Synthetic Communications

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Novel thiosemicarbazone derivatives and their

metal complexes: Recent development

Neelam P. Prajapati & Hitesh D. Patel

To cite this article: Neelam P. Prajapati & Hitesh D. Patel (2019): Novel thiosemicarbazone
derivatives and their metal complexes: Recent development, Synthetic Communications, DOI:
10.1080/00397911.2019.1649432

To link to this article: https://doi.org/10.1080/00397911.2019.1649432

Published online: 08 Aug 2019.

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https://doi.org/10.1080/00397911.2019.1649432

SYNTHETIC COMMUNICATIONS REVIEWS

Novel thiosemicarbazone derivatives and their metal

complexes: Recent development
Neelam P. Prajapati and Hitesh D. Patel
1
Department of Chemistry, School of Sciences, Gujarat University, Ahmedabad, India

ABSTRACT ARTICLE HISTORY

Thiosemicarbazones (TSCs) have turned out as an important class of Received 16 January 2019
N, S-donor ligands over a span of time due to their variable donor
properties, structural diversity and biological applications. This review KEYWORDS
gives a detailed account in words of synthesis and applications of Biological activity; DNA
degradation; metal
thiosemicarbazones and their metal coordinates reported recently. complexes;
All the derivatives of thiosemicarbazones and their metal chelates thiosemicarbazones
have been descripted, which were explored by researchers in last
5 years. The coordination compounds were disclosed with respect to
their bonding with metal ions and geometry. Further, the biological
and analytical applications of newly reported TSCs and their metal
chelates are conveyed comprehensively to point out the importance
of ligands and complexes under consideration.

GRAPHICAL ABSTRACT

-Complexes

Introduction
Over several decades, thiosemicarbazone derivatives, having general formulae
R1R2C¼N–NH–C(¼S)–NR3R4, are a critical category of organic compounds owing to
their diverse synthesis and biological, medicinal and pharmaceutical applications.[1–5]
They have presented a wide spectrum of properties against a range of diseases- antibac-
terial, antifungal,[6] antidiabetic,[7] antitumor,[8a,b] antiproliferative,[9] anticancer,[10] her-
bicidal,[11] anticorrosion and antiinflammatory[7] activities.
Thiosemicarbazone derivatives are versatile ligands as they confer better coordin-
ation tendency, better selectivity, and stability towards a wide variety of metal ions.

CONTACT Hitesh D. Patel drhiteshpatel1@gmail.com Department of Chemistry, School of Sciences, Gujarat

University, Navrangpura, Ahmedabad 380009, India.
Color versions of one or more of the figures in the article can be found online at www.tandfonline.com/lsyc.
ß 2019 Taylor & Francis Group, LLC
2 N. P. PRAJAPATI AND H. D. PATEL

They can coordinate as neutral (keto form) molecules or after deprotonation as

anionic (enol form) ligands and can adopt a variety of different coordination modes
with various metal ions. The chelating capacity of thiosemicarbazone moiety can be
increased by inserting some donor atom containing motif to render the ligand poly-
dentate.[12] Additionally, heterocyclic thiosemicarbazones have aroused considerable
interest in chemistry and biological activity owing to their ability to diffuse through
the semipermeable membrane of the cell lines.[13] They show biological
activities including anti-tubercular,[14a–c] antibacterial,[15a–d] antimalarial,[16] anti-lep-
rosy,[17] anti-parasitic,[18] antineoplastic,[19a–c] antiviral,[20] antiproliferative,[21a,b] anti-
oxidant,[22a,b] and antitumor[1,23a–c] activities. Surprisingly, the coordination of
thiosemicarbazones to metal ions have been found beneficial in the way to enhance
their activity or notably decrease the side effects of the ligands.[24] Studies on thio-
carbamide complexes help researchers to understand the metal-protein binding in
the organism.[25]
Until now, much has been published about developments in metal-thiosemicarbazone
chemistry and may be of considerable usefulness.[26] This review article sheds light on
the comprehensive account of synthetic aspects, characterization, structural coordin-
ation, biological and analytical applications of thiosemicarbazones and their metal com-
plexes in the last 5 years. Our main focus is on the synthetic aspects of various
thiosemicarbazone derivatives with varied organic motifs reported in the past few years
so the sections are arranged based on the organic motifs.

Synthesis and applications of thiosemicarbazone (TSC) ligands and their

metal complexes
Thiosemicarbazones are known to coordinate with various metal ions to form coordin-
ation compounds in different modes. It can be involved in complex formation as both
neutral molecule and deprotonated form. The presence of both neutral and deproto-
nated thiosemicarbazide species in a single complex is also possible. Most of the thiose-
micarbazone derivatives were synthesized using substituted hydrazine hydrate and
abundant isothiocyanates precursors. Whereas some are modified by inserting suitable
aldehyde, ketone or acid chloride possessing a further donor atom to render the ligand
polydentate to increase the chelating property. The synthetic procedures are almost the
same in both routes. Most of the ligands and their metal complexes have been synthe-
sized in refluxing methanol or ethanol for the required time. Due to these reasons, this
review is attentive more towards the application of novel ligand as well as metal com-
plexes found in recent literature.

TSCs and its metal complexes synthesized from substituted hydrazine hydrate
and isothiocyanates
Metal complexes of Hg(II), Cd(II) and Zn(II) metal ions with N1-ethyl-N2-(pyridine-2-
yl) hydrazine-1,2-bis(carbothioamide) ligand (H2PET, 1) have been prepared and identi-
fied using physicochemical measurements by El-Gammal and colleagues (Scheme 1).
The ligand behaves as monobasic tridentate in Hg(II) 2 and Cd(II) 3 metal chelates
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Scheme 1. Synthesis of metal-complexes of N1-ethyl-N2-(pyridine-2-yl) hydrazine-1,2-bis(carbothioa-

mide) ligand (H2PET, 1).

