between medicinal

properties of inorganic drugs and specific biological properties. The elucidation of a drug

mechanism is however complex and the activity of many drugs remain unknown. Many

naturally occurring coordination compounds are proved to be vital for living organisms.

The metabolic activity of biological compounds like vitamin B12, chlorophyll and

hemoglobin had been a puzzle to all chemists and induced them to think seriously about

the fundamental studies on the principles of coordination chemistry. Among the

coordination compounds, transition metal complexes constitute a distinct class that are

widely studied due to their interesting structural features and captivating application in

diverse fields such as catalysis, molecular electronics and medicine.

The chemistry of transition elements is being investigated for over several

decades with so much of newer concepts and exciting results. During the past few

decades, these elements and their compounds were proven to be a nearly ideal touchstone

for many of the models that have been developed to understand the principles of structure

and bonding in coordination compounds. Most of the first row transition metals are

biologically essential, with a number of their complexes demonstrating potential

2

Introduction

P. Sathyadevi, 2011

bioactivities such as DNA binding, DNA cleavage, protein binding, cytotoxicity etc.

Among them, nickel, cobalt, copper and ruthenium are of significant and are described in

the following discussions. Recent years have witnessed a phenomenal growth in the

coordination chemistry of transition metal complexes of Schiff base ligands because of

their biochemical significance.

Transition metal complexes act as homogeneous catalysts in many industrially

important reactions such as hydrogenation, hydrosilation, hydroformylation,

polymerisation, isomerisation, acylation and oxidative hydrolysis of olefins. Binuclear

transition metal complexes have also received much attention in recent years and interest

in a particular system is stimulated by a number of factors. Bimetallic coordination

complexes may serve as model for variety of biological reactions such as oxygen

transport, oxygen activation, photosynthesis, electron transfer process, metal-metal

interactions and multi centered catalysis.

Transition metal ions with different oxidation states have a strong role in

bioinorganic chemistry and redox enzyme systems and may provide the basis of models

for active sites of biological systems. To mention a few, nickel is an essential component

in atleast 4 types of enzymes viz. urease, carbon monoxide dehydrogenase (CODH) or

acetyl coenzyme A synthase, hydrogenase and methyl-S-coenzyme M reductase. There is

spectroscopic evidence for nickel-methyl complexes in CODH of anaerobic bacteria. The

interaction of Co(II) complexes in solution with O2 has been the subject of intensive

study. Some of these complexes behave as reversible carriers of O2 and have been used as

models for natural oxygen transport systems as reported by Macke and Williams 1988. In

2003, Cotton et al studied Schiff base complexes such as [Co2+

(acacen)(DMF)O2], which

in solution (pyridine, DMF or similar solvents) pick up O2. Polydentate Co(II) complexes

with ligands capable of intercalation into DNA strands are capable of inducing DNA

cleavage under photochemical conditions were studied by Bhattacharya and Mandal.

Since the recognition of Vitamin B12 and synthesis of cobalmines are responsible for

erythrocytes (RBC) formation in human body, much study of model systems was

undertaken. Copper complexes are known to play important role in the active site of

3

Introduction

P. Sathyadevi, 2011

many copper proteins in vivo as well as in homogeneous and heterogeneous catalysis for

organic chemical reactions. A large body of evidence indicates that copper chelation is an

effective method to inhibit tumor growth and copper chelators have become promising

agents in the treatment of cancer. It has been found that some copper chelators acquire

more effective or novel bioactivity after forming complexes. Recent studies indicated that

Cu2+

was critically needed for PDTC induced apoptosis in HL-60 cells and the copper

complex of salicylaldehyde benzoylhydrazone (SBH) derivatives showed increased

potency of growth inhibition in several cancer cell lines, compared with the metal-free

organics. Copper-SBH complexes were significantly more cytotoxic than complexes of

other transitional metals (Cu > Ni > Zn > Mn > Fe > Cr > Co) in MOLT-4 cells, an

established human T-cell leukaemia cell line. It was noted that SBHs, especially their

copper complexes appeared to be unusually potent inhibitors of DNA synthesis and cell

growth in a variety of human cancer cell lines, including the human lung epithelial cancer

cell line, SKMES-1 and rodent cancer cell lines. A series of, novel salicylaldehyde

pyrazole hydrazone (SPH) derivatives were found capable of inhibiting the growth of

A549 lung carcinoma cells.

Ruthenium complexes are versatile in the field of catalysis of many organic

reactions. Ruthenium complexes are of importance not only because of their use in

catalytic reactions like oxidation and hydrogenation, reduction, dynamic kinetic

resolution, racemisation but also to their medicinal properties. Ruthenium compounds are

well suited for medicinal applications due to the properties such as

Rate of ligand exchange

The range of accessible oxidation states

The ability of ruthenium to mimic iron in binding to certain biological molecules.

Ruthenium anticancer chemistry has already yielded many promising results.

Several compounds display activities comparable to that of cisplatin, and in some cases,

activities are even better. Ruthenium complex ImH[trans-Ru(III)Cl4(DMSO)Im] (Im =

imidazole) was the first to enter clinical trials against metastases and KP 1019 has been

introduced into phase I clinical trials against colon carcinomas and their metastases. More

4

Introduction

P. Sathyadevi, 2011

recent studies demonstrate that ruthenium(II) complexes containing polypyridyl ligand

also show high antitumor activity in vitro and these complexes can effectively inhibit the

cell proliferation. Further, many octahedral ruthenium(II) complexes have also been

proved to bind with DNA through intercalative mode. The complex [Ru(bpy)2(dppz)]2+

(dppz = dipyrido[3,2-a:2',3'-c]phenazine) acted as ‘‘molecular light switch’’ and exhibits

cytotoxic activity at low micromolar IC50 values.

Hydrazones

Intensive research on the physicochemical properties and molecular structure of

complexes with organic derivatives of hydrazine has provided several new results. One of the

reasons for significant attention paid to the formation of complexes of these ligands with

transition metals are their biological activity.1-11 General formula of acid hydrazones is given

in Fig. 1.1.

Fig. 1.1 General formula of acid hydrazones.

Hydrazones are the azomethines, characterized by the tri-atomic grouping

C=N‒ N in their molecule. Hydrazones are of great importance because of their ability

towards complexation with metal ions and their involvement in diversified biological

processes those are attributed to the formation of stable chelates with transition metals

that catalyze the corresponding physiological processes. Aroylhydrazones of carbonyl

compounds coordinate to a metal ion via phenolate- or enolate-O, imine-N and

deprotonated amide-O atoms. With flexible ligands, the competition between bridging

and chelating coordination modes is an important factor in producing mono, di and

polynuclear metal complexes.

5

Introduction

P. Sathyadevi, 2011

R1 N

NR3

R1 N

N R3

R1 N

N R3

R2 H R2

R2

O O O

-H

Fig. 1.2 General formula of acyl-/aroyl-hydrazones and mesomerism of the anion obtained by deprotonation.

In coordination chemistry, hydrazones find application as multidentate ligand

forming chelates with metals, usually from the transition series. Studies have shown that

the azomethine group having a lone pair of electrons in either a p or sp2 hybridized orbital

on trigonally hybridized nitrogen has considerable biological importance. There are

several reports on the synthesis, structural characterization and biological activities of

transition metal complexes containing different types of hydrazone ligands including

Co(II), Ni(II), Cu(II), Cd(II), V(II), Pd(II) and Ru(II).12-29

Diversity in the chelation of hydrazones

The ‒ NH‒ C=O functional group present in hydrazones makes them to behave as

bidentate ligand for metal ions. Acid hydrazones show keto-enol (amido-iminol) tautomerism

as shown in the Fig. 1.3. In solid state, they exist in keto form but in solution, they exist as an

equilibrium mixture of keto and enol forms.

