Open access peer-reviewed chapter

Cytotoxic Activity of Schiff Bases and Their Complexes

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Narjala Rama Jyothi and Snehalatha Pulivarthi

Submitted: October 6th, 2022 Reviewed: October 12th, 2022 Published: November 27th, 2022

DOI: 10.5772/intechopen.108570

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Abstract

Various organic chelating agents have many applications in treating the several diseases and they act as antibacterial, antiviral, antimalarial and cytotoxic agents. Among the organic chelating agents thiosemicarbazones and their derivatives play a unique role in various fields of medicine. Thiosemicarbazones and their derivatives find a numerous applications and among them cytotoxic activity occupies a major portion due to the severity of the cancer treatment. In this present chapter we described and discussed the cytotoxic activity of thiosemicarbazones, their derivatives and various metal complexes of them. For this purpose, we reviewed the research articles published in various reputed international journals since 35 years. We summarized the results of those research findings and it is found that among the various metal ions, mostly the platinum and palladium complexes are effective cytotoxic agents than other metal complexes.

Keywords

  • thiosemicarbazones
  • metal complexes
  • cytotoxic activity
  • Schiff bases

1. Introduction

A Schiff base is a nitrogen analog of a carbonyl compound (aldehyde or ketone) in which the C=O group is replaced by C=N–R group. Generally, Schiff bases are considered as imines bearing a hydrocarbyl group on the nitrogen atom R2C=NR′ (R′ ≠ H). Schiff bases are usually synthesized by the condensation of a carbonyl compound with a primary amine as shown in the following Figure 1.

Figure 1.

Formation of Schiff base.

Schiff bases had various applications in different fields, such as medical [1], pharmaceutical [2] and biological [3]. Due to the presence of electron donating groups, such as sulfur and nitrogen atoms they can bind with metal ions in enzymes. Among various Schiff bases, thiosemicarbazones occupy a major role by having electron donating nitrogen and sulfur atoms. Thiosemicarbazones are a group of compounds obtained by condensing thiosemicarbazide with carbonyl compounds in the presence of a few drops of glacial acetic acid. These reagents function as good chelating agents and form complexes with several metal ions, by bonding through thionate sulfur atom and hydrazino nitrogen atom. In the last few years, much interest has been directed towards the use of chelating ligands containing sulfur and nitrogen in analytical studies as well as in structural studies of metal complexes. The wide applications and rapid growth in the popularity of sulfur ligands is due to their remarkable property as potential donors to form stable as well as characterized complexes in which the back bonding from the metal ion is possible under favorable conditions. In addition, the presence of nitrogen along with sulfur tends to lower the solubility of the complexes, making the isolation of these complexes easier.

Thiosemicarbazones are having great biological activities due to their ability to coordinate to the metal centers in enzymes. A number of studies reveals the biological and pharmacological activities of thiosemicarbazones and their metal complexes, such as anti-bacterial, anti-viral, anti-malarial and antineoplastic [4]. Anticancer activities of thiosemicarbazones were reported by various authors over worldwide [5]. Because of having various applications, in recent years a large number of authors reported the synthesis and characterization studies of different thiosemicarbazone ligands. The importance of thiosemicarbazones both in analytical and biological fields owe to us to synthesize new thiosemicarbazones.

Based on the starting compounds thiosemicarbazones can be classified into four types as shown below:

  1. Aldehydes or substituted aldehydes with thiosemicarbazide.

  2. Aldehydes or substituted aldehydes with substituted thiosemicarbazide.

  3. Ketones or substituted ketones with thiosemicarbazide, and

  4. Ketones or substituted ketones with substituted thiosemicarbazide.

Depending on the type of parent aldehyde or ketone used for condensation they can act as unidentate, bidentate or multidentate chelating agents during complexation with metal ions. Thio- and/or phenylthiosemicarbazones are synthesized by the condensation of carbonyl compound (with or without substitutes) with thio (phenylthio-) semicarbazides.

