1

CHAPTER I

METAL COMPLEXES OF THIOSEMICARBAZONES - A SURVEY

1. Introduction

Thiosemicarbazones constitute an important class of N , S - donor

ligands and known for about 50 years. They were studied for a considerable

period of time for their biological activities. Interest on these compounds dates

back to the beginning of 20th

century and the first reports on their medical

applications appeared in the fifties as drugs against Tuberculosis and

Leprosy[1,2]. With the discovery of antiviral properties in the sixties, a huge

amount of research was carried out on these compounds that eventually led to

the commercialization of some of the thiosemicarbazone compounds, an

example being Marboran for the treatment of small pox[3]. One of the most

promising areas in which thiosemicarbazone compounds are expected to play a

vital role is against various types of cancers. Antitumor activity of these

compounds is extremely differentiated and it is very much dependent on the

topology of tumor cells i.e., they are selective, an important property that

renders the whole class of compounds biologically important. In many cases

their activity in biological systems was enhanced by coordination with metal

ions and a clear relation exists between chelate formation in the complexes and

in-vivo activity[4,5]. The presence of metal ion systematically increases the

activity and contributes to mitigate the side effects of the organic parent

compounds.

2

Thiosemicarbazones of various aldehydes and ketones occupy a special

place among organic ligands due to various donor atoms present in them and

their ability to change their denticity depending on the starting reagents and

reaction conditions. Thiosemicarbazones can also be easily modified by

varying the parent aldehyde or ketone used for the synthesis, particularly with

compounds having additional potential coordinating sites or by substitution on

the terminal N4 position. Structure - activity relationship studies revealed

that the presence of a bulky group attached to the terminal nitrogen of the

thiosemicarbazone moiety strongly enhanced the pharmacological activity

of these compounds[6]. Thus substituted thiosemicarbazones and their

complexes were studied exclusively due to their important biological

activities[7-14]. Studies were also reported on metal complexes with a wide

range of thiosemicarbazones and substituted thiosemicarbazones[15,16].

1.1 Structural aspects of Thiosemicarbazone ligands

Thiosemicarbazones are basically schiff bases obtained by the

condensation of an aldehyde or a ketone with thiosemicarbazide.

Thiosemicarbazones are broadly classified as mono-thiosemicarbazones and bis-

thiosemicarbazones.

R 2 C O N H 3 N H C

S

N H 2 R 2 C H N N H C N H 2

S

3

Mono-thiosemicarbazones

Mono-thiosemicarbazones are the compounds in which one (C=O)

group from an aldehyde / ketone and one NH2 group from thiosemicarbazide

condense forming a (C=N) linkage by the elimination of a water molecule.

Mono-thiosemicarbazone ligands have different substituents at R1, R

2, R

3 and

R4

positions. Depending on the nature of substituents, various sub-classes of

ligands are proposed. They are

a) Mono-thiosemicarbazones based on aldehydes(MTsc-A)

b) Mono-thiosemicarbazones based on ketones (MTsc-K)

Mono- thiosemicarbazones based on aldehydes contain alkyl/ aryl/ hetero cyclic

groups at R1, Hydrogen at R

2 and both H’s on R

3 and R

4 or one H at R

3 and

alkyl/aryl at R4.

R1=alkyl/aryl/heterocyclic group R

3= R

4 = H (or)

R2 =H and R

3= H R

4 = alkyl/aryl

Mono-thiosemicarbazones based on ketones contain alkyl or aryl groups on both

R1 and R

2 and both H’s on R

3 and R

4 or one H at R

3 and one alkyl/aryl at R

4

R1= alkyl/aryl R

3= R

4 = H (or)

R2 = alkyl/aryl and R

3 = H R

4 = alkyl/aryl

4

All other groups are similar in both the aldehyde and ketone based thiosemi-

carbazones.

Fig. 1.1 Structure of Mono-thiosemicarbazone

Bis - thiosemicarbazones

Bis-thiosemicarbazones are the compounds in which two (C=O)

groups from two aldehyde/ ketone molecules and two NH2 groups from two

thiosemicarbazide molecules condense forming two (C=N) linkages by the

elimination of two water molecules. Bis-thiosemicarbazones have two arms

connected by a ring or a C- C bond as shown in Fig. 1.2 and Fig. 1.3.

Fig. 1.2 Structure of Bis-thiosemicarbazone via ring formation

C N

NH2 C

S

N

R2

R1 R3

R4

C S R 4 R 3 N

N H

N

H C R 2 R 2

C H

N

C

N H

S N R 3 R 4

3

1

2

2 2

2

1

3

R 1

5

Fig. 1.3 Structure of Bis-thiosemicarbazone via C-C bond formation

1.2 Literature Survey

Several important aspects of thiosemicarbazones such as

synthesis of metal complexes, spectroscopic properties, crystal structures and

biological applications were reviewed in great detail. Akbar Ali and

Livingstone for the first time reviewed the chemistry of thiosemicarbazones in

1974 along with the other N, S-donor ligands[17], followed by Campbell in

1975[18]. Further developments in metal-thiosemicarbazone chemistry were

reviewed by Padhye and Kauffman in 1985[19], West et.al. in 1991 and

1993[20,7], Casas et.al. in 1999 and 2000[21,22] and the latest by T.S Lobana

et.al. in 2009[23]. Reports during 1950 to 1960 revealed thiosemicarbazones as

simple chelating ligands bonding with transition metal ions[24,25]. In some

cases the ligands were bi-dentate and in a few cases they were monodentate

bonding through sulphur only[24].

6

Relatively, few transition metal complexes of thiosemicarbazones

were synthesized and studied in detail during this period. Among those studied

were Ni(II) complexes, synthesized and characterized by Jensen et. al.[26].

Anti-tubercular activity of thiosemicarbazones was reported for the first

time in 4-acetyl aminobenzaldehydethiosemicarbazone by Domagk et. al. in

1946[27]. Reports appeared on their activity against influenza[28], protozoa [29],

smallpox[30] and certain kinds of tumors[31] and were suggested as possible

pesticides and fungicides[32,33]. The biological activity of these compounds

was reported to be due to their ability to chelate trace metals. Liebermeister

showed that the presence of copper ions enhanced the anti-tubercular activity

of p-acetamidobenzaldehyde thiosemicarbazone[34]. Petering and co-workers

suggested that the active intermediate in the tumour activity of 3-ethoxy-2-

oxobutyraldehyde bis(thiosemicarbazone) was a metal chelate. These findings,

further led to an increased interest in the chemistry of transition metal

complexes of thiosemicarbazones from 1960 onwards.