R2

N

R1

HN

R3

O

R2

N

R1

N

R3

OH

Amido form (I) Iminol form (II)

Fig. 1.3 Tautomerisation of hydrazone ligands.

These compounds are expected to exist in a trans form, but in such situation, they

may act as a unidentate ligand, by bonding through enolate oxygen. It is well evident that the

stereochemistry of the ligand is much decided by the steric effects of the various substituents

in the hydrazone moiety. It was found that most of the hydrazones coordinate to the metal ion

through cisform. This phenomenon is assumed to be due to better electron delocalisation

in the chelate ring system that increases the stability upon coordination with metal atoms.

The composition and structure of the complexes are determined by the electronic structure of

6

Introduction

P. Sathyadevi, 2011

metal as well as preparation conditions.30,31 Hydrazones form coordination compounds

through the oxygen atom of either carbonyl32,33 or the enol group and through the imine

nitrogen atom, a five membered chelate ring is being produced as shown in Fig. 1.4.

R2

N

R3

N

R1 OM

Fig. 1.4 General bidentate coordination mode of acid hydrazones.

Hydrazones may behave as a terdentate chelating agent if R1 residue provides a donor

atom in a suitable position, as it occurs in salicyloylhydrazide derivatives, although

hydrazones act commonly as ON donor ligand if R2 and R3 do not show chelating

tendency.34-36 Terdentate ligands may also be obtained if R2 and/or R3 residues are groups

such as o-hydroxyphenyl (ONO) ligands.37-39 Chelating ligand with higher number of

coordination position may be prepared by convenient selection of the condensation products:

Neutral tridentate Uninegative tridentate

N

HN

O

MN

N

N

O

MN

N

HN

OM O

NN

OM O

Uninegative tridentate Binegative tridentate

Uninegative bidentateNeutral bidentate Uninegative bidentate

N

HN

O

M

N

N

O

M

HN

HN

O

M

Fig. 1.5 General coordination modes of acid hydrazones.

7

Introduction

P. Sathyadevi, 2011

aroyl hydrazide (R‒ CONHNH2) and di or tri ketones.40-47 The oxidation state of the metal

ion

plays an important role in predicting the stability of the complexes of acid hydrazones. The

stability of the complexes also increases with an increase in electron delocalisation, size of

the molecule and also the nature and size of the chelate rings formed.48 General coordination

modes of hydrazones are presented in Fig. 1.5.

Applications

The chemistry of transition metals with ligands from the hydrazine family has

been of interest to coordination as well as bioinorganic chemists due to their versatile

bonding modes with both electron-rich and electron-deficient metals.49-52

Heterocyclic

hydrazones constitute an important class of biologically active drugs that have attracted

the attention of medicinal chemists due to their wide range of pharmacological properties

like antifungal, antibacterial, anticonvulsant etc.53-57

The metallochemistry of biomolecules has been largely focused on proteins,

amino acids, nucleic acids and carbohydrates.58-61

During the last two or three decades,

there has been an increasing attention on the binding study of small molecules to DNA,

since it is an important genetic substance in living organisms.62-64

Errors in gene

expression can often cause diseases and play a secondary role in the outcome and severity

of human diseases.65

Hence, a complete understanding of DNA-drug binding is

significant in the rational design of DNA structural probe, DNA footprinting, sequence-

specific cleaving agents and potential anti-cancer drugs.66-69

To design effective

chemotherapeutic agents and better anticancer drugs, it is essential to explore the

interaction of metal complexes with DNA.

Serum albumin is the major soluble protein constituent in the circulatory system

of a wide variety of organisms and it has the ability to reversibly bind to a large variety of

endogenous and exogenous ligands such as fatty acids, drugs and metal ions in the

bloodstream.70,71

The drug-protein complex not only strongly affects the absorption,

distribution, metabolism and excretion properties of drugs, but also influence the drug

stability and toxicity during the chemotherapeutic process. Therefore, knowledge on the

8

Introduction

P. Sathyadevi, 2011

mechanism of interaction between the selected drug and protein has become very vital to

design several new drugs with improved potential.72,73

Many chemicals exert antitumor effects through binding to DNA thereby

changing the replication of it and inhibiting the growth of tumor cells, which is the basis

to design new and more efficient antitumor drugs and their effectiveness depends on the

mode and affinity of the binding. The task of the synthetic inorganic chemists is not only

confined with the synthesis of new complexes having well defined structures, but also to

understand the structure-activity relationship of them.

Hence, we decided to study the chelating properties of hydrazone ligands and the

effect of coordination of them on the composition and geometry of the complexes

containing cobalt(II), nickel(II), copper(I/II) and ruthenium(II) ions were undertaken as

the subject of the present work. Additionally, comparison on the biological properties of

hydrazone complexes with respect to DNA / BSA interactions, free radical scavenging

and cytotoxicity under in vitro conditions have been carried out.

Literature survey

There are numerous reports available in the literature describing the reactions of

transition metal complexes containing hydrazones with various coordination modes and

pharmacological properties. In this connection, some important reports related to our

research work that were published very recently are presented in the following section of

this chapter.

From the reaction between Cu(II) and Ni(II) salts and the Schiff base 6-amino-5-

formyl-1,3-dimethyluracil-benzoylhydrazone (H2BEZDO), in dimethylformamide

(DMF)-water and ammonia media, the complexes [Ni(BEZDO)]·H2O·NH3 (1),

[Cu(BEZDO)]·H2O·NH3 (2) and [Cu(BEZDO)(H2O)]·H2O (3) containing the dianionic

organic ligand have been obtained. These compounds have been studied by IR, electronic

and EPR spectroscopy and magnetic measurements. The structure of

[Cu(BEZDO)(H2O)]H2O has been solved by means of X-ray diffraction methods. The

coordination environment around the Cu(II) may be described as a square planar structure

9

Introduction

P. Sathyadevi, 2011

in which the Schiff base acts as tridentate ligand through the N(6), N(51) and O(52)

atoms, making two five and six membered chelate rings. The coordination sphere is

completed with the oxygen atom of a water molecule.74

NN

ONH

Cu

OHH

O

O

H3C

CH3

3

Cobalt(III) complexes of diacetyl monooxime benzoyl hydrazone (dmoBH2) and

diacetyl monooxime isonicotinoyl hydrazone (dmoInH2) have been synthesized and

characterized by elemental analyses and spectroscopic methods by Naskar et al.75 The X-

ray crystal structure of the hydrazone ligands, as well as that of the cobalt(III) complex

[CoIII

(dmoInH)2]Cl·2H2O (1) were also reported in which the amide and the oxime

hydrogens are deprotonated in both the ligands, while the isonicotine nitrogens are

protonated. In the [CoIII

(dmoBH)2]Cl (2) complex, only the amide nitrogens are

deprotonated. It was shown that the additional hydrogen bonding capability of the

isonicotine nitrogen results in different conformation and supramolecular structure for

dmoInH2, compared to dmoBH2, in the solid state. Comparing the structure of the

[CoIII

(dmoInH)2]Cl·2H2O with that of the Zn(II) complex of the same ligand reported

earlier, it is seen that the metal ion has a profound influence on the supramolecular

structure due to change in geometrical dispositions of the chelate rings.