whereas binuclear in Zn(II) 4 complex, ligand behaves as two types, where H2PET act
as dibasic tetradentate towards two Zn atoms and also acts as monobasic tridentate
towards the same Zn atoms. Authors have also tested antioxidant, anti-hemolytic and
cytotoxic activities of the prepared metal complexes and its free ligand. In DPPH free
radical scavenging activity, the ligand H2PET, Zn(II) 4 and Hg(II) 2 complexes found
better as compared to Cd(II) 3 complex. H2PET 1 and Zn(II) complex 4 showed high
antioxidant activity as compared to ascorbic acid using ABTS inhibition, as well as,
showed the highest cytotoxic activity. The antioxidant activity for erythrocyte hemolysis
of the compounds under investigation decreases in the order: Cd(II) complex 3 > Zn(II)
complex 4 > H2PET 1 > Hg(II) complex 2.[27]
Mohamed and coauthors have prepared and characterized mixed ligand transition
metal complexes of Cu(II), Co(II), Ni(II) and Mn(II) with N-ethyl-2-picolinoylhydrazi-
necarbothioamide (EPHC, 5) and 1,10-phenanthroline (1,10-phen) ligands (Scheme 2).
The elemental, spectral and magnetic moment measurements exposed the octahedral
structure of all the metal coordinates. Antibacterial and antifungal activities of ligand 5
and its metal complexes were explained by authors. The organisms used in the investi-
gation included two gram-positive Escherichia coli and Psudomonas aeuroginosa and
two gram-negative Staphylococcus aureus and Bacillus subtillis bacterial strains, whereas
Aspergillus flavus, Penicillium italicum, and Geotrichum candidum as three fungal
strains. Compound 5 has shown good antibacterial as well as antifungal activity as com-
pared to standard drugs Gentamicin and Ampicillin and Amphotericin respectively.
Among the metal complexes of compound 5, complex with Cu metal ion 6 has been
found more potent as compared to the Co(II) 7, Ni(II) 8 and Mn(II) 9 metal complexes
of ligand compound 5.[28]
9,10-Dihydro-9,10-ethanoanthracene-11,12-dicarbonyl)bis(N-ethylhydrazine-1-carbothio-
amide) (H6ETS, 10) and its metal complexes with Cu(II) 11, Ni(II) 12 and Co(II) 13 have
4 N. P. PRAJAPATI AND H. D. PATEL

Scheme 2. Synthesis of metal complexes of N-ethyl-2-picolinoylhydrazinecarbothioamide (EPHC, 5).

Scheme 3. Synthesis of metal complexes of 9,10-Dihydro-9,10-ethanoanthracene-11,12-

dicarbonyl)bis(N-ethylhydrazine-1-carbothio-amide) (H6ETS, 10).

been prepared and described using spectral, thermal, kinetic and EPR analysis by El-
Gammal and coauthors (Scheme 3). According to spectral data the ligand acts as a bi- or
mono-negative multi-dentate in chelation, which evidenced the square-planar geometry of
Ni(II) and Cu(II) complexes while tetrahedral of Co(II) complexes. All the complexes, as
well as ligand H6ETS 10, were found to be much better free radical scavenger as compar-
able to that of standard L-ascorbic acid. Cu(II) complex 11 has significant antibacterial
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Scheme 4. Synthesis of metal complexes of 4-allyl-1-(2-hydroxybenzoyl) thiosemicarbazide (L1, 14).

activity against the four bacterial organisms as compared to the standard drug as well as
other remaining metal chelates.[29]
4-allyl-1-(2-hydroxybenzoyl) thiosemicarbazide (L1, 14) and its Co(II), Cu(II) and
Zn(II) metal chelates with and without 2,20 -dipyridyl have been derived and structurally
characterized by Mlahi and team (Scheme 4). The characterization results suggested that
the ligand molecule coordinates as ONS-tridentate fashion with a metal ion. The geom-
etry of all the metal chelates was confirmed using the DFT method from DMOL3.[30]
Synthesis and structural characterization of novel ligand N-ethyl-2-isonicotinoylhydra-
zinecarbothioamide (HEITSC, 21) and its metal complexes with Cu(II) 22, Ni(II) 23
and Co(II) 24 have been reported by Orif and coworkers (Scheme 5). Based on the
characterization, authors have found that metal complexes have octahedral geometry
except for Cu(II) complex which has square planar geometry. The experimental data of
the metal complexes compared with the DFT calculated spectral data in good agree-
ment. The antimicrobial activity results have exposed that none of the compound exhib-
ited satisfactory inhibition except Co(II) complex 24 which exhibited MIC equal to that
of Ampicillin against B. subtilis and S. aureus. Moreover, only Ni(II) complex 23 was
found powerful effect to degrade the Calf Thymus DNA.[31]
6 N. P. PRAJAPATI AND H. D. PATEL

Scheme 5. Synthesis of metal complexes of N-ethyl-2-isonicotinoylhydrazinecarbothio-amide

(HEITSC, 21).

Azhari et al. have prepared binary and ternary complexes of 4-ethyl-1-(2-hydroxyben-

zoyl) thiosemicarbazide (L1, 25) with MCl2 where, M ¼ Co(II), Co(II) and Zn(II), and
Zn(Ac)2 using 2,20 -dipyridyl (L2) as co-ligand (Scheme 6). All the metal coordinates and
parent ligand were identified using the spectral, magnetic moment and thermal analysis.
Moreover, the DFT method from DMOL3 has evaluated the bond lengths, bond angles,
chemical reactivates, energy components, binding energies and dipole moments for the
prepared complexes. A genotoxicity study on the Calf Thymus DNA has applied on the
ligands derived from ethyl, allyl and phenyl substituted 2-hydroxybenzoyl TSC and it
can conclude that the ethyl group is more effective as this group is an electron-donating
group. Hence, this group increases its effect on the interaction with both the metal salts
and Calf Thymus DNA. The results revealed that binary complex of Cu having formu-
lae [Cu(L1-H)2]  EtOH 28 was most effective than the other ligands and their metal
complexes for calf thymus DNA. In the case of the phenyl and allyl group, the effect is
small on DNA than the ethyl group.[32]
Yousef et al. have prepared Mn(II) complexes of the ligands (Z)-N-benzoyl-N0 -(2-
oxo-2-(phenylamino) acetyl)carbamohydrazonothioic acid H2PABT 32 and 1-(2-oxo-2-
(phenylamino)acetyl)-4-phenylthio-semicarbazide H2PAPT 33, which were previously
synthesized from 2-hydrazino-2-oxo-N-phenylacetamide, benzoyl isothiocyanates and
phenyl isothiocyanate in refluxing ethanol respectively (Scheme 7). The physicochemical
and spectroscopic study assigned the formulas of complexes [Mn(HPABT)Cl(H2O)2] 34
and [Mn(HPAPT)Cl] 35 respectively. Moreover, the study of HOMO-LUMO, bond
length, bond angles, and dipole moment calculations display the high stability of com-
plexes. These newly prepared ligands and their metal complexes have been evaluated for
their antibacterial activity against B. subtilis and E. coli, as well as antitumor activity
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Scheme 6. Synthesis of metal complexes of 4-ethyl-1-(2-hydroxybenzoyl) thiosemicarbazide (L1, 25).