Structural studies of thiosemicarbazone complexes dominated the

literature during the seventies. In 1969, for the first time, crystal structure

determination of thiosemicarbazide appeared in the literature[35]. Polymeric

Ag(I) complexes containing thiosemicarbazones were reported to have

coordinated only through sulphur [36-38]. The most interesting feature was the

presence of both cis- and trans- isomers of Ni(Tsc)22+

cation in the compound

Ni(Tsc)2SO4[39]. A paramagnetic 6-coordinate complex [Ni(Tsc)2(NO2)2]

(H2O)2 was reported with nickel approximately in an octahedral geometry

7

with two O, two N and two S atoms in trans-positions relative to each other and

the Ni-N distances were in the range usually found for octahedral Ni(II)

complexes and the Ni-S bond lengths were intermediate between those found

for 4- and 6-coordinated Ni(II) complexes of thiosemicarbazones[40,41]. The

structures of two 6-coordinate, paramagnetic complexes of Ni(II) with

thiosemicarbazones of l-formaldehydeisoquinoline (TscFIQ) and 2-

formaldehyde pyridine(TscFPY) ligands were determined establishing the

tridentate nature of ligands[42,43].

Copper(II) complexes, Cu(Tsc)2SO4 and Cu(Tsc)2(NO3)2 were studied

by single crystal methods[44,45]. EPR and optical data obtained from single

crystal study of CuN2S2 established that both Cu-N and Cu-S bonds were

highly covalent[46]. Mossbauer spectra of a number of thiosemicarbazone

complexes of iron with a general formula [Fe(Tsc)2X2] nH2O were reported

[47]. According to A.V. Ablov et.al. both the Fe(II) and Fe(III) Tsc complexes

existed in high spin and low spin states with tridentate coordinaton of

ligands[48]. Studies on substituted thiosemicarbazones occupied most of the

literature from 1980 onwards. Gerbeleu and co-workers showed that alkylation

of the thiocarbonyl sulfur in thiosemicarbazone derivatives induced not only

complexation through the terminal amino group but also induced enough acidic

character to it to function as a monoacidic ligand[49]. In the presence of various

metals e.g., Cu(II), Ni(II), V(IV) these ligands were capable of condensing at

the terminal amino nitrogen atom through another aldehyde or ketone to yield

quadridentate ligands. The authors also isolated thiosemi-carbazone complexes

8

without sulfur coordination[50]. Monomeric oxo-vanadium, V(IV) complexes

of cyclohexanone semicarbazone and thiosemicarbazone ligands of the type

[VOL,X]X (L = the ligand and X = Cl, Br, or l/2 SO) with tetragonal structures

were reported by Chandra and Pandeya[51]. Matsumoto and co-workers

characterized ionic [Cr(HTsc)3]Cl3 3H2O and neutral [Cr(Tsc)3] complexes

on the basis of spectral data[52]. Penta coordinate Fe(III) complex with a

square pyramidal configuration derived from 2-hydroxy-1-naphthaldehyde

thiosemicarbazone ligand was described by Bhoon[53]. The synthesis and

properties of Ni(II), Pd(II) and Pt(II) complexes with a paramagnetic

thiosemicarbazone derivative obtained from 4-formyl-2,2,5,5-tetramethyl-3-

imidazoline-l-oxyl thiosemicarbazone were investigated by Ovcharenko and

Larionov [54].

Work on thiosemicarbazone complexes was mostly in three directions

from 1990 onwards: i) Bonding and structures of the complexes ii) Biological

applications of the complexes and iii) Analytical applications such as ion

sensors, metal ion extractants etc. A brief account of synthetic aspects and

spectroscopic properties were also part of them. Structural characterization of

thiosemicarbazone complexes that emerged during this period established

thiosemicarbazones as an important class of ligands for a variety of reasons,

such as variable donor properties, structural diversity and biological

applications[17-21]. The denticity of ligands varied widely, affected by the

substituents at C2

of thiosemicarbazone. The substituents at C2

carbon

induced metal–carbon bond formation (ortho-metallation) in complexes with

9

metals such as palladium and platinum[55]. Studies in the area of coordination

chemistry of thiosemicarbazones were pursued further, modifying the ligands

by varying aldehyde or ketone or a substitution carried out on

thiosemicarbazide. Anti-cancer, anti-bacterial, anti-fungal and anti-viral

activities of a large number of thiosemicarbazones were reported by

Klayman[56,57], Scovill[58] and Blanksma[59]. A series of Co(III) octahedral

complexes of the type [Co(III)L2]X were reported in which a uninegative

thiosemicarbazone coordinated to the cobalt center via N4, N

3, S, or O, N

3, S

donor atoms[60-62]. Uninegative tridentate thiosemicarbazones were also

prepared by the deprotonation of –NH2 group in [Co(III)(HL)2][BF4], while –

OH group was deprotonated in [Co(III)(HL)2]Cl[63,64]. 2-Benzoylpyridine

thiosemicarbazone and its Cu(II) complexes exhibited antifungal activity

against various strains of pathogenic fungi and the activity varied with the

nature of the substituent on the amino nitrogen of thiosemicarbazone[65]. The

period from 1990 to 2000 covered a lot of active research on the biological

activities of these compounds. It was shown that most of the thiosemicarbazone

complexes displaying anti-bacterial activities had a pyridyl group at the C2

carbon of thiosemicarbazone moiety. Enhanced inhibitory effects of

complexes compared to their free ligands were attributed to the increased

lipophilicity of complexes in aqueous solutions. N1-substituted 2-acetyl

pyridine thiosemicarbazones showed a remarkable activity on complexation

with various metals such as Pt(II), Bi(III), Hg(II) and Zn(II)[66-69].

10

Anti-cancer properties of thiosemicarbazones took a thrust during this

period and studies were directed in this direction from the year 2000 onwards.

Anticancer properties of thiosemicarbazones were noted when apoptosis was

induced by them leading to DNA fragmentation[70]. Some of the copper

complexes, [Cu(H2L)(OH2)Cl]Cl where (H2L) was pyridoxal thiosemi-

carbazone[71], [Cu(H3L)Cl2], [Cu(H3L)H2O(SO4)], [Cu(H3L)(OH2)2(NO3)2]

H2O where (H3L) was 5-formyluracilthiosemicarbazone[72,73] and [Co(HL)L]

H2O where (HL)L was α-ketoglutaric acid thiosemicarbazone[74] were tested

in- vitro on the human leukemia cell lines and were found to be active in the

treatment of cancer .