H3CN

N

NO

N+

CoH3C

O-

N+

NO

NCH3

CH3N

-O

Cl-

1

H H

10

Introduction

P. Sathyadevi, 2011

Dioxo- and oxovanadium(V) complexes of biomimetic, ONO and NNS donor

hydrazone ligands with catalytic activity was reported by Monfared et al.76 Oxo- and

dioxo-vanadium(V) complexes of hydrazone ligands with the formula [VVO(μ2-

OCH3)(L1)]2 (1) and [V

VO2(L

2)]·H2O (2) were synthesized by the reaction of [VO(acac)2]

with proton-transfer complexes of benzenetricarboxylic acid / benzoylhydrazide and

benzenetricarboxylic acid / isonicotinohydrazide, respectively (H2L1 = monocondensation

of benzoylhydrazide and acetylacetone, H2L2 = monocondensation of

isonicotinohydrazide and acetylacetone). Dioxo complex of V(V), [VO2(L3)] (3), was

H3C

NN

OO

CH3

V

O

OCH3

CH3

NN

OO

H3C

V

O

H3CO

H3C

NN

OO

NH+CH3

V

OO

1

3

synthesized by the reaction of equimolar amounts of VO(acac)2, 2-acetylpyridine and

thiosemicarbazide (H2L3 = hydrazone Schiff base of acetylpyridine and

thiosemicarbazide and Hacac = acetylacetone) and characterized by FT-IR, UV-visible

and NMR spectroscopic methods. The crystal structures of 1 and 2 were determined by

X-ray analyses. The 1H NMR spectrum of the complex 1 in CDCl3 solution indicated that

this dimeric complex is converted appreciably into its respective monomeric form. The

catalytic potential of the complexes has been tested for the oxidation of alkene, alkane

and aromatic hydrocarbons using H2O2 as the terminal oxidant.

A series of first row transition metal complexes with the unsymmetrically

disubstituted pyridazine ligand, picolinaldehyde (6-chloro-3-pyridazinyl)hydrazone

(PIPYH), featuring an easily abstractable proton were prepared by Grunwald et al.77

Reaction of PIPYH with divalent nickel, copper and zinc nitrates in ethanol led to

complexes of the type [CuII(PIPYH)(NO3)2] (1) or [M(PIPYH)2](NO3)2 [M =Ni

II (2) or

11

Introduction

P. Sathyadevi, 2011

ZnII (3)]. The above synthesis in the presence of triethylamine yielded fully or semi

deprotonated complexes [CuII(PIPY)(NO3)] (4), [Ni

II(PIPYH)(PIPY)](NO3) (5) and

[ZnII(PIPY)2] (6) respectively. Cobalt(II) nitrate is quantitatively oxidized under the

reaction conditions to [CoIII

(PIPY)2](NO3) (7) in both neutral and basic media. X-ray

diffraction analyses reveal a penta (1) or hexa coordinated (2, 3 and 7) metal center

surrounded by one or two tridentate ligands and eventually κ‒ O,O' nitrate ions. The

solid‒ state stoichiometry was confirmed by electron impact (EI) and electrospray

ionization (ESI) mass spectrometry. Diamagnetic complexes 5 and 6 were subjected to

1H NMR spectroscopy suggesting that the ligand to metal ratio remains constant in

solution. Electronic properties were analyzed by means of cyclic voltammetry and in case

of copper complexes 1 and 4, also by electron paramagnetic resonance (EPR) study,

showing increased symmetry upon deprotonation of the latter in accordance with the

proposed stoichiometry [CuII(PIPY)(NO3)].

Six new copper complexes of di-2-pyridyl ketone nicotinoylhydrazone and their

versatile binding properties (HDKN) have been studied by Mangalam et al.78 The

complexes have been characterized by a variety of spectroscopic techniques and the

structure of [Cu(DKN)2]·H2O (1) determined by single crystal X-ray diffraction was

proved to have distorted octahedral geometry. The EPR spectra of compounds

[Cu2(DKN)2(μ-N3)2] (2) and [Cu2(DKN)2(μ-NCS)2] (3) in polycrystalline state suggested

a dimeric structure as they exhibited a half field signal, which indicated the presence of a

weak interaction between two Cu(II) ions in these complexes.

NN

O

N

Cu

NN

O

N

1

12

Introduction

P. Sathyadevi, 2011

The coordination behavior of a new dihydrazone ligand, 2,6-bis[(3-

methoxysalicylidene)hydrazinocarbonyl]pyridine towards manganese(II), cobalt(II),

nickel(II), copper(II), zinc(II) and cadmium(II) has been described by Vadavia et al.79

The metal complexes were characterized by magnetic moments, conductivity

measurements, spectral (IR, NMR, UV-visible, FAB mass and EPR) and thermal studies.

IR spectral studies revealed the nonadentate behavior of the ligand. The X-band EPR

spectra of copper(II) complex at both room temperature and liquid nitrogen temperature

showed unresolved broad signals with giso = 2.106. Cyclic voltammetric studies of

copper(II) complex at different scan rates revealed that all the electrochemical reactions

are irreversible.

O

H3CO

NN

ON

N

O

N

OCH3

OM

Cl ClH2O

MM

OH2 OH2

OH2

H2OH2O

H2O

where, M = Mn(II), Co(II), Ni(II), Cu(II), Zn(II) and Cd(II)

Complexes of Co(II), Ni(II), Cu(II), Mn(II), Cd(II), Zn(II), Hg(II) and U(IV)O2

with N′-(1-(4-hydroxyphenyl)-ethylidene)-2-oxo-2-(phenylamino)acetohydrazide

H3OPAH) have been prepared and characterized by various spectroscopic techniques like

IR, UV-visible, 1H NMR and EPR as well as magnetic and thermal (TG and DTA)

measurements.80

It was found that the ligand behaves as neutral bidentate, monoanionic

tridentate or tetradentate and dianionic tetradentate in these complexes. An octahedral

geometry for [Mn(H3OPAH)2Cl2], [Co2(H2OPAH)2Cl2(H2O)4] and

[(UO2)2(HOPAH)(OAc)2(H2O)2] complexes, a square planar geometry for

[Cu2(H2OPAH)Cl3(H2O)]·H2O complex and a tetrahedral structure for

[Cd(H3OPAH)Cl2], [Zn(H3OPAH)(OAc)2] and [Hg(H3OPAH)Cl2]H2O complexes. The

binuclear [Ni2(HOPAH)Cl2(H2O)2]·H2O complex possessed a mixed tetrahedral and

square planar structures.

13

Introduction

P. Sathyadevi, 2011

A novel hydrazone, N′-(2,4-dimethoxy benzylidene)-2-hydroxybenzohydrazide

(DBH) has been synthesized and characterized, which is an analogue of isonicotinic acid

(3-hydroxy-naphthalen-2-ylmethylene)-hydrazide possessing potent anticancer activity.

The interactions between DBH and bovine serum albumin (BSA) have been investigated

systematically by fluorescence, molecular docking, circular dichroism, UV-visible

absorption and electrochemical impedance spectroscopy methods under physiological

conditions. The fluorescence quenching observed is attributed to the formation of a

complex between BSA and DBH and the reverse temperature effect of the fluorescence

quenching has been found and discussed. The effects of iron on the system of DBH-BSA

have also been investigated and found that iron could compete against BSA to bind DBH.

All of these results are supported by a docking study using a BSA crystal model. It is

shown that DBH can efficiently bind with BSA and be transported to the focuses

needed.81

Anticancer activity, structure and theoretical calculation of N-(1-phenyl-3-methyl-

4-propyl-pyrazolone-5)-salicylidene hydrazone (H2L) and its copper(II) complex

[Cu2L2CH3OH]·2CH3OH has been studied by Zhang et al.82 The crystallographic

structural analysis of the complex revealed that the two Cu centers display different

coordination patterns. The pharmacological result showed that the coordination effect

improves the antitumor activity of the ligand. The calculated Fukui function for H2L and

its deprotonated form L2 predicts that the most probable reactive sites for electrophilic

attack are oxygen atoms and the theoretical data were in good agreement with the

experimental data.