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2. Cytotoxic activity of metal thiosemicarbazone complexes

2.1 Pd (II) and Pt(II) complexes

Recently many authors were reported the anticancer activity of thiosemicarbazones and their palladium and platinum complexes. Nguyena et al. [6] reported the anticancer activities of Pd(II) and Pt(II) complexes of 1-picolinoyl-4-substituted Thiosemicarbazones against MCF7 and HepG2 cancer cell lines. Anti-proliferative activity of N-Substituted Indole thiosemicarbazones and its Pd(II) complexes against HeLa S3 cancer cell lines was reported by [7]. Nyawade et al. [8] reported cytotoxic activity of 2-acetyl-5-methyl thiophene and cinnamaldehyde thiosemicarbazones and their palladium(II) complexes cytotoxic activity on human cancer cell lines, Caco-2(Colon), HeLa(Cervical), Hept-G2 (hepatocellular) and PC-3 (Prostate) cell lines. Complexes shows excellent activity than ligands. Matesanz et al. [9] studied anticancer activity of Pd(II) and Pt(II) complexes of pyrrol-2-carbaldehyde N-p-chlorophenylthiosemicarbazone.

The palladium complexes of N-Substituted isatin thiosemicarbazones shows significant in vitro cytotoxicity against human breast (MCF) and lung (A549) cell lines [10] cancer cell lines (A549) than the ligand and cisplatin [11]. Pd(II) and Pt(II) complexes of Chlorophenyl substituted thiosemicarbazones were studied and performed the in-vitro anti-cancer activity of the ligand and complexes against T-47D, A2780 and A2780cus R human cell lines. The results indicate that the ligand has more activity than the complexes [12].

Isatin thiosemicarbazone derivatives and its complexes of Pt(II) shows potent activity against human colorectal carcinoma cell line (HCT 116) [13]. 2,6-Diacetylpyridine bis(4N-tolylthiosemicarbazone) complexes of Pd(II) and Pt(II) show the activity against cisplatin resistant A2780cisR tumor cells. These were shows high antiproliferative activity against breast cancer cell MCR-F-7 cells [14]. 2-Oxo-1,2-dihydroquinoline-3-carbaldehyde thiosemicarbazones complexes of Pd(II) shows a good cytotoxic activity against human cancer cell lines such as HeLa, KEp-2, Hep G2, and A431. It was evaluated and found the relationship between the structure and the activity of palladium complexes [15].

6-Methoxy-2-oxo-1,2-dihydro quinoline-3-carbaldehyde 4N-substituted thiosemicarbazones and its complexes of Pd(II) shows better cytotoxic activity against human lung cancer cell line A549 than other complexes and even cisplatin. All the complexes had strong anti-oxidant property [16]. Pd(II), Ni(II), Pt(II) complexes of 5-Acetylbarbituric-4N-dimethylthiosemicarbazones studies show that one of the complex had sufficient cytotoxicity against HeLa cells [17]. 3,5-Diacetyl-1,2,4-triazol bis(4N-substituted thiosemicarbazone) and its complexes of Pd(II) were tested for antiproliferative activity against NCI-H460, A2780 and A2780cisR human cancer cell lines and found that they exhibit low toxicity on kidney cells with respect to cisplatin [18].

Pt(II) complexes of Bis(thiosemicarbazones) of the 3,5-diacetyl-1,2,4-triazol series were tested cytotoxic activity against NCI-H460, A2780, and A2780cisR cancer cell lines and the results indicates that they were active against those cell lines and had high activity against NCI-H460 cell line [19]. 5-Substitutedthiophene-2-Carboxaldehyde thiosemicarbazones and its complexes of Pt(II), Pd(II) shows better cytotoxic activity than free ligand, but palladium complexes shows lesser activity than free ligands [20]. Pt(II) complexes of 3,5-Diacetyl-1,2,4-triazol bis(4,4-dimethylthiosemicarbazone) Anti-proliferative activity of ligand and its complexes was tested against NCI-H460, A2780 and A2780cisR human cancer cell lines. The results show that the compounds exhibits better activity against A2780cisR cell line than cisplatin [21].