It was during this time that Gold was introduced in the place of

Platinum and a linear Au(I) complex, [Au(PEt3)(HL)] (HL = Vitamin K3

thiosemicarbazone) synthesized showed cytotoxicity against cisplatin sensitive

cell line A2780 and 10 times more against cisplatin-resistant cell line

A2780cisR[75]. Square planar Au(III) complexes, [Au(Hdamp-Cl)Cl(L1)]PF6,

[Au(Hdamp-C1)Cl(L2)]Cl, [Au(Hdamp-C1) Cl(H2L3)]Cl2.MeOH, [Au(Hdamp-

C1)(L5)]Cl2 and [Au(Hdamp-C1)(L4)]Cl2.2MeOH (damp- dimethyl amino

methyl phenyl) exhibited anti-proliferative activity against human breast cancer

cell lines[76-77]. Labelled Copper(II)thiosemicarbazone complexes were shown

to have applications as imaging agents. 64

Cu or 67

Cu labelled complexes of p-

carboxyalkylphenylglyoxal and p-carboxyalkyl-1,2-diketo-bis-(N4-methyl

thiosemicarbazone) ligands were used for tumor imaging[78]. The copper

complex of pyruvaldehyde-bis (N-4-methylthiosemicarbazone) acted as a

11

potential imaging agent for heart and brain when labeled with 64

Cu or 67

Cu with

no adverse effects[79]. 64

Cu-diacetylbis(N4-ethylthiosemicarbazone) and

64Cu-

diacetylbis (N4-methylthiosemicarbazone) complexes showed similar hypoxia

selectivity [80].

After obtaining the first comprehensive breakthrough on the

antitumor effects of thiosemicarbazones, research was directed to obtain better

activities by modifying the aromatic system. Thiosemicarbazones with an

added advantage of high formation constants for their metal complexes and

ability to sequester iron from the cell environment led Finch et. al to suggest

that Fe(II) complex of 1-formylisoquinoline thiosemicarbazone was the active

species in their studies[81]. A drug based on thiosemicarbazones, Triapine[3-

amino-2-formylpyridine thiosemicarbazone] had undergone phase II clinical

trial on many types of tumours[82-83]. Kowol et. al. reported the synthesis,

characterization and biological assays of complexes of Fe(III) and Ga(III) and

concluded that the coordination to Ga(III) increased the cytotoxic activity,

while coordination to Fe(III) reduced the cytotoxic activity compared to metal

free thiosemicarbazones[84,85]. Ga(III) complexes of 4-methyl and 4-ethyl

derivatives showed MIC50 (Minimum Inhibition Concentration) values which

were 20-fold more potent than cisplatin. Recently the activity of Mn(II),

Co(III), Ni(II), Cu(II) and Zn(II) complexes obtained from these ligands were

studied on these lines and divalent Mn(II), Ni(II), Cu(II) and Zn(II) complexes

were found to be equally active in preventing proliferation[86]. Thus a highly

promising class of compounds based on thiosemicarbazones have been

12

introduced with anti- cancer activities and expected to occupy a prominent

place in cancer therapy.

A vast majority of thiosemicarbazones reported in the

literature have a polar head of thiosemicarbazide part and an aromatic

hydrophobic part. The coordination allows the ligand to hide partially around

the metal and the hydrophobic moiety gets exposed to the solvent, a feature

necessary for crossing the cell membrane [87]. Otero et. al. in 2006 published a

study on the activity of 5- nitrofuryl-3-acroleine thiosemicarbazone Pd(II)

complexes against Trypanosoma cruzi and Nifurtimox and confirmed that the

activity of the ligand increased as a result of complexation[88]. Perez et. al.

reported that N4-methyl-4-nitro acetophenone thiosemicarbazone, N

4,N

4-

dimethylnitro acetophenone thiosemicarbazone, N4-piperidyl-4-nitroaceto

phenone thiosemicarbazone complexes of copper(II) and of 3-(5-nitrofuryl)

acroleinethiosemicarbazone complex of Pt(II) exhibited anti-trypanosomal

activity[89]. Biot et. al. reported the design, synthesis and anti-malarial activity

of thiosemicarbazones in combination with ferroquine, a molecule well known

for its anti-malarial properties[90-93]. Another important area in which

thiosemicarbazone metal complexes are receiving a great attention is their use

as carriers for radiotracers. Studies have been reported on a class of copper(II)

thiosemicarbazones as radio tracers[93].

13

1.3 Importance of N4-substitution on Thiosemicarbazones

The activity of thiosemicarbazones was shown to be significantly

affected by the substitution at the moiety's N4

position. Anti-viral activity of

N4-methyl and N

4-ethyl thiosemicarbazones was very high compared to

unsubstituted thiosemicarbazones[94]. Reports on N4substituted thiosemi-

carbazones had concluded that an additional potential bonding site together

with the presence of a bulky group at N4 position of the thiosemicarbazone

moiety greatly enhanced the biological activity[95-98]. Some of the significant

reports appeared on synthesis and characterization of N4-substituted

thiosemicarbazone complexes with various transition metals [99-101].

1.4 Gold complexes and their biological activity

Gold, like copper and silver, has a single electron with an

electronic configuration 1s2 2s

2 2p

6 4s

2 3d

10 4s

2 4d

10 4f

14 5s

2 5p

6 5d

10 6s

1[102]

and exists in a number of oxidation states, -I, 0, I, II, III, IV and V, but only

0, I and III are stable in aqueous systems and biological environments. Gold

chemistry in complexes mostly revolves around two oxidation states, Au(I) and

Au(III). Au(I) complexes have a common coordination number of two with

linear stereochemistry and thus are coordinately unsaturated 14 electron

complexes. Relative small energy difference between the d-orbitals and the

s-orbital on gold permits the extensive hybridization of these orbitals[103].

Higher coordination numbers of three and four with trigonal and tetrahedral

geometries are rare for Au(I) as they require the participation of high energy

6py and 6pz orbitals, which need high promotion energies.

14

Gold(III) is usually regarded as oxidizing and the appropriate choice of

ligand can stabilize the higher oxidation state of gold, controlling the

instability, light sensibility and reduction to metallic gold. Thus gold(III)

complexes have been evaluated for their potential biological activities,

especially their anti-tumour activity. The design and testing of gold complexes

for anti-tumour activity has been based on [86].