O

N N

O

N N

O

O

CuCuOH3C

H

14

Introduction

P. Sathyadevi, 2011

Binuclear complexes [Zn2(HL1)2(CH3COO)2] (1) and [Zn2(L

2)2] (2) were

synthesized with salicylaldehyde semicarbazones (H2L1) and salicylaldehyde-4-

chlorobenzoyl hydrazone (H2L2) respectively by Parrilha et al.83

Upon recrystallization of

previously prepared [Zn2(HL2)2(Cl)2] (3) in 1:9 DMSO:acetone crystals of

[Zn2(L2)2(H2O)2]·[Zn2(L

2)2(DMSO)4] (3a) were obtained. The crystal structure of 3a was

also determined. All crystal structures revealed the presence of phenoxo-bridged

binuclear zinc(II) complexes.

ONN

H2N O

Zn

OS

CH3

H3C

O NN

NH2O

Zn

OS

H3C

CH3

1

Complexation of iron(III) with the chelating agent 3,5-di-tert-butylsalicylidene

benzoylhydrazine (H2(3,5-tBu2)salbh), in the absence or presence of a base afforded the

complex cation [Fe{H(3,5-tBu2)salbh}2]

+(1) or the neutral compound [Fe{H(3,5-

tBu2)-

salbh}{(3,5-tBu2)salbh}] (2) respectively as revealed by single crystal X-ray analyses.

Such a synthetic and crystallographic demonstration of the coordination versatility of an

aroylhydrazone toward iron is uncommon. The oxidation and spin states of the iron have

been verified with magnetic and spectroscopic measurements.84

Bu2t

N

HN

OO

Fe

tBu2

NN

OOtBu2

tBu2

Bu2t

N

HN

OO

Fe

tBu2

NNH

OOtBu2

tBu2

1 2

15

Introduction

P. Sathyadevi, 2011

Novel, Ln(III) complexes with hesperetin-4-one-(benzoyl) hydrazone (H4L) have

been synthesized and characterized.85

Electronic absorption spectroscopy, fluorescence

spectra, ethidium bromide displacement experiments, iodide quenching experiments, salt

effect and viscosity measurements indicated that the ligand and Ln(III) complexes,

especially the Nd(III) complex strongly bind to calf thymus DNA presumably via an

intercalation mechanism. The intrinsic binding constants of the Nd(III) complex and

ligand with DNA were 2.39×106 and 2.7×10

5 M

-1, respectively. Further, the in vitro

antioxidant activity of the ligand and Ln(III) complexes was determined by superoxide

and hydroxyl radical scavenging method indicated that the ligand and Ln(III) complexes

have the activity to suppress O2-. and HO

. and the Ln(III) complexes were more effective

than the free ligand.

Metal complexes of 2-methyl-1H-benzimidazole-5-carboxylic acid hydrazide and

its Schiff base, 2-methyl-N-(propan-2-ylidene)-1H-benzimidazole-5-carbohydrazide with

copper, silver, nickel, iron and manganese were prepared and their antitumor activity has

been studied. Among the complexes, the silver containing one displayed cytotoxicity

(IC50 = 2 μM) against both human lung cancer cell line A549 and human breast cancer

cell line MCF 7.86

Considering the metal complexation approach with bioactive ligands as one of the

possible strategies for improving the biological efficacy of ATZ, a series of new

ruthenium-ATZ complexes [RuCl2ATZCOD] (where ATZ = aryl-4-

oxothiazolylhydrazones; COD is 1,5-cyclooctadiene) were prepared and characterized.87

R

SN

R1

HN

N

SR2

O

Ru

Cl

Cl

( )n

where, R = ATZ1: R1 = H (or) , R2 = H, n = 1

16

Introduction

P. Sathyadevi, 2011

Two of these complexes presented antitrypanosomal activity at non-cytotoxic

concentrations on mammalian cells and of higher potency than free ligands, while the

metallic precursor [RuCl2COD(MeCN)2] showed only moderate antitrypanosomal

activity. Comparative analysis between the ruthenium complexes and free ligands

demonstrated the usefulness of this approach with the establishment of new SAR data.

Additional pharmacological tests, including a DNA binding assay provided explanation

for the molecular origin of the bioactivity.

A new diferrocene Schiff base 1'-formyl[(2,2-diferrocenyl)propane]isonicotinoyl

hydrazone (HL) was prepared by condensing 1'-formyl[(2,2-diferrocenyl)propane] with

isonictinoyl hydrazine. Its chelates of the type Ln(HL)2Cl3(H2O)n, where Ln = La, Dy,

Yb, Gd, Sm, Nd; n = 1-5, were prepared and characterized by elemental analysis, IR and

NMR spectra by Yao-feng et al.88 In these chelates, the ligand coordinated to lanthanide

ions in the keto form and some chloride ions and water molecules participate in

coordination to the metal ion. The redox properties of the ligand and its complexes were

investigated using cyclic voltammetric method. Both the ligand and its lanthanide

complexes exhibited two distinct pairs of redox peaks displaying electrochemical

characteristics of multi-component system.

Five oxovanadium(IV) complexes of 2-hydroxy-4-methoxybenzaldehyde

nicotinic acid hydrazone (H2L1), 2-hydroxy-4-methoxyacetophenone nicotinic acid

hydrazone (H2L2) and a binuclear oxovanadium(V) complex of H2L

2 have been

synthesized and characterized by different physicochemical techniques like electronic,

infrared and EPR spectral studies by Seena et al.89 The complexes [VOL

1]2·H2O (1) and

[VOL2]2·H2O (4) are binuclear and [VOL

1bipy] (2), [VOL

1phen]·1.5H2O (3) and

[VOL2phen]·2H2O (6) are heterocyclic base adducts and are EPR active. In frozen DMF

at 77 K, all the oxovanadium(IV) complexes show axial anisotropy with two sets of eight

line patterns. The complex [VOL2·OCH3]2 (5) is an unusual product and has distorted

octahedral geometry as revealed by X-ray diffraction studies.

17

Introduction

P. Sathyadevi, 2011

The synthesis and characterization of Co(II), Ni(II), Cu(II), Zn(II), Cd(I1) and

UO22+

complexes of biacetylmonoxime isonicotinoylhydrazone (BMINH) were reported

by Ibrahim et al.90

Elemental analysis, magnetic, thermal and spectral (IR, UV-visible

and NMR) measurements have been used to characterize the complexes. IR spectral data

showed that the ligand behaves in a bidentate and / or tridentate manner. An octahedral

structure was proposed for the Ni(I1) complexes, while a square planar structure is

proposed for both Co(I1) and Cu(II) complexes on the basis of magnetic and spectral

measurements.

The XRD structure and the influence of the conformation in the molecular orbitals

of the pteridine-benzoylhydrazone ligand (1) (BZLMH = benzoylhydrazone of 6-acetyl-

1,3,7-trimethyllumazine, lumazine = (1H,3H)-pteridin-2,4-dione) have been studied.91

Complexes of BZLMH with nickel(II), zinc(II) and mercury(II) have been prepared and

spectroscopically characterized. XRD studies have showed two different coordination

patterns in the complexes [Ni3(BZLMH)3(OH)(H2O)(CH3CN)2](ClO4)5 ·2H2O·CH3CN

(2) and [Zn(NO3)(BZLMH)(H2O)](NO3) (3). Compound (2) is a trinuclear

hydroxo‒ centered complex with a central hydroxo group bridging the three nickel(II)

ions. The [Ni3(μ3-OH)]5+

core is planar with the benzoylhydrazone ligands coordinated in

the bis-bidentate mode. In the case of zinc(II) compound, the BZLMH ligand acted in a

tridentate fashion using N, N and O donor atoms.