2-Acetylpyridine-N(4)-methyl-thiosemicarbazone and 2-Acetylpyridine-N(4)-phenyl-thiosemicarbazone and its palladium complexes were act as cytotoxic agents similar to cisplatin. All the compounds show better activity against Mycobacterium tuberculosis [22]. Cytotoxic activity of the ligands (3,5-Diacetyl-1,2,4-triazol bis(4-substituted) thiosemicarbazones) and their Pd(II) and Pt(II) complexes was tested against human A2780 and A2780cisR epithelial ovarian carcinoma cell lines. The results show that the activity of these compounds were in the range similar to cisplatin drug [23]. Anti-proliferative activity was studied on Phenanthrenequinone thiosemicarbazone and its complexes of Pd(II). The palladium complex had cytotoxic activity against breast cancer cell lines and nontoxic towards the normal mammary epithelial cells [24].

2-Acetyl Pyridine N(4)-Ethyl-thiosemicarbazones, 2-Acetyl Pyridine N(4)-1-(2-pyridyl)-piperazinyl TSC, 2-Formyl Pyridine N(4)-1-(2-pyridyl)-piperazinyl TSC and its complexes of Pt(II), Pd(II) shows antiproliferative activity against gram +ve bacteria but not on gram –ve bacteria. Some of the complexes overcome the cisplatin resistance of A2780/Cp8 cells [25]. 2-Acetylpridine thiosemicarbazone and Platinum complexes were effective on gram + bacteria. They were also effective on yeast. Few of the complexes were exhibits antitumor activity [26]. 2-Acetylpyridine and pyridine-2-carbaldehyde N(4)-ethyl thiosemicarbazones and Platinum complexes were found to be overcome the cisplatin resistant tumor cells, A2780/Cp8 [27].

Pyridine-2-carbaldehyde thiosemicarbazone and its complexes of Pd(II) and Pt(II) exhibits the higher in vivo antitumor activity [28]. Pd(II) and its complexes of 3,5-Diacyl-1,2,4-triazole bis(thiosemicarbazone); 2,6-diacylpyridine bis(TSC); benzyl bis(TSC) shows better antitumor activity against several human, monkey and murine cell lines [29]. p-Isopropylbenzaldehyde thiosemicarbazone and its Pd(II) and Pt(II) complexes show cytotoxic activity of the complexes reported against cisplatin resistant tumor cell lines (Figure 2) [30].

Figure 2.

Cytotoxic activity of Pd(II) and Pt(II) complexes of thiosemicarbazones.

Isopropylbenzaldehyde thiosemicarbazone and its complexes of Pd(II) and Pt(II) show anticancer activity against several human and murine cell lines were reported by [31]. Phenylacetaldehyde thiosemicarbazone and its complexes of Pd(II) and Pt(II) cytotoxic activity was studied and observed that Cis-DDP-resistant tumor cells has high activity [32].

3,5-Diacyl-1,2,4-triazole bis(thiosemicarbazone); 2,6-diacylpyridine bis(TSC); benzyl bis(TSC) and its Pd(II) complexes shows better antitumor activity against several human, monkey and murine cell lines [29]. p-Isopropylbenzaldehyde thiosemicarbazone and its complexes of Pd(II) Pt(II) Cytotoxic activity reported against cisplatin resistant tumor cell lines [30]. p-Isopropylbenzaldehyde thiosemicarbazone and its complexes of Pd(II) and Pt(II) show anticancer activity against several human and murine cell lines [31].