Analogies between square planar complexes of Pt(II) and Au(III);

(d8 ions, isoelectronic and isostructural)

Analogy to the immunomodulatory effects of Gold(I) anti-arthritic agents;

Coordination of Gold(I) and Gold(III) with known anti-tumour agents to

form new compounds with enhanced activity;

Gold(III) complexes present good stabilities in physiological

environments [104,105].

Au(III) complexes prefer four coordination with square planar geometry.

Gold has a 16-electron configuration in these complexes with a vacant 6pz

orbital. In organometallic derivatives, this is the most common geometry for

stable Au(III) complexes. Coordination numbers five and six are known for

Au(III) complexes, and both three and five-coordinate organogold(III)

complexes have been proposed as reaction intermediates[106-109]. Though

medicinal and therapeutic value of gold was recognized thousands of years ago,

its rational use in medicine did not begin until the early 1920s. Cisplatin, a

Pt(II) based anticancer drug is one of the first metal-containing compounds

with anti-cancer activity discovered in the 1960s. Au(III), which is

15

isoelectronic with Pt(II), opens the possibility of exhibiting similar activity in

its complexes. Despite the fact that cisplatin treatment is efficient for several

types of solid tumors, its effectiveness is limited by toxic side effects and tumor

resistance that often leads to the occurrence of secondary malignancies.

Au(III) is isoelectronic with Pt(II) and tetra coordinate Au(III)

complexes have the same square-planar geometries as cisplatin. Based on these

similarities, the anticancer activity of Au(III) compounds attained importance

in investigations. Previous studies suggested that, in contrast to cisplatin, gold

complexes target proteins but not DNA[110,111]. Au(III) complexes are

expected to emerge as a new class of metal complexes with potential

antitumor activities and this is because of the fact that Au(III) complexes are

stable under physiological conditions with relevant anti-proliferative properties

against selected human tumor cell lines. Considerable interest was shown by

researchers in understanding the exact biochemical mechanisms of these novel

Gold(III)complexes as cytotoxic agents[112]. Relatively, few studies have been

directed towards the isolation and characterization of complexes with Au(III).

Cytotoxic studies of Au(III) complexes of polydentate amines showed that

they were more effective against certain tumor cell lines compared to

cisplatin[113]. It was shown that the bis(ethyleneldiamine)Au(III) complex

binds to calf thymus DNA non-covalently through electrostatic

interactions[114]. A resurgence of interest in squareplanar Gold(III) compounds

had occurred in the last decade and a wide variety of mono and dinuclear,

neutral and charged, coordination and organometallics have been

16

developed[115]. Promising indications were received on these lines with reports

on a series of digold phosphine complexes,[dppe(AuCl)2] bis[1,2-bis(diphenyl

phosphino)ethane]gold(I) chloride. Studies on dppe (bis[1,2-

bis(diphenylphosphino)ethane] ligand alone indicated its anti-tumour activity

and in the compound gold serves to protect the ligand from oxidation and with

the delivery of the active species. A direct role for the gold in the anticancer

activity of this complex was established from the study[116].

One avenue of investigation has been to synthesize gold complexes

containing ligands with known anti-tumour activity. Some of the examples are

Gold(III) complex of streptonigrin, a substituted 7-amino-quinoline-5,8,-

dione[117], a series of Ph3PAu(I)-nucleotide complexes containing ligands such

as 5-fluorouracil and 6-mercaptopurine, phosphine gold(I) ferrocene

complexes such as [p-I,1-bisbis(diphenylphosphino)ferrocene bis (chlorogold

(I) and nitrogen containing phosphine gold(I)ferrocene complexes[118]. A

gold(I) thiocyanate complex [Au(SCN)(PMe3)] demonstrated activity against

Gram positive bacteria[119]. A series of Au(I) phosphonium dithiocarboxylate

complexes, [AuCI2(damp)] and [Au(OAc)2(damp)] of Au(III) exhibited a broad

spectrum of activity against a range of organisms[120]. In a broad sense, Au(III)

complexes have not been as thoroughly investigated as Au(I) complexes,

primarily because of their reactivity. In-vitro activities in test systems were

demonstrated against both gram negative and gram positive bacteria by Au(III)

complexes. At present most of the work is directed towards tumor cell lines and

little work has been reported on the antimicrobial activity of Au(III)

17

complexes[119-120]. There is a growing clinical need for new antimicrobial

agents. The therapeutic efficacy of drugs available at present for the treatment

of a class of bacteria known as the 'problem Gram positive cocci is limited by

the emergence of multiple resistant strains such as methicillin-resistant

Staphylococusaureus[121]. It is possible that an improved understanding of the

molecular and biochemical mechanism of gold compounds provide an impetus

for new advances in the use of gold drugs.

1.5 Studies on Au(III) and Au(I) thiosemicarbazone complexes

Thiosemicarbazones as well as their metal complexes are of great

interest because of their promising chemical and pharmacological properties

[8].Although a number of studies deal with thiosemicarbazone complexes with

metal ions, few reports appeared in the literature on Gold thiosemicarbazone

complexes or Gold substituted thiosemicarbazone complexes.

Square-planar Gold(III) complexes with damp (dimethylamino

methyl phenyl) ligand, [Au(damp-C1,N)Cl2] and [Au(damp-C

1,N) (OOCCH3)2]

were studied for ligand exchange reactions of chloro and acetato

groups[122,123]. K. Ortner and U. Abram reported the first Au(III) thiosemi-

carbazone complexes by reaction between [Au(damp-C1N)Cl2] and aromatic

thiosemicarbazones, (2-acetylpyridine (HAPTsc) or 4-hydroxy-3-

ethoxybenzaldehyde or vanilline thiosemicarbazone(HVTsc)[77]. The reaction

between Gold(III) chloride and N(4) 2-benzoylpyridine thiosemi-carbazone

and N(4)-(butane-1,4-diyl)thiosemicarbazone led to the formation of

Gold(III)thiosemicarbazone complexes. Spectroscopic characterization and

18

preliminary biological activity of [Au(Hdamp-C1)(VTsc)Cl]Cl and

[Au(Hdamp-C1)(APTsc)]Cl2 complexes were reported by Parish et. al[124].