N

NN

N

H3C

O

CH3

O

N

HN

O

CH3CH3

Zn

NO3

F

F

F

F

F

H2O

3

NO3-

+

.

A series of new coordination complexes of MnII, Co

II, Ni

II, Cu

II and Hg

II with

the new hydrazones derived from formylferrocene / acetylferrocene and 2-furoyl

hydrazide have been synthesized and characterized by elemental analyses, electrical

18

Introduction

P. Sathyadevi, 2011

conductance, IR spectra, 1H NMR spectra and TGA thermal analyses by Qing Bao et al.92

These organometallic compounds act as uninegative bidentate (NO) ligands in the

complexes. The IR spectra of the complexes revealed that the oxygen in the fury1 ring

does not participate in coordination.

Cyclometallated Ru(II) complexes of the type [Ru(CO)(EPh3)2(L)] (E = P or As;

L = tridentate hydrazone-derived ligand) have been obtained by refluxing an ethanolic

solution of [RuHCl(CO)(PPh3)3] or [RuHCl(CO)(AsPh3)3] with the hydrazone derivatives

H2php = (2-[(2,4-dinitro-phenyl)-hydrazonomethyl]-phenol), H2phm = (2-[(2,4-dinitro-

phenyl)-hydrazonomethyl]-6-methoxy-phenol) and H2phn = (2-[(2,4-dinitro-phenyl)-

hydrazonomethyl]-naphthalen-1-ol). The formation of stable cyclometallated complexes

has been authenticated by single crystal X-ray structure determination of two of the

complexes and the mechanism of C–H activation was discussed in detail.93

The spectral

(IR, UV-visible and 1H NMR) and electrochemical data for all the complexes are

reported. Electrochemistry showed a substantial variation in the metal redox potentials

with regard to the electronic nature of the substituents present in the hydrazone

derivative.

Several new pentacoordinated ruthenium(I1) compounds, [Ru(PPh3)2L], of Schiff

bases were reported by Pardhy et al.94 The Schiff bases used have been derived from

isonicotinoyl hydrazone and β-diketones or salicylaldehyde or azines and mixed azines

obtained from salicylaldehyde, benzoylacetone or 2-hydroxyacetophenone. These new

compounds are highly coloured crystalline solids, stable and monomeric in toluene. They

readily absorb carbon monoxide gas to give a carbonyl derivative of the type

[Ru(PPh3)2CO(L)] in quantitative yields.

NN

OO

Ru

Ph3P PPh3

CO N

N

O

O

Ru

E

PPh3

CO

where, E = PPh3

19

Introduction

P. Sathyadevi, 2011

Barbazan et al.95 have reported the synthesis and studies on a novel ferrocenyl

carbaldehyde benzoylhydrazone ligand H(Fe)L1 and its reaction with [ReBr(CO)3

(CH3CN)2] to afford the complex [ReBr(CO)3{H(Fe)L1}] in good yield. The hydrazide is

O,N-bidentate and afforded a five-membered chelate ring with rhenium in an octahedral

geometry.

Fe

N

HN

O Re

CO

COBr

OC

Ternary copper(II) complexes [Cu(L)(L')](ClO4), where HL is NSO-donor Schiff

base (2-(methylthio)phenyl)salicylaldimine and L' is NN-donor phenanthroline bases like

1,10-phenanthroline (phen), dipyridoquinoxaline (dpq) and 2,9-dimethyl-1,10-

phenanthroline (dmp) were prepared and structurally characterized using X-ray

crystallography by Reddy et al.96 The complexes have a distorted square-pyramidal

CuN3OS coordination geometry, while [CuL(phen)](ClO4) (1) and [CuL(dpq)](ClO4) (2)

showed axial sulfur ligation and [CuL(dmp)](ClO4) (3) has the sulfur bonded at the

equatorial site. The paramagnetic complexes exhibited resonance in dimethylformamide

glass at 77 K. The complexes are redox active and a quasi-reversible electron transfer

process in DMF-Tris buffer involving Cu(II)/Cu(I) couple is observed for the phen and

dpq complexes. The dmp complex exhibits an irreversible reduction process forming

bis(dmp)copper(I) species. A profound effect of the substituents of the phenanthroline

bases was observed on the binding of the complexes to the calf thymus DNA (CT DNA)

and in the cleavage of supercoiled (SC) pUC19 DNA. The phen and dpq complexes

showed DNA cleavage activity in presence of mercaptopropionic acid (MPA). All the

complexes show photocleavage activity when irradiated with a monochromatic UV light

of 312 nm. The dpq complex also cleaves SC DNA on visible light irradiation at 436, 532

and 632 nm but with a longer exposure time and higher complex concentration. The

cleavage reactions in presence of MPA are found to involve hydroxyl radical. The

photocleavage reactions are found to occur under aerobic conditions showing an

enhancement of cleavage in D2O and inhibition with azide addition suggesting formation

20

Introduction

P. Sathyadevi, 2011

of singlet oxygen as a reactive species. The roles of sulfur of the Schiff base as

photosensitizer and the phenanthroline bases as minor groove binder and their influence

on the photocleavage activity are discussed. The quinoxaline ligand exhibits significant

photosensitizing effect assisted by the copper(II) center.

O

N

Cu

S CH3

N

N

N

N

2

N

SCH3Cu

O

N NCH3

H3C

3

Six complexes of the composition [M(HL)2].nH2O (M = Co, Ni and Fe; n = 4)

with two ligands, 2-carboxy-benzaldehydebenzoylhydrazone (H2L1) and 2-

carboxybenzaldehyde-(4'-methoxy)benzoylhydrazone (H2L2) have been synthesized and

characterized on the basis of elemental analyses, molar conductivities, IR spectra and

thermal analyses. In addition, the radical suppression ratio for O2-.

and OH. were

determined with a spectrophotometer. In general, the antioxidative activities increased as

the concentration of these complexes increased up to a selected extent.97

A novel binuclear cobalt(II) complex with N-(2-propionic acid)-salicyloyl

hydrazone was prepared and characterized. The crystal structure of Co2+

ion is six-

coordinated by the carboxyl and acyl O atoms and azomethine N atoms of two tridentate

N-(2-propionicacid)-salicyloyl hydrazone ligands, which form two stable five-numbered

rings sharing one side in the keto form. The coordination environment around the Co2+

ion might be described as a distorted octahedron. Abundant hydrogen bonds of the types

O−H···N and O−H···O between the water molecules and ligands not only form the three-

dimensional network but also provide an extra stability for the crystal. The complex was

studied for the interaction with calf thymus DNA by electronic absorption titration and

emission titration. The results showed that the complex was bound to calf thymus DNA

mainly by intercalation.98

21

Introduction

P. Sathyadevi, 2011

O

HN

N

H3C

O

O

NH

O

N

CH3

O

O

Co

HO OH

Crystal structures, antioxidation and DNA binding properties of Yb(III)

complexes with Schiff-base ligands derived from 8-hydroxyquinoline-2-carbaldehyde

and four aroylhydrazines have been investigated by Liu et al.99 X-ray crystal and other

structural analyses indicated that these newly synthesized ligands yielded binuclear

Yb(III) complexes with a 1:1 metal to ligand stoichiometry with octa-coordination at the

Yb(III) center. Investigations of DNA binding properties show that all the ligands and

Yb(III) complexes can bind to calf thymus DNA through intercalations with binding

constants in the order of magnitude 105-10

7 M

-1. Investigations of antioxidation

properties show that all the ligands and Yb(III) complexes have strong scavenging effects

for hydroxyl radicals and superoxide radicals but Yb(III) complexes show stronger

scavenging effects for hydroxyl radicals than ligands.