Cytotoxic activity of phenylacetaldehyde thiosemicarbazone and its Pd(II) and Pt(II) complexes were studied and it was reported that cis-DDP-resistant tumor cells has reacted highly [32]. 2-Acetylpyridine N(4)-methyl, N(4)-ethyl and N(4)-phenyl thiosemicarbazones and its complexes of Pd(II) Antitumor studies indicates that all the palladium complexes were active in the inhibition of DNA synthesis on P388 and L1210 cell cultures (mice bearing tumors) [33]. 2-Acetylpyridine N(4)-propyl, N(4)-dipropyl- and 3-hexamethyleneiminyl thiosemicarbazones and its Palladium complexes does not had antifungal activity against the tested species. But they had significant anti-tumor activity against P388 and L1212 cell cultures [34].

2.2 Copper complexes

Thiosemicarbazone and its copper (II) complexes exhibits high anticancer activity due its highest stability and membrane permeability [35]. 2-Picoline and 5,5-dimethylbipyridine and its Cu(II) complexes cytotoxic activity was reported on MDA-MB-231 breast cancer cell line [36]. Chitosan-functionalized pyridine-based Thiosemicarbazones and their Cu(II) complexes shows antiproliferative activity against MCDK and MCF-7 cancer cell lines and their complexes shows high cytotoxic activity than ligands [37]. N-substitution in isatin thiosemicarbazones and its Cu(II) complexes MTT assays were done on A549,HeLa S3, Jurkat and IMR90 cells, its complexes exhibits more cytotoxic activity on HeLa S3 and Jurkat cell lines than cisplatin and morphological changes were observed [38]. Series of thiosemicarbazones and their Cu(II) complexes cytotoxic activity was studied and was noted that ligands chelation with Cu(II) enhances its antitumor activity well [39]. Copper(II) complexes of pyridoxal dithiocarbazate and thiosemicarbazone ligands are prone to study antitumor activities (Ehrlich and S-180 cells) and it was observed that these complexes were very active towards the cell death and they will act as excellent drug against cancer in future [40]. Copper(II) complexes bearing 2-hydroxynaphthaldehyde-based thiosemicarbazones shows cytotoxic activity against lung cancer (A549) cell line and human kidney (HEK-293 T) cell lines and it was observed that these complexes are active in cell death and it was showing excellent medical properties [41].

6-Methyl-2-oxo-quinoline-3-carbaldehydethiosemicarbazone and its Cu(II) complexes Cytotoxic activities were evaluated for both the ligand and three complexes. In vitro anti-tumor studies revealed that copper complex shows better activity towards SK-OV-3 and MGC80-3 tumor cell lines than the commercial anticancer drug, cisplatin. But all the complexes show lower activity against human liver cell lines than cisplatin [42]. 3-Phenyl (substituted)-1-pyridin-2-ylprop-2-en-1-one thiosemicarbazone and its Cu(II) Cytotoxic activity were tested against human cancer cell lines such as HL60, MDA-MB 231, and HCT-116. The results indicate that coordination of copper increases the cytotoxic activity of the compounds [43].

Glyoxal-bis(4-methyl-4-phenyl-3-thiosemicarbazone) and its Copper complex has better cytotoxic activity against various human cancer cell lines than the Adriamycin, a commercial drug. The copper complex significantly inhibits the growth of tumor HCT 116 xenografts in nude mice [44]. Cu(II) and its complexes of 2-Oxo-1,2-dihydroquinoline-3-carbaldehyde4(N,N)-dimethylthiosemicarbazone Cytotoxic activity of the complex and ligand was tested against HeLa, Hep G2, and HEp-2 cancer cell lines and found that the copper complex has significant activity on HeLa cell line than others [45]. N-substituted-2-oxo-1,2-dihydroquinoline-3-carbaldehyde thiosemicarbazones and its complexes of Cu(II) antiproliferative activities were studied the substituent at terminal nitrogen atom was observed. The ethyl and phenyl substituted complexes shows better activity against NIH 3 T3 and HeLa cell lines [46].