against liver (HePG2) and breast (MCF-7) cancer cells. The results revealed that the
ligands and their metal complexes exhibited moderate activity against both bacterial
strains as compared to Ampicillin whereas complexation with metal ion has no enhanc-
ing effect on the cytotoxicity.[33]
Metal coordinates of Zn(II), Mn(II) and Ni(II) having general formula
[M(ppts)2].CHCl3/THF, with 1-picolinoyl-4-phenyl-3- thiosemicarbazide (Hppts, 36) lig-
and have been invented by Bharti and coworkers (Scheme 8). All the compounds were
characterized by spectral, magnetic, thermal, electrochemical and crystallographic ana-
lysis. Zn(II) 37 and Mn(II) 39 complexes were found to be fluorescent despite its ligand
Hppts was non-fluorescent. This could be due to the fluorescence properties enhanced
8 N. P. PRAJAPATI AND H. D. PATEL

Scheme 7. Synthesis of metal complexes of (Z)-N-benzoyl-N’-(2-oxo-2-(phenylamino) acetyl)carbamo-

hydrazonothioic acid H2PABT 32 and 1-(2-oxo-2-(phenylamino)acetyl)-4-phenylthio-semicarbazide
(H2PAPT 33).

Scheme 8. Synthesis of metal complexes of 1-picolinoyl-4-phenyl-3-thiosemicarbazide (Hppts, 36).

by the formation of four or five-membered rings around the metal ions during
chelation.[34]

TSCs modified using various aldehyde derivatives and their metal complexes
The novel metal complexes of Ni(II) 41, Cu(II) 42 and VO(IV) 43 having the general
formulae [M(N2O2)] where N2O2 is S-ethyl-N1-(2-hydroxyacetophenone)-N4-(salicyli-
dene) isothiosemicarbazide, have been prepared by Ahmadi and coworkers. The N2O2
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Scheme 9. Synthesis of metal complexes of S-ethyl-N1-(2-hydroxyacetophenone)-N4-(salicylidene) iso-

thiosemicarbazide (H2L, 40).

has been prepared from Schiff base 2-hydroxyacetophenone S-ethylisothiosemicarbazone

hydroiodide and salicyalaldehyde (H2L, 40) (Scheme 9). All the metal complexes along
with free ligand have been identified using elemental, spectral, molar conductance, ther-
mal and X-ray diffraction analysis. The geometry of Ni(II) 41 and Cu(II) 42 complexes
found to be distorted square planner whereas VO(IV) 43 complex possess distorted
square pyramidal geometry observed from the characterization. The thermal decompos-
ition of the complex resulted in pure metal oxides NiO, CuO, and V2O5 as residue hav-
ing a particle size in nm, determined by XRD analysis.[35]
3-Hydroxysalicylaldehyde-S-methylthiosemicarbazone and its Ni(II), Fe(III), and VO(IV)
complexes have been prepared and characterized using elemental, electronic and spectral
techniques by Bal-Demirci and coauthors (Scheme 10). All the metal coordinates and its
parent ligand have tested for their in-vitro antioxidant, as well as radical scavenging activity
of reactive oxygen species (ROS). The ligand and its Fe(III) complex 48 exhibited better anti-
oxidant activity than the other complexes whereas, V(IV) and Fe(III) complexes showed
10 N. P. PRAJAPATI AND H. D. PATEL

Scheme 10. Synthesis of metal complexes of 3-hydroxysalicylaldehyde-S-methylthiosemicarbazone.

Scheme 11. Synthesis of metal complexes of sodium 3-f[(aminocarbonothioyl)hydrazono]-methylg-4-

hydroxybenzenesulfonate (NaH2L, 50).

high ROS scavenging property as compared to the ligand and trolox which was used as a
reference.[36]
A novel sulfonato-substituted Schiff base ligand namely sodium 3-f[(amino-
carbonothioyl)hydrazono]methylg-4-hydroxybenzenesulfonate (NaH2L, 50) and its
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Scheme 12. Synthesis of metal complexes of pyridoxal thiosemicarbazone (PLTSC, 54).

Cu(II) 51, Zn(II) 52 and Ni(II) 53 metal complexes have been introduced by Hosseini-
Yazdi and colleagues (Scheme 11). Both the Schiff base ligand and its metal complexes
except Zn-complex, are found to be water-soluble. Metal-complexes were well character-
ized by physicochemical and spectral studies. X-ray crystallography study of Cu(II)
complex has shown that it has distorted square pyramidal geometry. The Schiff base lig-
and 50 have noted highest radical scavenging property for DPPH radicals as compared
to its Cu(II) 51 and Ni(II) 53 complexes as well as the L-ascorbic acid used as a stand-
ard. Moreover, authors have observed that the Cu(II) 51 complex decreased the viability
of K562 cells of human chronic myeloid leukemia.[37]
Ivkovic et al. have prepared pyridoxal thiosemicarbazone (PLTSC, 54) ligand and its
first octahedral Fe complex having the formula [Fe(PLTSC)Cl2(H2O)]Cl 55 and charac-
terized by single-crystal X-ray analysis (Scheme 12). This PLTSC cation from
PLTSC.HCl.H2O as a different planar conformation compared to the other five previ-
ously reported compounds of this type. The structural property of metal coordinate
revealed that the ligand was coordinated in its zwitterionic form in ONS-triden-
tate manner.[38]
Further, authors have also introduced the first Cu(II) complex having the formula
[Cu(PLITSC-H)H2O]Br.H2O 57 with a monoanionic form of the pyridoxal S-methyliso-
thiosemicarbazone (PLITSC, 56) ligand (Scheme 13). Authors have also characterized
newly synthesized metal complex with two previously prepared complexes
[Cu(PLITSC)Br2] and [Cu(PLITSC)Br(MeOH)]Br which concluded the square planner
geometry of [Cu(PLITSC-H)H2O]Br.H2O.[39]
Seminal contribution has been made by Mitesh et al. by introducing a series of metal
complexes of Cu(II) 59, Co(II) 60, Ni(II) 61 and Zn(II) 62 3-chlorovanillin thiosemicar-
bazone (3-CVTSC, 58) ligand synthesized using 3-chloro-4-hydroxy-5-
12 N. P. PRAJAPATI AND H. D. PATEL

Scheme 13. Synthesis of metal complexes of S-methylisothiosemicarbazone (PLITSC, 56).