OHNN

NO

O

Yb

NO

O

O

D

OH NN

N

O

O

Yb

N O

O

O

D

where, D = DMF

Six organometallic complexes of the general formula [MIICl(η6

-p-cymene)(L)]Cl,

where M = Ru (1a, 2a, 3a) or Os (1b, 2b, 3b) and L = 3-(1H-benzimidazol-2-yl)-1H-

pyrazolo-[3,4-b]pyridines (L1-L3) have been synthesized.100

The latter are known as

potential cyclin-dependent kinase (Cdk) inhibitors. All these have been comprehensively

characterized by elemental analysis, one and two-dimensional NMR ,UV-visible, ESI

22

Introduction

P. Sathyadevi, 2011

mass spectroscopic and X-ray crystallographic (1b and 2b) methods. Structure reactivity

relationships with regard to cytotoxicity and cell cycle effects in human cancer cells as

well as Cdk inhibitory activity are also reported.

NH

N

NHN

N

X

Y

MCl Cl-

+

where, X = H, Y = H (L1): M = Ru (1a), Os (1b); X = Br, Y = H (L2): M = Ru (2a), Os (2b) X = Br, Y = CH2OCH3 (L3): M = Ru (3a), Os (3b)

2-Phenylquinoline-4-carboylhydrazide (HL) and its novel nickel(II) and zinc(II)

complexes, [M(HL)2(L)].2H2O.NO3 (M = Ni (1), M = Zn (2)) have been synthesized and

characterized by elemental analysis, molar conductivity and IR spectra by Xi et al.101 The

crystal structure of [Ni(HL)2(L)].2H2O.NO3 obtained from ethanol solution was

determined by X-ray diffraction analysis. The interactions of the complexes and the

ligand with calf thymus DNA had been investigated using UV-visible spectra, fluorescent

spectra, circular dichroism spectra, cyclic voltammetry and viscosity measurements.

These compounds tested against MFC (mouse forestomach carcinoma) cell lines

demonstrated that 1 showed significant cytotoxic activity against MFC cell lines. The

cleavage reaction on plasmid DNA monitored by agarose gel electrophoresis suggested

that the two complexes 1 and 2 bound to DNA via a groove binding mode.

Inhibition of the growth of LoVo human colon adenocarcinoma and MiaPaCa

pancreatic cancer cell lines by two new organometallic ruthenium(II) complexes of the

general formula [Ru(η5-C5H5)(PP)L][CF3SO3], (where PP is 1,2-bis(diphenylphosphino)

ethane and L is 1,3,5-triazine (Tzn) (1) or PP is 2 molecules of triphenylphosphine and L

is pyridazine (Pyd) (2)) has been investigated.102

Crystal structures of compounds 1 and 2

were determined by X-ray diffraction studies. Atomic force microscopy (AFM) images

23

Introduction

P. Sathyadevi, 2011

suggested different mechanism of interaction with the plasmid pBR322 DNA i.e., the

mode of binding of compound 1 was intercalation between base pairs of DNA while

compound 2 involved in a covalent bond formation with N from the purine base.

RuP

P

L

where, 1: (PP) = dppe; L = Tzn

2 : (PP) = 2 PPh3; L = Pyd

+

(CF3SO3)-

Neutral, mixed ligand mononuclear square-pyramidal copper(II) complexes of the

type [Cu(cpf)(Ln)Cl] (cpf = ciprofloxacin and L

n = phenanthroline derivatives) were

synthesized and characterized.103

The complexes were screened for their antibacterial

activity and bactericidal activity against few Gram(+ve) and Gram(-ve) microorganisms

and the results showed that all complexes studied are more potent than the standard drug

N

O

CH3

N

FO

O

HN

Cu

N N

NHN

R

Cl

where, R = Br (1), Cl (2), F (3), Me (4), OMe (5)

24

Introduction

P. Sathyadevi, 2011

ciprofloxacin. Absorption titration, viscosity and thermal denaturation measurement

studies revealed that each of these square-pyramidal complexes moderately interacts with

calf thymus DNA. Based on the data obtained in the DNA binding studies, an

intercalative mode of binding was suggested for these complexes. The nucleolytic

cleavage activity of adducts and gyrase inhibition assay were studied on double stranded

pUC19 DNA by gel electrophoresis experiments. From the superoxide dismutase mimic

study, it was reported that 0.45 μM to 1.45 μM concentration of complexes are enough to

inhibit the reduction rate of nitroblue tetrazolium (NBT) by 50% (IC50) in NADH/PMS

system.

Three new, diorganotin(IV) derivatives of pyruvic acid picolinoacylhydrazone,

{Me2Sn[(2-C5H4N)CONHNC(CH3)COO]}2·MeOH (1), {nBu2Sn[(2-C5H4N)CO

NHNC(CH3)COO]}2 (2) and {Ph2Sn[(2-C5H4N)CONHNC(CH3)COO]}2 (3) were

synthesized by the reaction of Me2SnCl2, nBu2SnCl2 and Ph2SnCl2 with pyruvic acid

picolinoacylhydrazone, respectively in the presence of sodium ethoxide.104

The prepared

compounds were characterized by elemental analysis, IR and 1H,

13C and

119Sn NMR

spectroscopy. Compounds 1 and 2 were also characterized by X-ray diffraction analysis,

which revealed that the compounds have similar structures containing two-center-two-

ligand skeletons. Further, weak but significant intermolecular hydrogen bonds assemble

these compounds into 1D or 2D supramolecular frameworks.

New copper(II) complexes of the hydrazone ligands H2salhyhb (1), H2salhyhp (2)

and H2salhyhh (3) derived from salicylaldehyde and ω-hydroxy carbonic acid hydrazides

have been synthesized and characterized by Roth et al.105 Two fundamental structures

were found in solid state depending on the pH of the reaction. Acidic conditions lead to

the formation of the di-μ-phenoxo-bridged dicationic complex dimers

[{Cu(Hsalhyhb)}2]2+

(1a), [{Cu(Hsalhyhp)}2]2+

(2a) and [{Cu(Hsalhyhh)}2]2+

(3a),

isolated as perchlorate salts. Higher pH resulted in the aggregation of neutral copper

ligand fragments to the one-dimensional coordination polymers [{Cu(salhyhb)}n] (1b),

[{Cu(salhyhp)}n] (2b) and [{Cu(salhyhh)}n] (3b). 3b has been examined by means of X-

25

Introduction

P. Sathyadevi, 2011

ray crystallography and represents the first example of a structurally characterized

copper(II) N-salicylidenehydrazide complex without additional ligands.

The in situ formed hydrazone Schiff base ligand (E)-N'-(2-hydroxy-3-

methoxybenzylidene)benzohydrazide (H2L1) and nicotinamide (L

2) on reaction with

copper(II) acetate gave the copper(II) complex [Cu(L1)(L

2)]. In the solid state, two

copper atoms are linked by nicotinamide through coordination with its pyridyl nitrogen

atom and amide C=O group to the dicopper(II) complex [CuL1(μ-L

2)Cu(L

1)(L

2)]. The

coordination polyhedra are a CuO2N2 square planar and a CuO3N2 square pyramidal.