Gold(III) thiosemi-carbazone complexes derived from [Au(damp-C1,N)Cl2]

were screened in the study for in-vitro anti-malarial and anti-tubercular

activities. Although incorporation of Au(III) centre into thiosemicarbazone

scaffolds enhanced their efficacy against the malarial parasite Plasmodium

falciparum, this trend was not observed for the anti-tubercular activity of

selected thiosemicarbazones against the Mycobacterium tuberculosis virulent

strains[125]. A variety of (bis)thiosemicarbazone based ligand systems

containing ethyl, propyl or butyl backbone between the two imine N donors

have been investigated to evaluate chelate ring size effects on Au(III) complex

stability[126]. A series of new bis(thiosemicarbazonate) gold(III) complexes

were synthesized with a general formula [Au(L)]Cl.

where

L= L1 = glyoxal-bis (N4-methylthiosemicarbazone)

L2 = glyoxal-bis(N4-ethylthiosemicarbazone)

L3 = diacetyl-bis(N4-methylthiosemicarbazone)

L4 = diacetyl-bis(N4-ethylthiosemicarbazone)

and were found to be active against (HIV)virus[127]. [Au2(3-NO2-

HbTsc)4]Cl2.2CH3CN was the first ionic Gold(I) complex with a

thiosemicarbazone [128] and [Au(PEt3)HL] (HL-Vit.K3thiosemi-carbazone)

was the first neutral Au(I) thiosemicarbazone complex reported[129]. Apart

from their anti-HIV activities, Gold(I) complexes exhibited considerable

19

amount of anti-malarial activity and the relation between anti-malarial activity

(in-vitro) and complexation with Au(III) was established[130].

1.6 Studies on Ru(III) thiosemicarbazone complexes

Metals are in use for medicinal purposes for at least 3500 years. The

biological targets or mechanism of action of many metal drugs are now being

resolved step by step, and this information is then used to design improved

drugs with increased potency and reduced side effects[131].

Many platinum drugs are used in the clinics and even more are being

evaluated in clinical trials, not just to treat cancer but to treat a range of

diseases, including parasitic and bacterial infections. Gold and silver, are well

known for their medicinal value. In the search for new therapies Ruthenium

compounds have always attracted attention due to their special features[132-

135].

a) Analogous ligand-exchange abilities to platinum complexes.

b) Range of accessible oxidation states.

c) Cytotoxicity against cancer cells.

d) Ability of ruthenium to mimic iron in binding to certain biological

molecules.

e) Reduced toxicity against healthy tissues using iron transport.

Ruthenium is unique among the metals in that the oxidation states II and

III are accessible under physiological conditions. The redox potential of

ruthenium compounds can be exploited to improve the effectiveness of drugs in

the clinic. One of the first ruthenium compounds described to have anticancer

20

activity was Ruthenium Red[136-137]. Anti-cancer potential of Ruthenium-

containing drugs with specific targets were also reported[138,139]. Several

teams have synthesized and characterized compounds containing Ru(II) and

Ru(III)[140-145]. Ru(II) with o-vanillin(4-methyl thiosemicarbazone) and o-

vinillin(4-phenyl-thiosemicarbazone) were synthesized, characterized and

their anti-bacterial, anti-fungal and anti-amoeboidal activities were reported.

The compounds were efficient anti-infective agents too[146]. Structurally,

unusual coordination modes were exhibited salicylaldehyde-N-

phenylthiosemicarbazone (H2-Sal-PTsc) ligand reacted with

[RuHCl(CO)(PPh3)3] to form Ru(III) carbonyl complex[147].

Studies on the mode of action of ruthenium-containing compounds

indicated their interaction with DNA[148]. The low toxicity of ruthenium drugs

is also believed to be due to the ability of ruthenium to mimic iron in binding to

many bio-molecules, thereby reducing its toxicity[149]. The synthetic,

spectroscopic and biological studies of ring-substituted 4- phenyl- and 4-

nitrophenylthiosemicarbazones of anisaldehyde, 4-chloro and 4-fluorobenz-

aldehyde and vanillin with Ru(III) were reported with significant activities

[150].

1.7 Studies on Benzil and Benzil thiosemicarbazone metal complexes

Various 1,2-diketones and their derivatives act as chelating agents to

form complexes with metals having different pharmacological activities [151-

153]. Benzil (C6H5COCOC6H5) is an aromatic diketone, readily soluble in

organic solvents and is widely used as a chelating ligand and catalyst precursor.

21

A series of benzil derivatives were synthesized by the oxidation of diaryl

alkynes in good to excellent yields and their biological activities were

reported[154]. Complexes with general formulae [M(Bsodh)]Cl and

[M(Bsmdh)]Cl, where M = Co(II), Ni(II), Cu(II), Zn(II,) Cd(II); HBsodh =

Benzil salicylaldehyde oxalicacid dihydrazone and HBsmdh = Benzil

salicylaldehyde malonicacid dihydrazone were synthesized and

characterized[155]. Significant antibacterial activity was reported against

Bacillus subtilis and Pseudomonas fluorescence by these ligands and their

complexes.

A new series of macrocyclic complexes, [M(C48H32N4)X2], where

M = Co(II), Ni(II), Cu(II) and Zn(II); X = Cl-, NO3

-, CH3COO

- were

synthesized by condensation of 1,8-diaminonaphthalene with benzil. These

complexes were found to exhibit good antibacterial activities against some of

the important bacterial strains[156]. Benzil and its derivatives form complexes

with many transition metal ions. Synthesis, spectral characterization and

antifungal activity of Co(II) and Cu(II) complexes with a macrocyclic ligand

(3,4,12,13-tetraphenyl-1,2,5,6,10,11,14,15-octaazacyclooctadecane-7,9,16,18-

tetraone-2,4,11,13-tetraene) were reported[157].

The stereochemistry and complexation behavior of diphenyl diketone

monothiosemicarbazone(DKTS) with Cu(II), Co(II), Ni(II), Cd(II), Zn(II),

Pd((II), Pt(II), Ru(III), Rh(III) and Ir(III) metal ions were investigated by

means of chemical studies, magnetic studies and IR, Raman, 1H NMR and

13C

NMR spectral studies. The ligand (DKTS) formed distorted octahedral

22

complexes of the type M(DKTS)2 with Ni(II), Cu(II) and Co(II) metal ions.

The absence of ʋ(M-X) band in their IR spectra, coupled with their 1:1

electrolytic conductances, suggested that Ru(III), Rh(III) and Ir(III) formed

octahedral complexes of the type [M(DKTS)2]Cl[158]. Ti(1V)benzil

monothiosemicarbazone complexes in 1:1, 1:2, 1:3 and 1:4 molar ratios were

synthesized and characterized on the basis of elemental analysis, molecular

weight determinations and IR and PMR spectral studies[159].