Scheme 14. Synthesis of metal complexes of 3-chlorovanillin thiosemicarbazone (3-CVTSC, 58).

methoxybenzaldehyde and thiosemicarbazide in absolute ethanol in the catalytic amount

of glacial acetic acid (Scheme 14). All the metal complexes have been characterized by
spectroscopic, elemental, and thermal analysis which demonstrated the binding of the
ligand to the metal ion in square planner geometry. Additionally, 3-CVTSC and its
metal complexes evaluated for their antimicrobial activity. The bioassay results have
shown that Ni(II) 61 and Zn(II) 62 complexes found more potent against tested bacter-
ial strains and Co(II) 60 and Zn(II) 62 complexes found more potent against fungal
strains as compared to the ligand.[40]
The metal complex of Ni(II) having general formula NiL2 64, with 4-phenyl-1-(3-
phenylallylidene)thiosemicarbazide (HL, 63) have been disclosed by Song and coworkers
(Scheme 15). The ligand and metal chelate have been characterized by DFT calculation,
NPA analysis, electronic spectra, and thermal analysis. Additionally, X-ray single crystal
diffraction of both ligand and its Ni(II) complex 64 have also been carried out. In
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Scheme 15. Synthesis of metal complexes of 4-phenyl-1-(3-phenylallylidene)thiosemi-carbazide

(HL, 63).

Scheme 16. Synthesis of metal complexes of 4-formylpyridine-N4-(2-pyridyl)thiosemi-carbazone

(HFPTS, 65).

NiCl2 metal complex, two deprotonated ligand molecule coordinates with Niþ2 metal
ion and adopts a distorted square planner configuration.[25]
A series of metal complexes of Cd(II) 66, Co(II) 67, Cu(II) 68, Hg(II) 69, Fe(III) 70,
Mn(II) 71, Ni(II) 73 and UO2(II) 73 metal ions with 4-formylpyridine-N4-(2-pyridyl)thiose-
micarbazone (HFPTS, 65) ligand have been proposed by El Metwally and colleagues
(Scheme 16). All the metal chelates were structurally identified by elemental, spectral, mag-
netic and thermal analysis. In most of the complexes, ligand exhibit neutral bidentate coord-
ination mode and tetrahedral geometry whereas mononegative bidentate and neutral
tridentate in UO2(II) 73 and Cu(II) 68 complexes respectively. In-vitro antimicrobial study
results exposed Hg(II) 69 and UO2(II) 73 complex as most effective towards all screened
microorganisms.[41]
14 N. P. PRAJAPATI AND H. D. PATEL

Scheme 17. Synthesis of metal complexes of 3-methyl-(S/R)-pyrrolidine-2-carboxylate-2-formylpyridine

thiosemicarbazone (L/D-Pro-FTSC or (S/R)-H2L1, 74, 75) and 3-methyl-(S)-pyrrolidine-2-carboxylate-2-for-
mylpyridine-4,4-dimethyl-thiosemicarbazone (dm-L-Pro-FTSC or (S)-H2L2, 76).

Some proline-thiosemicarbazone hybrids 3-methyl-(S)-pyrrolidine-2-carboxylate-2-

formylpyridine thiosemicarbazone (L-Pro-FTSC or (S)-H2L1, 74) and 3-methyl-(R)-pyr-
rolidine-2-carboxylate-2-formylpyridine thiosemicarbazone (D-ProFTSC or (R)-H2L1,
75), as well as 3-methyl-(S)-pyrrolidine-2-carboxylate-2-formylpyridine-4,4-dimethyl-thi-
osemicarbazone (dm-L-Pro-FTSC or (S)-H2L2, 76) and its metal complexes with Ni(II),
Cu(II), and Zn(II) were isolated and characterized by physicochemical analysis have
been evaluated by Bacher et al. (Scheme 17). In-vitro antiproliferative activity has also
been studied and the results concluded that introduction of more lipophilic substitute
into proline-thiosemicarbazone hybrids increases cytotoxicity and hR2 RNR
inhibition.[42]
Ibrahim et al. have introduced a new thiosemicarbazone ligand LH2 84 synthesizes
via condensation reaction of indole-7-carbaldehyde and thiosemicarbazide. Metal com-
plexes of Zn(II), Cd(II), Pd(II) and Pt(II) with LH2 have also been prepared and charac-
terized by spectral and crystal structure studies (Scheme 18). In this study, ligands
coordinate with metal ions mainly as S-monodentate and NNS-tridentate manner.
Authors have explored that the Pt(II) 85 complex was having significant cytotoxicity
against DA-MB-231, MCF-7, HT-29, and HCT-116 cancer cell lines except for the nor-
mal liver WRL-68 cell line. Further, apoptosis study of Pt(II) complex was explored
using different apoptotic assay methods.[43]
Two water-soluble thiosemicaebazone proline hybrid ligands namely L-proline- and
homoproline-4-N-pyrrolidine-3-thiosemicarbazone (HL1 92 and HL2 93) and their
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Scheme 18. Synthesis of metal complexes of indole-7-carbaldehyde thiosemicarbazone (LH2 84).