α-Heterocyclic-N4-substituted thiosemicarbazones and its Cu(II) complex Anti-proliferative activity were tested against breast cancer cell line SK-BR-3. The ligands shows better catalytic inhibition property of topoisomerase-Iiα than complexes [47]. Cu(II) complexes of 2-Acetylpyridine-4,4-dimethyl-3-thiosemicarbazone, di-2-pyridyl ketone-4,4-dimethyl-3-TSC shows better anti-proliferative activity than ligand [48]. 2-Hydroxy-8-R-tricyclo [7.3.1.0.2,7] tridecane-13-one thiosemicarbazone and its complexes of Cu(II), Pd(II) shows Anti-microbial activities and cytotoxic activities of the compounds were reported [49]. Salicylaldehyde semi−/thiosemicarbazones and its complexes of Cu(II) were tested for cytotoxic activity against MCF-7 human breast cancer cell lines. The results revealed that ligands were inactive but copper complex of thiosemicarbazone was more active than others [50].

5-Formyluracil thiosemicarbazone derivatives and its Cu(II) Complexes were exhibits DNA interaction by electrostatic and groove binding. But these were no activity against human leukemic cell line U937 [51]. α-Ketoglutaric acid thiosemicarbazone and its Cu(II) Copper complexes has antiproliferative activity against human cell line U937 and no effect on the K562 cell line [52]. 10-Deacetylbaccatin thiosemicarbazone and its Cu(II) Cytotoxic activity of the ligand and its complex was tested against human breast cancer cell line MCF-7 [53].

Ref. [54] reported the cytotoxic activity of Cu(II) and its complexes of 2-Acetylpyrazone-N-substituted thiosemicarbazones. Ref. [55] studied the anticancer activity of 5-Formyluracil thiosemicarbazone and its Cu(II) complexes against human leukemic cell lines K562 and CEM (Figure 3).

Figure 3.

Cytotoxic activity of Cu(II) complexes of thiosemicarbazones.

2.3 Cu(II) and Zn(II) complexes

Hydroxyquinoline-thiosemicarbazones and its Cu(II) and Zn(II) complexes shows more cytotoxic activity towards human lung cell lines (A549) than their parent ligands [56]. Methyl pyruvate thiosemicarbazones and its Cu(II), Zn(II) complexes anti-proliferative activity studies reveals that copper complex was most effective on human leukemic cell line U937 than other compounds [57].

2.4 Cu(II) and Ni(II) complexes

Cu(II), Ni(II) complexes and its N-Ethyl-2-(phenyl(pyridin-2-yl)methylene) hydrazine carbothioamide cytotoxic activity was evaluated against human lung cancer cell lines (A549) and normal cell lines (L929). The results indicates that the copper complexes shows better activity than nickel complexes and both complexes were less harmful to normal cells [58]. 2,4′-Dibromoacetophenone thiosemicarbazone and its Cu(II), Ni(II), Pd(II) complexes, Antioxidant and antitumor activities were studied. Nickel complex shows good antitumor activity against HepG2 hepatoblastoma cell lines [59]. Cu(II) and Ni(II) complexes and its Cinnamaldehyde and cuminaldehyde thiosemicarbazones were tested in vitro anti-leukemic activity on U937 human cell line. Metal complexes shows better activity than ligands [60]. 3,4-Difluoroacetophenone thiosemicarbazone; 2-bromo-4′-chloroacetophenone TSC and its Cu(II), Ni(II) complexes were tested for antitumor activity against HepG2 human hepatoblastoma cells. The results indicates that the copper complexes of the both ligands had better activity than others against cancer cell line [61]. (Z)-2-(Amino(pyridin-2-yl) methylene)-N-methylhydrazine carbothioamide and its Cu(II), Zn(II) complexes Cytotoxic activity was studied against HeLa, HepG-2 and SGC-7901 cell lines. The results shows that copper complex had better activity among the others [62].