Reactions of diphenyl lead(IV) chloride with benzil bis(thiosemi-

carbazone) (L1H6) and benzil bis(4-methyl-3-thiosemicarbazone) (L1Me2H4)

led to the formation of novel bis(thiosemicarbazone) complexes. Mononuclear

[PbPh2Cl(L1H5)]3H2O and [PbPh2Cl(L1Me2H3)] complexes containing one lead

atom and a binuclear complex [PbPh(L1Me2H2)]2.H2O containing two lead

atoms were reported[160]. These complexes exhibited structural diversity

depending on the nature of ligand and the working conditions.

The reaction between cadmium nitrate dihydrate and benzil bis(4-

methyl-3-thiosemicarbazone), was shown to depend on the working conditions.

In methanol, a novel complex [Cd(LMe2H4)(NO3)2] [Cd(LMe2H4)

(NO3)(H2O)]NO3 H2O was found to exist with two cadmium atoms of

different coordination numbers, seven and eight. One cadmium atom had the

coordination sphere completed by a bidentate nitrato group and a water

molecule, whereas the other cadmium atom was bonded to two bidentate

nitrato groups. Both the molecules joined to a nitrate ion and to an additional

water molecule by hydrogen bonds[161]. Reactions of benzil bis

23

thiosemicarbazone with Ni(II), Co(II) and Fe(III) chlorides and nitrates

produced different complexes depending on the salts used and working

conditions provided. Electrochemical behavior of these complexes studied by

cyclic voltammetry indicated metal-centered reduction processes in which the

reduction-oxidation potential values depend on the structures of the

complexes[162]. The literature so far studied indicated that no studies have been

reported on Au(III)benzil thiosemicarbazones or Au(III) benzil (substituted)

thiosemicarbazones.

1.8 Studies on Isatin and Isatinthiosemicarbazone complexes

Thiosemicarbazones of various aldehydes and ketones occupy a

special place among organic ligands as they contain various donor atoms and

are able to change their denticity depending on the starting materials and

reaction conditions. Ligands containing oxygen and nitrogen as donor atoms

are by far the most extensively studied group of ligands. Interest in sulfur donor

chelating agents has grown over the years with the number of studies in this

area increasing considerably [163]. 1-Methyl-isatin-3-thiosemicarbazone was

found to be active in the treatment of smallpox and this led to an extensive

research on the biological activities of Isatin-3-thiosemicarbazones (1H-indole-

2,3-dione-3-thiosemicarbazones)[164-176]. The basis for this observation was

that the drug inhibited vaccine virus replication by preventing late viral-protein

synthesis. A wide range of anti-bacterial, anti-viral, anti-tuberculosis, anti-

cancer, anti-fungal and anti-HIV activities were exhibited by isatin (2,3-

indolinedione)-3-thiosemicarbazones and their metal complexes[177-184]. It was

24

suggested that inhibition of virus growth was by binding to copper ions which

were constituents of the virus. This led to improvements in the constitution of

ligands resulting in a wide range of substituted thiosemicarbazones[185] and

substituted isatinthiosemicarbazone ligands like 5-methoxyisatin-3-(N-phenyl)

thiosemicarbazone, 5-methoxyisatin-3(N-benzyl)thiosemicarbazone, and 5-

methoxyisatin-3-(N-(4-chlorophenyl))thiosemicarbazone[186]. Zinc(II) complex

of 5-fluoroisatin-3-(N-benzyl) thiosemicarbazone was synthesized and

characterized [185,187]. Recently Bal et. al. published a paper on the synthesis

and evaluation of anti-HIV activity of isatin- β-thiosemicarbazone derivatives

of 5-substituted-1-(arylmethyl/alkylmethyl)-1H-indole-2,3-dione-3-(N-hydroxy

/methoxy thiosemicarbazone)[175]. Studies indicated isatin-3-thiosemi

carbazones generally coordinated through N, S, O donor atoms and

coordination through O donor atoms depends on the nature of the metal and is

weak in some cases[174]. Interest in the complexes of these ligand systems

pervades several fields ranging from effect of sulfur and electron delocalization

in transition metal complexes to potential biological activities and practical

applications[188-189]. Importance of substitution at N4-position of the

thiosemicarbazone moiety came to light when isatin N4-substituted

thiosemicarbazones were found to reduce anti-smallpox activity [190]. It was

also reported that two butyl groups attached at the N4-position demonstrated

activity against Ectromelia (vaccina virus unaffected by Marboran) and also

against type 2 polio, which is an entero virus and quite unrelated to the vaccina

family[191]. Metal complexes of N4-2-pyridyl-, N

4-phenyl-, N

4-ethyl- and N

4-

25

dimethyl thiosemicarbazones derived from isatin have been studied[182-185].

Metal complexes of isatin 3-hexamethyleneiminyl thiosemicarbazone,

[M(Ishexim)2], M =Co(II), Ni(II), Cu(II), Zn(II), Cd(II), Pb(II) and Tl(I)

complex, [Tl(Ishexim] have been prepared by electro-chemical synthesis[173].

1.9 Studies on Alloxan and Alloxanthiosemicarbazone complexes.

Pyrimidine derivatives are known for their varied biological activities.

Alloxan, [2,4,5,6(1H,3H)-pyrimidinetetrone], a Pyrimidine derivative, was

found to possess anti-neoplastic properties[192]. It was used to induce

experimental diabetes in animals, is a potent beta-cell toxin, causing

destruction via hydroxyl radical formation[193]. Alloxan is widely used in the

studies of diabetes as it destroys pancreatic islet-cells with specific selectivity

[194-195]. A study on the mechanism of action of typical diabetogenic agent is

of great importance for elucidating the cause of insulin-dependent diabetes

mellitus. Alloxan inhibits proinsulin synthesis in pancreatic islets [196]. Islet

DNA strand breaks were observed in-vivo by the administration of alloxan to

rats[197]. Uchigata et. al. proposed that alloxan caused DNA strand breaks to

stimulate nuclear poly(ADP-ribose) synthetase, thereby depleting intracellular

NAD level and inhibiting proinsulin synthesis[198-200]. Alloxan is a

biologically active molecule and thus imparts interest in its complexation

reactions with metal ions. Co(II), Ni(II) and Cu(II) complexes with alloxan,

ML2 5H2O, were isolated from aqueous alkaline solutions[201]. Mn(II)

alloxanate was obtained by evaporation of an acidified solvent at room

temperature[202] and Ce(III) formed a soluble complex, ML2 with alloxan [203].