metal complexes with Ni(II), Pd(II) and Cu(II) have been invented by Dobrova and col-
leagues through the multi-step procedure (Scheme 19). These ligands and their metal
complexes were screened for in-vitro antiproliferative activity for three human cancer
cell lines A549, CH1 and SW480 in which Cu(II) complex 96 of ligand HL1 found to
be most potent against all three cell lines.[44]
The coordination liability of a series of Schiff base ligands (L1 98, L2 99) prepared by
condensation between o-substituted thiosemicarbazides and 8-formyl-7-hydroxy-4-meth-
ylcoumarin towards Co(II), Ni(II), and Cu(II) transition metal ions has been examined
by Maddireddy et al. (Scheme 20). The synthesized metal complexes were characterized
by spectral, analytical, magnetic and thermal analysis, which confirms the octahedral
geometry of complexes. All the ligand molecules, as well as their metal complexes, have
tested for antibacterial and antifungal activities. Additionally, DNA cleavage study
resulted that the Cu complexes 102 and 105 have shown cleavage of DNA. Some of the
synthesized compounds 101, 103 and 105 have also exhibited good cytotoxic activity on
brine shrimp whereas Schiff base metal complexes found more potent towards a higher
anthelmintic activity as compared to their corresponding Schiff bases.[45]
Metal complexes of pyridoxal thiosemicaebazones (PLTSC, 106) ligand with Cr(III)
metal ion was introduced by Vojinovic-Je
sic and colleagues. The reaction of ligand
(PLTSC) with Cr(NO3)3 and K3[Cr(NCS)6] in 1:1 and 1:2 mole ratio in refluxing etha-
nol produced [Cr(PLTSC)(NCS)3].2H2O 108 and [Cr(PLTSC)(PLTSC-H)(NO3)2].2H2O
107 metal complexes (Scheme 21). [Cr(PLTSC)2](NO3)2 has produced as by-product
16 N. P. PRAJAPATI AND H. D. PATEL

Scheme 19. Synthesis of metal complexes of L-proline- and homoproline-4-N-pyrrolidine-3-thiosemi-

carbazone (HL1 92 and HL2 93).

from the leftover liquor of the reaction mixture after filtration of [Cr(PLTSC)(PLTSC-
H)(NO3)2].2H2O. This has occurred due to the pyridoxalic part, which is zwitterion,
thus X-ray analysis was used to characterize neutral (thion) and protonated (thiol)
forms. All the complexes were well characterized by spectral, electrochemical and ther-
mal analysis to confirm mer-octahedral structure.[46]
Metal complexes having general composition [M(H3L)(CH3COO)2H2O].nH2O of, Zn(II)
110, Ni(II) 111, Cu(II) 112, Cd(II) 113, Mn(II) 114, Co(II) 115 and Vo(II) 116 and 2-
((4,9-dimethoxy-5-oxo-5H-furo[3,2-g]chromen-6-yl)methylene)hydrazinecarbothioamide
(H3L, 109) have been synthesized and identified using various spectroscopic and analytical
methods by Shakdofa and team (Scheme 22). Structural characterization has suggested the
octahedral or distorted octahedral geometry of isolated metal chelates. Authors have
screened the metal complexes as well as its ligand for anti-proliferative activity against
breast cancer (MCF-7), liver cancer (HepG2) and lung cancer (A549) tumor cell lines using
SRB fluorometric assay and cis-platin as a positive control. The results of treatment of pre-
pared complexes on HepG2 cells cytotoxicity measured with SRB assay method depicted as
H3L 109 > Zn 110 > Ni 111 > Cu 112 > VO 116 > Co 115 > Mn 114 > Cd 113. The
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Scheme 20. Synthesis of metal complexes of (E)-2-((7-hydroxy-4-methyl-2-oxo-2H-chromen-8-

yl)methylene)-N-(2-substitutedphenyl)hydrazinecarbothioamide (L1 98, L2 99).

results concluded that the metal complexes have noteworthy antitumor activity analogous
to the activity of antitumor drug cis-platin.[47]
A series of transition metal complexes of Co(II) 118, Ni(II) 119, Zn(II) 120, Cd(II) 121,
Hg(II) 122, Cu(II) 123 and Fe(III) 124 metal ions with 3-methyl butanalthiosemicarbazone
(MBTSC, 117) ligand derived from the condensation reaction of 3-methylbutaraldehyde
with thiosemicarbazide have been invented and characterized by Venkatesh and coworkers
(Scheme 23) All the metal complexes confirmed octahedral geometry based on data analysis.
In-vitro antibacterial study of ligand and its metal complexes has shown that all the com-
pound except Cu complex 123, showed moderate inhibition against some bacterial strain as
compared to standard Ciprofloxacin. Cu Complex 123 exhibited more potency towards all
the tested bacterial strains as compared to the remaining metal chelates.[48]
Some Schiff base ligand 2,6-pyridinedicarboxaldehydethiosemicarbazone (PDCTC,
125) metal-complexes of Cu(II) 126, Co(II) 127, Ni(II) 128, and Cr(III) 129 have been
synthesized by Ahmed et al. using conventional as well as microwave methods
(Scheme 24). Microwave-assisted synthesis was proved more efficient in terms of reac-
tion time and availability of the product with better yield as compared to conventional
synthesis. All the synthesized compounds were identified by physicochemical, spectral
and magnetic analysis. Moreover, all the complexes were found semiconductors as per
electrical conductivity data. Schiff base ligand and their complexes were also evaluated
for their antimicrobial activity on selected bacteria E. coli and S. aureus and two fungi
Aspergillus niger and Candida albicans. Metal complexes were found more potent as
compared to the parent ligand molecule due to chelation which makes the ligand act as
more powerful and potent bactericidal agent.[49]
18 N. P. PRAJAPATI AND H. D. PATEL

Scheme 21. Synthesis of metal complexes of pyridoxal thiosemicaebazones (PLTSC, 106).

TSCs modified using various ketone derivatives and their metal complexes
A series of mononuclear and binuclear metal complexes of Cr(III), Mn(II), Co(II), Ni(II),
Cu(II), Zn(II), and Cd(II) metal ion with 2,4-dihydrazino-thioamido-1-ethoxybutane (HL,
130) have been explained by El-Tabl and coauthors (Scheme 25). The metal chelates have
been identified as having octahedral and tetrahedral geometry on the basis of
the elemental, spectral, physicochemical and thermal analysis. The antitumor activity
of the free ligand and its metal complexes [(H2L)Cu(OAc)2].2H2O 153,
[(H2L)(Cu)2(OAc)4(H2O)4].H2O 152, [(H2L)(Cu)Cl2].2H2O 151, [(H2L)(Zn)(SO4)
(H2O)].2H2O 146, [(H2L)(Zn)2(SO4)2(H2O)2].2H2O 145 and [(H2L)(Cu)(Zn)(SO4)2
(H2O)6].H2O 140 were evaluated against liver carcinoma HEPG-2 cell line and complexes
[(H2L)Cu(OAc)2].2H2O 153, [(H2L)(Cu)2(OAc)4(H2O)4].H2O 152, [(H2L)(Cu)Cl2].2H2O
151 and [(H2L)(Zn)(SO4)(H2O)].2H2O146 against breast carcinoma MCF-7 cell line where
compound [(H2L)(Zn)(SO4)(H2O)].2H2O 146 and [(H2L)(Cu)Cl2].2H2O 151 have exhibited
excellent activity against HEPG-2 and MCF-7, respectively.[50]
Coordination of Fe(III), Co(II), Ni(II), Cu(II), Zn(II), Cd(II), Hg(II), Pd(II) and
Pt(II) with 2,5-hexanedione-bis(thiosemicarbazone) (HBTS, 155) ligand and its struc-
tural identification using elemental, spectral, magnetic and thermal studies has been
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Scheme 22. Synthesis of metal complexes of 2-((4,9-dimethoxy-5-oxo-5H-furo[3,2-g]chromen-6-yl)

methylene)hydrazinecarbothioamide (H3L, 109).