Cyclic voltammetric experiments of the solution species [Cu(L1)(L

2)] in DMF revealed

the reduction of ligand L1

along with a reduction at -0.5 V assigned to the decomposition

of the complex.106

The interaction of lanthanum(III) 2-oxo-propionic acid salicyloyl hydrazone

complex [(LaIII

(L)2)] with bovine serum albumin (BSA) was studied under physiological

conditions. Fluorescence spectroscopy in combination with UV-visible absorption and

circular dichroism spectroscopy were used to investigate the binding mechanism, binding

constants and conformational changes of BSA in the presence of [LaIII

(L)2]. It was found

that the fluorescence quenching of BSA by [LaIII

(L)2] resulted mainly from the formation

of a [LaIII

(L)2]-BSA complex. The enthalpy change (ΔH) and entropy change (ΔS) were

found to be -41.03 kJ/mol and -32.61 J/mol/K, respectively which indicated that

Vanderwaals’ interactions and hydrogen bonds were the predominant intermolecular

forces in stabilizing the complex. The distance between the donor (BSA) and acceptor

[LaIII

(L)2] was found to be 4.35 nm, according to Forster theory of non-radioactive

energy transfer. The experimental results confirmed both microenvironmental and

conformational changes of BSA molecules in the presence of [LaIII

(L)2].107

Organometallic Cd(II) compounds have recently attracted attention for their

anticancer activity. The interaction of the dinuclear complex of Cd(II) with the

condensation product of 2-acetylpyridine and malonic acid dihydrazide, N', N'2-bis[(1E)-

1-(2-pyridyl)ethylidene]propanedihydrazide [Cd(II)H2L] with calf thymus DNA (CT

DNA) was monitored by a blue shift in UV-visible spectra of the complex. The binding

26

Introduction

P. Sathyadevi, 2011

constant of [Cd(II)H2L] complex with CT DNA was determined (KB = 1.8×104 M

-1) and

was indicative of minor groove binding. Agarose gel electrophoretic changes in mobility

of supercoiled and circular forms of pBR322 and pUC18 plasmids in the presence of the

complex suggested that conformational changes in the plasmids occur upon binding of

the [Cd(II)H2L] complex. The [Cd(II)H2L] complex induced perturbation of the cell cycle

phase distribution and an increase in the percentage of cells in the sub-G1 phase of

human cervical cancer HeLa cell line and murine melanoma B16 cell line.

Immunoblotting analysis showed the over-expression of Bcl-2 protein with the

[Cd(II)H2L] complex.108

N

N

CH3 HN

O

HN

O

N

CH3

N

N

N

CH3

NH

O

NH

O

N

CH3

N

Cd Cd DD

D = H2O

(ClO4)4. 4H2O

The bimetallic [Ni2(H2L1)2](ClO4)4 (1), [Ni2(HL1)(H2L1)](ClO4)3 (2) and

[Zn2(H2L1)2](BF4)4 (3) complexes (H2L1 = N',N'-2-bis[(1E)-1-(2-pyridyl)ethylidene]

propanedihydrazide) were synthesized and characterized109

and the structure of

complexes (1) and (2) were established by X-ray analysis. The complexes (1) and (2)

were obtained from the same synthetic reaction and two crystal types of these complexes

have been isolated during the fractional crystallization process. In complex (1) each

Ni(II) ion is coordinated with two NNO donor atom sets from two H2L1 ligands forming

an octahedral geometry. Similarly, in complex (2) the octahedral geometry of each Ni(II)

ion is attained by coordination of two NNO donor atom sets, one from the neutral and the

other from the monoanionic form of the ligand. The antimicrobial activity of the ligand

and complexes is also presented.

27

Introduction

P. Sathyadevi, 2011

Control of self-assembly through the influence of terminal hydroxymethyl groups

on the metal coordination of pyrimidine-hydrazone Cu(II) complexes was studied by

Hutchinson et al.110

The synthesis and characterization of 6-hydroxymethylpyridine-2-

carboxaldehyde (2-methyl-pyrimidine-4,6-diyl)bis(1-methylhydrazone) (1) was reported.

Ligand 1 was designed as a ditopic pyrimidine-hydrazone (pym-hyz) molecular strand

with hydroxymethyl groups attached to the terminal pyridine rings. Coordination of the

ligand 1 with Cu(ClO4)2·6H2O or Cu(SO3CF3)2·4H2O in a 1:2 molar ratio resulted in the

dinuclear Cu(II) complexes [Cu21(CH3CN)4](ClO4)4·CH3CN (2) and

[Cu21(SO3CF3)2(CH3CN)2] (SO3CF3)2·CH3CN (3). X-ray crystallography and 1H NMR

NOESY experiments showed that 1 adopted a horseshoe shape with both pyrimidine-

hydrazone (pym-hyz) bonds in a transoid conformation, while 2 and 3 were linear in

shape, with both pym-hyz bonds in a cisoid conformation. Coordination of 1 with

Cu(ClO4)2·6H2O or Cu(SO3CF3)2·4H2O in a 1:1 molar ratio resulted in three different

bent complexes, [Cu(1H)(ClO4)2](ClO4) (4), [Cu(1H)(CH3CN)](ClO4)3·0.5H2O (5) and

[Cu1(SO3CF3)]2-

(SO3CF3)2·CH3CN (6), where the pym-hyz bond of the occupied

coordination site adopted a cisoid conformation, while the pym-hyz bond of the

unoccupied site retained a transoid conformation. Both 4 and 5 showed protonation of the

pyridine nitrogen donor in the empty coordination site; complex 6, however, was not

protonated. A variety of Cu(II) coordination geometries were seen in structures 2 to 6,

including distorted octahedral, trigonal bipyramidal and square pyramidal geometries.

Coordination of the hydroxymethyl arm in the mono nuclear Cu(II) complexes 4, 5 and 6

appeared to inhibit the formation of a [2×2] grid by blocking further access to the Cu(II)

coordination sphere. In addition, the terminal hydroxymethyl groups contributed to the

supramolecular structures of the complexes through coordination to the Cu(II) ions and

hydrogen bonding.

The chemical reactivity, molecular structure and surface characteristics of Cu(I)

camphor hydrazone compounds along with a structural pathway for the conversion of

coordination polymers into dimers and vice versa was presented.111

By X-ray diffraction

analysis, two polymorphic forms of the chain compound [{CuCl}2(Me2NNC10H14O)]n

that essentially differ in the structural arrangement and geometry of the non-linear copper

28

Introduction

P. Sathyadevi, 2011

atom were identified. The characterization of the dimeric complexes [{Cu(Me2NNC10-

H14O)}2 (μ-X)2] (X = Cl or Br) was also achieved by X-ray diffraction analysis showing

the unusual arrangement of the camphor hydrazone ligands that occupy the same side of

the molecule. Bond lengths and torsion angles show that one of the polymorphic forms is

structurally close to the related dimer.

O

NH

N

CuCl

ClCu

NH

O

N

Abdou et al.112 reported the synthesis, characterisation and biological studies of

Mn(II), Fe(III), Co(II), Ni(II), Cu(II), Zn(II), La(III), Ru(III), Hf(IV), Zr(IV) and U(VI)

complexes of 4-methylphenylamino acetoacetylacetone hydrazone. The spectral data

showed that the ligand behaved in various coordination modes as a neutral bidentate,

neutral tridentate, monobasic bidentate, monobasic tridentate and dibasic tridentate type

towards the above metal ions. Antibacterial and antifungal tests of the ligand and some of

its metal complexes were also carried out.

A series of cobalt(II), nickel(II) and copper(II) complexes with two new

aroylhydrazones, 2-hydroxy-1-naphthaldehyde isonicotinoylhydrazone (H2L1) and 2-

hydroxy-1-naphthaldehyde-2-thenoyl-hydrazone (H2L2) have been investigated by Singh

et al.113 IR spectra suggested that the ligands act as a tridentate dibasic donor

coordinating through the deprotonated naphtholic oxygen atom, azomethine nitrogen

atom and enolic oxygen atom. EPR and ligand field spectra suggested an octahedral

geometry for Co(II) and Ni(II) complexes and a square planar geometry for Cu(II)

complexes.