26

Transition metal salts reacted with alloxan solutions to give colored complexes,

ranging from orange yellow or red [for Cd(II), Mg(II), Cu(II), Zn(II), Co(II),

Ni(II)] to dark blue in the presence of ammonia [for Fe(II)][197]. Studies

reported on the composition and properties of Pb(II), Hg(I), Hg(II) and Ag(I)

alloxanates were incomplete[204-207]. Kovalchukova et. al. reported studies on

Fe(III) and Co(III) complexes with alloxan[208-209]. Complexes of Co(II),

Ni(II) and Pd(II) alloxanates were also reported[210]. Studies on the

complexation of a series of d- and f- block metals with alloxan were reported

by Shebaldina et. al.[211]. Biological screening of alloxan complexes of various

transition metal ions compared to free alloxan was reported against different

bacterial and fungal species[212]. Though studies on alloxan complexes with

metal ions are available, alloxanthiosemicarbazone complexes are yet to be

investigated in full detail. Studies were reported in the literature on alloxan

thiosemicarbazones on optimized geometries and NMR[213]. Survey of

literature indicated, except for one study[214], there were no reports on the

complexes of alloxan thiosemicarbazones or alloxan substituted thiosemi-

carbazones with Au(III)[215]. In view of pharmacological importance of

Au(III), alloxanthiosemicarbazones and alloxan substituted thiosemicarbazone

complexes were synthesized and investigations were carried out into their

structural and activity aspects.

In conclusion, the present work is about synthesis, characterization and

biological activities of Au(III) complexes with N4-substituted thiosemi

carbazone ligands derived from Benzil, Isatin and Alloxan.

27

1.10 Introduction to the relevant analytical techniques

Various measurement techniques and methods employed for the

elucidation of structures of complexes and their biological activities include

Elemental analysis, Conductivity measurements, Magnetic susceptibility

measurements, NMR, IR, UV-Vis and well diffusion methods. Necessary

methods and instruments which are used in the present investigation are

described in brief in this chapter.

1.10.1 Elemental analysis

Elemental analysis of Carbon, Hydrogen and Nitrogen were carried out on

FLASH 2000 Series CHNS/O Analyzer at University of Hyderabad, A.P,

India.

CHN Analyzer is a scientific instrument which can determine

the elemental composition of a sample. The name is derived from the three

primary elements measured by the device: Carbon, Hydrogen and Nitrogen.

Sulfur and Oxygen can also be measured. It is based on two general

procedures. One involves the separation of carbon dioxide, nitrogen and water

by a gas chromatographic column. The other involves separation by means of

specific absorbents for water and carbon dioxide, the resulting change in

composition of the gas mixture being measured. Thermal conductivity is the

detection method in both the techniques. Results are calculated by analyzing

the standard and occasional blank.

28

1.10.2 Conductivity measurements

The molar conductivities of the complexes in DMF/DMSO solutions

(10-3

M) at room temperature were measured using a direct reading conductivity

meter at the Department of Chemistry, Acharya Nagarjuna University,

Nagarjuna Nagar.

1.10.3 Magnetic susceptibility measurements

The magnetic susceptibility and the magnetic moment are used to

describe the magnetic behavior of substances. A magnetic dipole is a

macroscopic or microscopic magnetic system in which the north and south

poles are separated by a short but definite distance. In the presence of a

magnetic field, magnetic dipoles within a material experience a turning effect

and become partially oriented. The magnetic moment refers to the turning

effect produced when a magnetic dipole is placed in a magnetic field. The

fundamental unit of magnetic moment is the Bohr Magneton(BM). For

isotropic substances the magnetic susceptibility (χ) is defined by,

χ = M/H

where M is the magnetic moment per unit volume (magnetization) and H is the

strength of magnetic field. The molar susceptibility χ M is simply defined as

the susceptibility per gram-mole. Hence,

χM

= χ x Molecular Weight

The magnetic susceptibility value calculated from magnetic measurements is

the sum of paramagnetic and diamagnetic susceptibilities. To calculate the

exact paramagnetic susceptibility, the value of diamagnetic susceptibility is

29

subtracted from the susceptibility calculated from observed results. When the

structural formula of the complexes is correctly known, diamagnetic correction

can be calculated from Pascal's constants. The magnetic susceptibility

measurements are carried out in the polycrystalline state on a Vibrating Sample

Magnetometer (VSM) at 5.0 kOe field strength at room temperature at

Sophisticated Analytical Instrumentation Facility (SAIF), Bombay.

1.10.4 FT-IR Spectroscopy

Infrared (IR) spectroscopy is one of the most common

spectroscopic techniques used by organic and inorganic chemists for structural

elucidation. The vibrational states of a molecule can be probed in a variety of

ways. The most direct way is IR spectroscopy because vibrational transitions

typically require an amount of energy that corresponds to the infrared region of

the spectrum between 4000 and 400 cm-1

. Radiation in this region is utilized in

structure determination in coordination chemistry by making use of the fact

that interatomic bonds in ligands and complexes absorb it. Simply, it is the

absorption measurement of different IR frequencies by a sample positioned in

the path of an IR beam. The main goal of IR spectroscopic analysis is to

determine the chemical functional groups in the sample. Different functional

groups absorb characteristic frequencies of IR radiation. Using various

sampling accessories, IR spectrometers can accept a wide range of sample

types such as gases, liquids and solids. Thus, IR spectroscopy is an important

and popular tool for structural elucidation and compound identification. The

typical block diagram of IR spectrometer is shown in Fig.1.4.

30

The far IR requires the use of specialized optical materials and sources.

It is used for analysis of organic, inorganic and organometallic compounds

involving heavy atoms (mass number over 19). It provides useful information

in structural studies such as conformation and lattice dynamics of samples.

Near IR spectroscopy needs minimal or no sample preparation. It offers high

speed quantitative analysis without consumption or destruction of the sample.

IR instrumentation is often combined with UV-visible

spectrometer and coupled with fiber optic devices for remote analysis. Near IR

spectroscopy has gained increased interest, especially in process control

applications. Naturally, some vibrations can be both IR and Raman active. The

total number of observed absorption bands are generally different from the total

number of fundamental vibrations. The number is reduced because some

modes are not IR active and a single frequency can cause more than one mode

of motion to occur. Conversely, additional bands are generated by the

appearance of overtones(integral multiples of the fundamental absorption

frequencies), combinations of fundamental frequencies, differences of

fundamental frequencies, coupling interactions of two fundamental absorption

frequencies, and coupling interactions between fundamental vibrations and

overtones or combination bands (Fermi resonance). The intensities of overtone,

combination and difference bands are less than those of the fundamental bands.