Scheme 23. Synthesis of metal complexes of 3-methyl butanalthiosemicarbazone (MBTSC, 117).

reported by Jeragh and colleagues (Scheme 26). All the measurement techniques sug-
gested that the ligand binds as N2S2-tetradentate or NS-bidentate manner. It was also
observed that the ligand formed enol-complexes with Cu(II) 161 and Hg(II) 156 metal
ions and keto-form with the rest of the metal ions. Moreover, single-crystal X-ray data
of [Pd(HBTS)]Cl2 158 exposed the cis-form of distorted square planner geometry.[51]
Netalkar et al. have prepared moisture stable metal complexes of transition
metals Co(III) 165, Cu(II) 166, Zn(II) 167 and Ni(II) 168 metal ions with the ligand
(E)-4-(4-chlorophenyl)-1-(1-hydroxypropan-2-ylidene)thiosemicarbazide (LH, 164) and
successfully identified as well (Scheme 27). Single crystal X-ray study of ligand and
20 N. P. PRAJAPATI AND H. D. PATEL

Scheme 24. Synthesis of metal complexes of 2,6-pyridinedicarboxaldehydethiosemi-carbazone

(PDCTC, 125).

Scheme 25. Syntesis of metal complexes of 2,4-dihydrazino-thioamido-1-ethoxybutane (HL, 130).

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Scheme 26. Synthesis of metal complexes of 2,5-hexanedione-bis(thiosemicarbazone) (HBTS, 155).

Scheme 27. Synthesis of metal complexes of (E)-4-(4-chlorophenyl)-1-(1-hydroxypropan-2-ylidene)thio-

semicarbazide (LH, 164).
22 N. P. PRAJAPATI AND H. D. PATEL

Scheme 28. Synthesis of metal complexes of (E)-1-(1-hydroxypropan-2-ylidene)thiosemicarbazide

(LH, 169).

complexes of Co(III) 165 and Ni(II) 168 were evaluated by authors. Additionally, DNA
binding and cleavage study has been carried out with Calf Thymus DNA and E. coli
DNA. The results have shown that ligand and Zn(II) 167 complex bind through partial
interaction and remaining compounds bind electrostatically while Co(III) 165, Ni(II)
168, and Zn(II) 167 complexes have high binding and cleavage potential towards E.
coli DNA.[52]
A series of transition metal complexes of Co(III) 170, Ni(II) 171, Zn(II) 172 and
Cu(II) 173 with a new analog (E)-1-(1-hydroxypropan-2-ylidene)thiosemicarbazide
(LH, 169) have been searched and successfully characterized by Netalkar and coau-
thors (Scheme 28). The single crystal X-ray diffraction has done of ligand LH 169,
Ni(II) 171 and Cu(II) 173 complexes. Ligand and their all metal complexes were
screened for their in-vitro antimicrobial study. Bioassay results has shown that
Co(II) 170 and Cu(II) 173 complexes has exhibited best activity against gram posi-
tive bacterial strain S. aureus and Enterococcus faecalis compared to standard
Ciprofloxacin. Whereas, only Cu(II) 173 complex has exhibited good activity against
gram-negative bacterial strain E. coli and Pseudomonas aeruginosa. Co(III) 170 and
Zn(II) 172 complexes exhibit excellent activity against C. albicans and A. niger as
compared to the standard Fluconazole.[53]
Schiff base (E)-2-(1-(4-hydroxyphenyl)ethylidene)-N-(pyridin-2-yl)hydrazinecarbo-
thioamide (H2PHAT, 174) and its metal complexes of Mn(II) 175, Cd(II) 176, Ni(II)
177, Hg(II) 178, Co(II) 179, Cu(II) 180 and UO2(IV) 181 metal ions have been synthe-
sized and structurally identified by physicochemical, elemental and thermal analysis by
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Scheme 29. Synthesis of metal complexes of (E)-2-(1-(4-hydroxyphenyl)ethylidene)-N-(pyridin-2-yl)

hydrazinecarbothioamide (H2PHAT, 174).

Yousef and team (Scheme 29). H2PAT behaves as NS-bidentate or NSN-tridentate lig-
and with metal ion which proposed square planner geometry is the most fitted one for
the metal complex motif. The bond length, bond angle, HOMO, LUMO and dipole
moment had been calculated from modeling studies to confirm the geometry of the
metal chelates. Authors have concluded that none of the compounds proved significant
against gram-positive and gram-negative bacteria while Cd(II) 176, UO2(IV) 181, Ni(II)
177 and Mn(II) 175 complexes found powerful and complete degradation effect on
DNA isolated of Calf Thymus.[54]
Bedier and colleagues have invented a new ligand (E)-2-((E)-2-(hydroxyimino)-1,2-
diphenylethylidene)-N-(pyridine-2-yl) hydrazinecarbothioamide (H2DPPT, 182) and its
metal complexes with Fe(III) 183, Zn(II) 184, Hg(II) 185 and Ni(II) 186 metal ions
(Scheme 30). All the newly prepared compounds were characterized by various physico-
chemical techniques. The ligand and its metal complexes were screened for their anti-
bacterial activity against S. aureus and Bacillus thuringiensis as gram-positive and P.
aeruginosa and E. coli as gram-negative bacterial strains. The results disclosed that the
metal complexes of Fe(III) 183 and Zn(II) 184 possess excellent bioassay towards S.
aureus and B. thuringiensis compared to the standard drug Gentamycin. Neither of the
ligand nor metal complexes exhibited significant effect towards gram-negative bacteria.
Moreover, Ni(II) 186 complex found out powerful effect on DNA degradation.[55]
A series of novel homotrinuclear complexes of Ni(II), Cu(II), and Co(II) having gen-
eral formula [M3(LH)2], with two vicinal dioxime ligands 3-acetyl- or 4-acetylpyridine
thiosemicarbazone (L1H2 187 and L2H2 188) have been prepared with M:L ratio of 3:2
by Babahan and colleagues (Scheme 31). Authors have also prepared BF2þ bridge con-
taining Ni(II) complex. All the prepared compounds were screened for antiproliferative
and apoptotic activities. [Co(L2H)2(H2O)2] 192 and [Ni(L2H)2] 190 complexes have
24 N. P. PRAJAPATI AND H. D. PATEL