Two lanthanide complexes (Ln = La, Pr) with a Schiff-base, 1-phenyl-3-methyl-5-

hydroxypyrazole-4-carbaldhyde-(benzoyl)hydrazone were synthesized and characterized

by Li et al.114 The crystal structure of the La complex determined by single-crystal X-ray

diffraction revealed that the coordination polyhedron is a tricapped trigonal prism

29

Introduction

P. Sathyadevi, 2011

configuration with the nine coordinate atoms composed of three nitrogens and six

oxygens from three ligands. The electronic absorption titration spectra, fluorescence

titration spectra, ethidium bromide competitive experiment, viscosity measurement and

CD spectra demonstrated that all the complexes were strongly bind with calf thymus

DNA, presumably via groove binding and intercalation mechanism. Further,

investigations of antioxidant properties showed that all the complexes have some

scavenging effects for hydroxyl radicals.

Different coordination modes of the Schiff base ligand [5-methyl-1-H-pyrazole-3-

carboxylic acid(1-pyridin-2-yl-ethylidene)-hydrazide] (H2L) towards metal centers were

reported with the syntheses and characterization of four mononuclear Mn(II), Co(II),

Cd(II) and Zn(II) complexes, [Mn(H2L)(H2O)2](ClO4-)2(MeOH) (1), [Co(H2L)(NCS)2]

(2), [Cd(H2L)(H2O)2](ClO4-) 2 (3) and [Zn(H2L)(H2O)2](ClO4

-)2 (4) and a binuclear Cu(II)

complex, [Cu2(L)2](ClO4-)2 (5) by Konar et al.115

In the complexes 1-4 the neutral ligand

serves as a 3N, 2O donor where the pyridine ring N, two azomethine N and two

carbohydrazine oxygen atoms are coordinatively active, leaving the pyrazole-N atoms

inactive. In the case of complex 5, each ligand molecule behaves as a 4N,O donor

utilizing the pyridine N, one azomethine N, the nitrogen atom proximal to the azomethine

of the remaining pendant arm and one pyrazole-N atom to one metal center and the

carbohydrazide oxygen atom to the second metal center. The complexes 1-4 are

pentagonal bipyramidal in geometry. In each case, the ligand molecule spans the

equatorial plane while the apical positions were occupied by water molecules in 1, 3 and

4 and two N bonded thiocyanate ions in 2. In complex 5, the two Cu(II) centers have

almost square pyramidal geometry. Four N atoms from a ligand molecule form the basal

plane and the carbohydrazide oxygen atom of a second ligand molecule sits in the apex of

the square pyramid. All the complexes have been X-ray crystallographically

characterized. The Zn(II) and Cd(II) complexes show considerable fluorescence emission

while the remaining complexes and the ligand molecule are fluorescent silent.

A novel class of ditopic ligand was synthesized by the reaction of 2,5-pyrazine-

dicarboxaldehyde with 2 equivalents of acyl / aroyl hydrazine and their structures were

30

Introduction

P. Sathyadevi, 2011

confirmed by 1D and 2D NMR and by X-ray crystallography. They formed heteroleptic

Cu(II) dinuclear rack-like complexes of the formula [Cu2(terpy)2](OTf)4. The solid-state

structures of these complexes were determined by X-ray crystallography.116

Three hydrazone ligands, H2L1-H2L3 from salicylaldehyde and ibuprofen or

naproxen derived hydrazides were prepared and transformed into the corresponding

copper(II) complexes [CuIIL1]·H2O, [Cu

IIL2] and [(Cu

II)2(L3)2]·H2O·DMF. The X-ray

crystal structure of the last mentioned complex was solved, showing square-planar

geometry and the single units were found to form a one-dimensional chain structure. The

interactions of these complexes with CT DNA were studied by different techniques

indicated that they all bound to DNA by classical and / or non-classical intercalation

modes.117

A series of mono and binuclear copper(II) complexes of general formulae

[CuL](ClO4) and [Cu2L](ClO4)2, respectively, have been synthesized from lateral

macrocyclic ligands that have different compartments, originated from their

corresponding precursor compounds 3,4:9,10-dibenzo-1,12-[N,N′-bis{(3-formyl-2-

hydroxy-5-methyl)-benzyl}diaza]-5,8-dioxacyclotetradecane (PC-1) and

3,4:9,10-dibenzo-1,12-[N,N′-bis{(3-formyl-2-hydroxy-5-methyl)-benzyl}diaza]-5,8-

O N O

CH3

N

O N O N

CH3

Cu(CH2)m (CH2)nCu

ClO4

+

where, L1a: m = 2, n = 2; L1b: m = 2, n = 3; L1c: m = 2, n = 4;

L2a: m = 3, n = 2; L2b: m = 3, n = 3; L2c: m = 3, n = 4

(ClO4-)2

31

Introduction

P. Sathyadevi, 2011

dioxacyclopentadecane) (PC-2). The structure of the precursor compound PC-1,

mononuclear copper(II) complex [CuL1a

](ClO4) and binuclear copper(II) complex

[Cu2L2c

](ClO4)2 were determined using single crystal XRD. In addition, electrochemical,

magnetic moment and EPR studies evidenced for mono and binuclear species. The

observed initial rate constant values of catechol oxidation, using complexes as catalysts,

range from 4.89×10-3

to 5.32×10-2

min-1

and the values are found to be higher for

binuclear complexes than for the corresponding mononuclear complexes.118

Copper(II) complexes with the non-steroidal anti-inflammatory drugs (NSAIDs)

naproxen (6-methoxy-α-methyl-2-naphthalene acetic acid) and diclofenac (sodium 2-

(2,6-dichlorophenylamino)phenylacetate) have been synthesized and characterized in the

presence of nitrogen donor heterocyclic ligands (2,2′-bipyridine, 1,10-phenanthroline or

pyridine). Naproxen and diclofenac act as deprotonated ligands coordinated to Cu(II) ion

through carboxylato oxygens. The crystal structures of [(2,2′-bipyridine)bis

(naproxenato)copper(II)] (1), [(1,10-phenanthroline)bis(naproxenato)copper(II)] (2) and

[bis(pyridine)bis(diclofenac)copper(II)] (4) have been determined by X-ray

crystallography. The NSAID ligands and their complexes exhibit good binding

propensity to DNA and human or bovine serum albumin protein having relatively high

binding constant values.119

Cl

ClN H

O

O Cu

Cl

ClNH

O

O

N

N

4

N NOCH3

CH3

O

OH3C

O

O

H3CO

Cu

1

Mononuclear zinc(II) complexes with quinolone antibacterial drug enrofloxacin in

the absence or presence of a nitrogen donor heterocyclic ligand 1,10-phenanthroline or

2,2′-bipyridine have been synthesized and characterized. Enrofloxacin acted as a

bidentate ligand coordinated to zinc ion through the ketone and a carboxylato oxygen

32

Introduction

P. Sathyadevi, 2011

atoms. The crystal structure of [bis(enrofloxacinato)(1,10-phenanthroline)zinc(II)] was

determined by X-ray crystallography. The binding of the complexes to calf thymus DNA

(CT DNA), human and bovine serum albumin proteins has been evaluated with UV and

fluorescence spectroscopies. Both the complexes displayed significant binding ability

with CT DNA, human and bovine serum albumin proteins.120

N

N

N

H3C

F

O

O

O

N

N

N

CH3

F

OO

O

N

NZn

33

Introduction

P. Sathyadevi, 2011

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