The combination and blending of all the factors thus create a unique IR

spectrum for each compound. The far IR spectra were recorded using

polyethylene pellets in the 500-100 cm in the region on a Nicolet Magna 550

31

FTIR instrument at Regional Sophisticated Instrument Facility, Indian Institute

of Technology, Bombay.

Fig. 1.4 Block diagram of FT-IR

1.10.5 UV-VIS-NIR Spectrophotometer

Electronic spectroscopy is the measurement of the wavelength and intensity of

absorption near-ultraviolet and visible light by a sample. UV-Vis spectroscopy

is usually applied to organic molecules and inorganic ions or complexes. The

absorption of UV or visible radiation corresponds to the excitation of outer

electrons. There are three types of electronic transitions that can be considered

for coordination compounds. These are transitions involving a) π,σ and n

electrons of ligands b) Charge-transfer electrons and c) d- and f-

electrons.Possible transitions of π,σ and n electrons are shown in the Fig..1.5.

32

Most of the absorption spectroscopy of ligands is based on n π* and π π*

transitions. Many inorganic species show Ligand -to-Metal Charge Transfer

(LMCT) transitions and MetalLigand Charge Transfer (MLCT) transitions

(not as common as LMCT).

Transition probability in ligand field transitions (d-d transitions) is determined

by the spin selection rule and the orbital (Laporte) selection rule.

Fig.1.5 π, σ and n- electron transitions

Electronic spectra were recorded on JASCO V670, a sophisticated computer

controlled spectrophotometer with an accuracy of 0.2 nm in UV-VIS and 1

nm in NIR region. The spectral range of this instrument is 190-3200 nm. The

sources of radiation in UV-VIS and NIR regions are deuterium (D2) lamp and

33

Iodine-Tungsten lamp (W1) respectively. The general optical alignment of the

spectrophotometer is shown in Fig. 1.6

The light from the source (D2 or W1) after reflection by the concave

mirror M1 passes through the mechanical chopper CH. Light pulses from the

chopper pass through the slit S1 and are directed to the prism P by the toroidal

mirror M2 and the concave mirror M3. The dispersed beam is focused onto the

second mono-chromator S2 by the concave mirror M3 and the plane mirrors

M4 and M5.

The light after crossing the monochromator S2 is reflected by the

concave mirror M6 and finally falls on the gratings G1 and G2, which act as

monochromators. The monochromatic light is then reflected by the concave

mirror M6 and plane mirror M7 and finally it is incident on the rotating mirror

M8 and splits into two beams.

Out of these two, one passes through the sample after reflection from

the mirrors M9 and M10 and the other through the reference (pure Nujol mull

sample) in the sample compartment after being reflected by the mirror M11.

These two beams of light, after passing through the sample compartment are

directed on to the detectors by the plane mirrors M12 and M1 and the toroidal

mirrors M14, M15 and M16. The difference in the intensities of the light

transmitted through the sample (mull form in Nujol) and the reference Nujol

are measured using suitable detectors.

The optical absorbance which is the difference in the intensities of the

transmitted light through the sample and the reference is plotted against

34

wavelength of light on the screen. The total data is stored in the computer and

the data can be magnified and displayed on the monitor. The spectrum is

finally recorded on a chart paper with the help of the printer attached to the

system.

Fig. 1.6 Block diagram of a UV-VIS spectrophotometer

1.10.6 1H NMR

1HNMR spectra were recorded using Bruker AV400 NMR

Spectrometer using TMS as an internal standard at University of Hyderabad,

A.P, India. The Block Diagram of NMR Spectrum shown in Fig. 1.7, NMR

35

spectrum is a plot of the intensity of NMR Signals versus the magnetic

field(frequency) in reference to Tri Methyl Silane(TMS). The intensity is

measured by the integration of the area under the triangles as shown in Fig. 1.8.

Fig. 1.7 Block Diagram of NMR

Fig. 1.8 NMR Signals versus Magnetic field (frequency)

36

1.10.8 Biological studies

The biological activities or the therapeutical ability of any

compound depends on the minimum amount by which a chemical or a

substance required to inhibit the growth or to kill the microorganism that

causes the disease. It must have minimum cytotoxicity or a potential to act as a

toxin that may generate undesirable symptoms that are harmful to the health of

living organisms and hence decides its drug value. The synthesized ligands

and their complexes were tested for anti-microbial activity. Anti-microbial

activity is the ability of a compound to inhibit the growth of a given

microorganism. The antimicrobial agent may be either bacteriostatic or

bactericidal. The effectiveness of an antimicrobial agent in sensitivity testing is

based on the size of the zones of inhibition. When the test substances are

introduced on to a bacterial culture by well diffusion method, if the bacteria are

sensitive, there develops a zone of no growth around the well, which is referred

to as the zone of inhibition. The diameter of the zone is measured to the nearest

millimeter.

Test organisms

Five bacterial species were selected for testing the activities. They are

1. Bacillus subtilis

2.Bacillus cereus

3.Staphylococcus aureus

4. Staphylococcus epidermidis

5.Pseudomonas aureginosa

37

The well diffusion method was used for screening the antimicrobial property

of the test samples.

Principle

The test compound is allowed to diffuse out into the medium and interact with

the test organisms. The resulting zones of inhibition will be uniformly circular

as there will be a confluent lawn of growth. The diameter of zone of inhibition

can be measured in millimeters.

Method

The stock solutions were prepared by dissolving the compounds

(0.001M) in 10ml of DMSO. A well (50μg) is made in the agar medium

inoculated with microorganisms. The well was filled with the test solution

using a micropipette and the plate was incubated at 350C for 48hrs. During this

period, the test solution diffused and the growth of the inoculated

microorganisms was affected inhibitory activity.

This chapter deals with an extensive literature study related to

thiosemicarbazones and their metal complexes. Many authors have reported the

anti-cancer, anti-tumor, anti-fungal, anti-bacterial, anti-malarial, anti-filarial,

anti-viral and anti-HIV activities of these compounds. The complexes have

been tested against leprosy, psoriasis, rheumatism and smallpox. A number of

metal complexes of thiosemicarbazones have found applications as analytical

reagents. The nature of the aldehyde/ ketone from which a thiosemicarbazone

is obtained and the nature of the substituents at N4 influence the biological

activity of the complexes. Based on preparative conditions and availability of

38

additional bonding sites on the ligand, complexes of thiosemicarbazones

assume various stereo chemical forms. The analytical methods utilized for

characterization of the complexes include elemental analysis, conductivity

measurements, magnetic susceptibility measurements and various spectral

studies.

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