Scheme 30. Synthesis of metal complexes of (E)-2-((E)-2-(hydroxyimino)-1,2-diphenylethylidene)-N-

(pyridine-2-yl) hydrazinecarbothioamide (H2DPPT, 182).

exhibited significant activity against HL-60 and HT-29 human cancer cell lines. The
results of the chemical-induced cell apoptosis were determined in a manner that L2H2
ligand containing metal complexes of Co 192 and Ni 190 triggered 60 and 65% apop-
tosis in HL-60 cell line, respectively, and also triggered apoptosis and necrosis in HT-29
cell line.[56]
Yousef and colleagues have synthesized a novel series of metal chelates of Mn(II)
196, Cu(II) 197, Ni(II) 198, Co(II) 199, Cd(II) 200 and Zn(II) 201 with (Z)-(2-((1,3-
diphenyl-1H-pyrazol-4-yl)methylene) hydrazinyl)(pyridin-2-ylamino)methanethiol (HL,
195) ligand and characterized by elemental, spectral, magnetic and EPR spectral analysis
(Scheme 32). Based on structural identification data, ligand coordinate as neutral NN-
bidentate, mononegative NSN-tridentate and mononegative NSNN-tetradentate with
various metal ions. All the metal complexes possess octahedral geometry whereas Cu-
complex possesses tetragonal distorted octahedral geometry. Among all metal chelates
Cd(II) 200 complex showed the highest inhibitory antioxidant activity. Moreover, Ni(II)
198, Zn(II) 201, and Cd(II) 200 complexes were found effective at inhibiting the tumor
cells of liver hepatocellular carcinoma HepG2 cells and breast cancer MCF-7 cells com-
pared to the free ligands. Ni(II) 198 complex has shown excellent activity identical to
that of standard Fluorouracil.[57]
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Scheme 31. Synthesis of metal complexes of 3-acetyl- or 4-acetylpyridine thiosemicarbazone (L1H2

187 and L2H2 188).

The transition metal coordinates of 5-benzylidene-3-(4-chlorophenyl)-6-oxo-5,6-dihy-

dro-1H-[1,2,4]triazine-2-carbothioicacidamide (HL1, 202) and 5-(3-bromo-4-methoxy-
benzylidene)-3-(4-chloro-phenyl)-6-oxo-5,6-dihydro-1H-[1,2,4]triazine-2-carbothioicaci-
damide (HL2, 203) with Cu(II) 204, 205 and Mn(II) 206 metal ions have been invented
by Refat and colleagues (Scheme 33). The structural identification based on the elemen-
tal, spectral, molar conductance, analytical and thermal investigation was done by
authors. In-vitro anticancer activity of novel metal complexes against breast cancer cells
26 N. P. PRAJAPATI AND H. D. PATEL

Scheme 32. Synthesis of metal complexes of (Z)-(2-((1,3-diphenyl-1H-pyrazol-4-yl)methylene) hydrazi-

nyl)(pyridin-2-ylamino)methanethiol (HL, 195).

Scheme 33. Synthesis of metal complexes of 5-benzylidene-3-(4-chlorophenyl)-6-oxo-5,6-dihydro-1H-

[1,2,4]triazine-2-carbothioicacidamide (HL1, 202) and 5-(3-bromo-4-methoxybenzylidene)-3-(4-chloro-
phenyl)-6-oxo-5,6-dihydro-1H-[1,2,4]triazine-2-carbothioicacidamide (HL2, 203).
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Scheme 34. Synthesis of metal complexes of 2-(benzofuran-2-carbonyl)-N-(4-chlorophenyl)hydrazine-

carbothioamide (207).

Scheme 35. Synthesis of metal complexes of a-(1,3-dioxoindan-2-yl)ethylidenethiosemi-carbazone

(IETS, 217).

(MCF-7), hepatocellular cancer cells (HePG-2) and colon cancer cells (HCT) have also
been investigated in this study. The results of the cytotoxicity study summarized that
ligand 202 and its Cu complex 203 was found to be potent against MCF-7, HEPG-2
and HCT cell line as compared to the standard drug doxorubicin.[58]
The metal complexes of transition metal ions Cu(II), Ni(II) and Co(II) with benzo-
furon-2-carbohydrazide, 1-chloro-4-isothiocyanatobenzene (2-(benzofuran-2-carbonyl)-
N-(4-chlorophenyl)hydrazinecarbothioamide, 207) and 2,3,4-trinitrophenol having gen-
eral formula [M2(HL)] have been prepared by Kumar and coauthors (Scheme 34). All
compounds were characterized by magnetic, spectral and physicochemical analysis.
Analytical data favored the presence of two metal ions in the molecule and they were
having six-coordinate octahedral geometry according to spectroscopical study.[59]
A series of metal complexes of Co(II), Ni(II), Cu(II), Zn(II), Cd(II), V(III), Cr(III),
and Fe(III) metal ions with Schiff base ligand a-(1,3-dioxoindan-2-yl)-
28 N. P. PRAJAPATI AND H. D. PATEL

Scheme 36. Synthesis of metal complexes of 2-butyl thioquinazoline-4-(3H)-thiosemicarbazone

(BTQT, 237).

ethylidenethiosemicarbazone (IETS, 217) have prepared by Devesh et al. (Scheme 35).