Bis(citronella thiosemicarbazone); Pyridoxal TSC and its Ni(II), Cu(II) Metal complexes were tested for antiretro-viral activity against HIV-1 and HTLV-1/−2. The results indicates that copper complex has potent anti HIV activity (Figure 4) [63].

Figure 4.

Cytotoxic activity of Cu(II), Zn(II) and Ni(II) complexes of thiosemicarbazones.

2.5 Cu(II), Ni(II) and Zn(II) complexes

2-Methoxybenzaldehyde-S-2-methylbenzyl dithiocarbamate and 3-methoxybenzalde hyde-S-2-methylbenzyl dithiocarbamate and its Cu(II), Ni(II), Zn(II) complexes were inactive against MCF-7 and MDA-MB-231 breast cancer cell lines [64].

2.6 Ni(II) complexes

Ni(II) and its complexes of 3-Methoxy-salicylaldehyde-4(N)-substituted thiosemicarbazones exhibits strong anti-oxidant property with strong radical scavenging ability. Some of the complexes shows better anticancer activity against lung cancer cell lines (A549) than the ligand and cisplatin [11]. N(4)-substituted thiosemicarbazone and its Ni(II) complexes Anti-cancer activity was tested against human breast cancer cell lines (MCF-7). All the complexes shows moderate activity compared to commercial anti-cancer drug, cisplatin [65].

Ni(II) and its complexes of dinucleating bis(thiosemicarbazones) were tested for cytotoxic activity against human cancer cell lines (A549 and HepG2). One of the nickel complex shows better activity against A549 cell line than cisplatin drug [66].

2-Hydroxy-1-naphthaldehydethiosemicarbazone; salicylaldehyde-4(N)-ethylthiosemicarbazone; 2-hydroxy-1-naphtha ldehyde-4(N)-ethyl TSC and Ni(II) complexes were tested for cytotoxic activity against human cancer cell lines (A549 and HepG2). One of the nickel complex shows better activity against A549 cell line than cisplatin drug [67]. Ortho-Naphthaquinone thiosemicarbazone; ortho-Naphthaquinone semicarbazone Anti-cancer activity and its Ni(II) complexes were tested against MCF-7 human breast cancer cell lines and results revealed that semicarbazone and nickel complexes were more active than thiosemicarbazone ligand [68].

p-Fluorobenzaldehdye thiosemicarbazones and its nickel complexes shows remarkable inhibition activity against human leukemic cell line U937 (Figure 5) [69].

Figure 5.

Cytotoxic activity of Ni(II) complexes of thiosemicarbazones.

2.7 Fe(II) and Fe(III) complexes

α-N-heterocyclic thiosemicarbazone and its complex of Fe(III) Anti-cancer activity was studied against human breast cancer cell lines, cervical cancer cell lines and liver cell lines. The results show that iron complex has better activity than its ligand. This study also evaluates the anti-cancer mechanism [70]. 2-Acetylpyridine thiosemicarbazones and its Fe(III) complexes Antiproliferative property were reported. The structure and activity relationship was determined [71]. 2-Acetylpyridine N,N-dimethylthiosemicarbazone; 2-acetyl pyridine N-pyrrolidinyl TSC; acetyl pyrazine N,N-dimethyl TSC; acetyl pyrazine N-pyrrolidinyl and acetylpyrazine-N-piperidinyl TSC and its Ga(III), Fe(III) complexes Cytotoxic activity were studied and it was reported that ligands were enhanced by the chelation with Ga(III) while weakens with Fe(III) [72].

Iron and its complexes of Series of Di-2-pyridyl ketone thiosemicarbazones had good antiproliferative activity against the tested tumor cells [73]. 1-Formylisoquinoline thiosemicarbazone; 4-Methyl-5-amino-1-formylisoquinoline TSC and its Fe(II), Fe(III) complexes were active against P 388 lymphocytic leukemia test system in mice (Figure 6) [74].