IETS ligand and its metal complexes were characterized by various physicochemical
analysis. The complexes were proved thermally stable at 300  C temperature which indi-
cated that the complexes to be polymeric in nature.[60]
Co(II) 238, Ni(II) 239 and Cu(II) 240 complexes of Schiff base ligand 2-butyl thio-
quinazoline-4-(3H)-thiosemicarbazone (BTQT, 237) have been prepared and identified
using spectral and physicochemical studies by Rai and team (Scheme 36). Spectral and
elemental analysis studies of the synthesized complexes indicate the octahedral environ-
ment around the central metal ion. Bioassay results of in-vitro antimicrobial screening
against gram-positive bacteria C. albicans and gram-negative bacteria E. coli proposed
that metal complexes have found more potent than the ligand molecule.[61]

TSCs modified using various acid chloride derivatives and their metal complexes
Gautam and coauthors have studied spectroscopic techniques to investigate the struc-
tural property of newly prepared ligand 1-isonicotinoyl-3-thiosemicarbazide (Hintsc,
241) and its metal complexes with Fe(III) 242, Ni(II) 243 and Mn(II) 244 (Scheme 37).
The single-crystal structure study has revealed the supramolecular architecture of ligand
stabilized through various intermolecular interactions. Raman spectroscopy, UV-visible
and DFT methods have disclosed the octahedral geometry of Ni(II), Mn(II) and Fe(III)
complexes with ligand.[62]

Polymeric metal coordinate of TSCs

Ahmad et al. have prepared two novel polymer–metal complexes of CuCl2 and ZnCl2
individually with a condensed polymer TTCPP 245 of terepthalaldehyde-thiosemicarba-
zide synthesized by polycondensation reaction of terepthalaldehyde and thiosemicarba-
zide (Scheme 38). Polymer TTCPP and its Cu(II) 246 and Zn(II) 247 metal chelates
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Scheme 37. Synthesis of metal complexes of 1-isonicotinoyl-3-thiosemicarbazide (Hintsc, 241).

Scheme 38. Synthesis of metal complexes of terepthalaldehyde-thiosemicarbazide (TTCPP 245).

were identified by elemental, spectral and electrochemical techniques. According to UV-

Vis and fluorescence data, these polymer–metal complexes exhibited good luminescence.
Moreover, Zn complex 247 possess excellent antibacterial activity against E. coli strain.
30 N. P. PRAJAPATI AND H. D. PATEL

Scheme 39. Synthesis of metal complexes of Schiff base coordination polymer ligand (STFB, 248).

Thus, structural modification with respective metal ions may lead to design antibacterial
polymer–metal chelates having photophysical properties.[63]
Another series of transition metal complexes of Mn(II) 249, Co(II) 250, Ni(II) 251,
Cu(II) 252 and Zn(II) 253 metal ions with Schiff base coordination polymer ligand
(STFB, 248) prepared by the condensation reaction of salicylaldehyde and thiosemicar-
bazide with formaldehyde have reported by Rasool and coworkers (Scheme 39). The
structural identification has been studied by elemental, spectral, magnetic and thermal
analysis. All the polymeric metal complexes and its parent ligand were exposed for their
in-vitro antimicrobial activity as well as thermal studies. Thermal stability of the poly-
meric compounds of STFB was in the order STFB-Cu(II) > STFB-Mn(II) > STFB-
Ni(II) > STFB-Co(II) > STFB-Zn(II) > STFB. The results of antimicrobial screening
indicate that as compared to the other coordination polymers, coordination polymers of
Cu(II) 252 possess the best activity. Authors have also concluded that the incorporation
of metal into an organic motif enhances the thermal as well as the antimicrobial activity
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Scheme 40. Synthesis of metal complexes of 4-nitro- 254, 3-nitro- 255, 4-hydroxy- 256 and 4-amino-
257 acetophenone thiosemicarbazone.

Scheme 41. Synthesis of metal complexes of 1-(1-(pyridine-2-yl)ethylidene)thiosemicarba-zide (L1,

266) and 1-(1-(2,4-dihydroxyphenyl)ethylidene)thiosemicarbazide (L2, 267).
32 N. P. PRAJAPATI AND H. D. PATEL

so, these compounds may work as thermally resistant as well as antimicrobial coating
materials.[64]

Miscellaneous
A series of ligands 4-nitro- 254, 3-nitro- 255, 4-hydroxy- 256 and 4-amino- 257 aceto-
phenone thiosemicarbazone and their Co(II) and Ni(II) complexes have been prepared
via conventional thermal and microwave irradiation method by Verma and coauthors
(Scheme 40). Metal complexes were well evaluated by elemental and spectral analysis.
The ligand and its metal complexes exhibited satisfactory results of bioassay studies
against E. coli, S. aureus, and B. subtilis bacterial strains. Among the various ligands
4HBT 256, 4AAT 257 and their Co (II) and Ni(II) complexes have been found out to
be most effective against these bacteria showing maximum clarity of zones.[65,66]
Schiff base metal complexes [ML1L2]X or [ML1L2X] has been produced using ligand
1-(1-(pyridine-2-yl)ethylidene)thiosemicarbazide (L1, 266) and 1-(1-(2,4-dihydroxyphe-
nyl)ethylidene)thiosemicarbazide (L2, 267) and metal salts of Cu(II) 268, Ni(II) 269,
Zn(II) 270, Co(II) 271, Mn(II) 272 and VO(IV) 273 by Sakthilatha and coworkers
(Scheme 41). The novel metal complexes were structurally characterized by elemental,
spectroscopic, magnetic, and electrochemical measurements. In-vitro antibacterial activ-
ity results disclose that Cu(II) 268 and Zn(II) 270 complexes inhibit the growth of bac-
teria more than ligands as well as standard Kanamycin.[67]

Conclusion
Out of the different aspects of thiosemicarbazone, this review presents a report on the
synthesis, structural characterization and diverse application of thiosemicarbazone deriv-
atives and their metal complexes as well. A number of derivatives of thiosemicarbazones
have been synthesized, and a wide variety of complexes have been reported since last
5 years. The metal complexes of thiosemicarbazones are far more biologically active
than uncoordinated thiosemicarbazones. Medicinal researchers have gained active inter-
est owing to their enhanced biological activity. These complexes can further find their
use in the treatment of other incurable diseases. This review will provide easy prepara-
tive methods of thiosemicarbazones which could provide a major attraction for the
development of versatile molecules for the various range of applications in the future.

Acknowledgments
We would like to express our sincere gratitude to the Department of Chemistry, Gujarat
University, Ahmedabad for providing the necessary facilities and also thankful to UGC-Info net
& INFLIBNET, Gujarat University for providing e-source facilities.

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