Figure 6.

Cytotoxic activity of iron complexes of thiosemicarbazones.

2.8 Organo Sn complexes

Cytotoxic activity of 2-Hydroxy-5-methoxy benzaldehyde-N(4)-methylthiosemicarbazone and its complexes Organotin (IV) were tested against human colorectal (HCT 116) cell lines and the results show that the complexes had better activity than the ligand [75]. 2-Benzoylpyridine N(4)-phenyl thiosemicarbazone; 2-Acetyl pyrazine N(4)-phenyl TSC and its Diorgano Sn(IV), Antibacterial activity and cytotoxic activity against K562 leukemia cells of the free ligands and complexes were reported [76]. Pyridoxal thiosemicarbazone and its complexes of Diorgano Sn(IV) antitumor activity were studied and observed that Ethyl, butyl, and phenyl substituted compounds suppress the proliferation of friend erythroleukemia cells (Figure 7) [77].

Figure 7.

Cytotoxic activity of Organo tin complexes of thiosemicarbazones.

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3. Miscellaneous

2-Benzoylpyridine N(4)-cyclohexyl thiosemicarbazone-Anti-proliferative activity of the ligand and its indium complexes was tested against human hepatocellular carcinoma. The studies revealed that the indium complex has better activity than the others [78]. N4-(2-Hydroxy-5-chlorobenzyliden e)-2-amino-5-chlorobenzophenone thiosemicarbazone; N4-(2-Hydroxy naphthalene-1-carbaldehyde)-2-amino-5-chlorobenzophenone TSC and its complexes of Ru(II) cytotoxic activity was studied and reported that, all the complexes showed better in vitro cytotoxic activity against MCF-7, Hop62, MDA-MB cell lines [79]. 7-Chloroquinoline thiosemicarbazone and its complexes of Ga(III), Cytotoxic and antimalarial activity were tested and proved that the complex shows 31 times better activity on colon cancer cell line than etoposide. The complex has better antimalarial activity against Plasmodium falciparum than lumefantrine [80].

2-Acetylpyridine-N(4)-Orthochlorophenyl thiosemicarbazone and their complexes of Ga(III), Sn(IV), Pd(II) and Pt(II) Cytotoxic activity was reported. The results indicate the ligands and metal complexes showed better cytotoxic activity [81]. (Z)-(2-((1,3-Diphenyl-1H-pyrazol-4-yl) methylene) and hydrazinyl)(pyridin-2-ylamino) methane-thiol thiosemicarbazones and their complexes of Mn(II), Co(II), Ni(II), Cu(II), Zn(II), Cd(II) Cd(II) and Zn(II) complexes had strong antioxidative property. Ni(II) complex shows excellent activity against HepG2 and MCF-7 cancer cell line [82]. Cd(II) and its complexes of 2-Acetylyuridine-N4-substituted thiosemicarbazones and their Cytotoxic activity against human breast cancer cell lines was tested and found that one of cadmium complexes has better activity than the cisplatin drug [83]. Bi(III) and its complexes of 2,6-Diacetylpyridine bis (4N-methylthiosemicarbazone) have much more anti-bacterial and anticancer activity than its parent ligand against Bacillus cereus and Salmonella Typhimurium and K562 leukemia cells [84]. Ru(II) and its complexes of Benzaldehyde thiosemicarbazones and their Cytotoxic activity were evaluated against the WHCO1 esophageal cancer cell line. Among the tested complexes two had moderate activity against the cancer cell line [85]. 2-Acetylpyridine thiosemicarbazone; 2-Acetylpyridine N(4)-methyl TSC; 2-Benzoylpyridine TSC; 2-Benzoyl pyridine N(4)-methyl TSC; 2-Benzoylpyridine N(4)-phenyl TSC and its complexes of Mn(II), Co(II), Zn(II) was tested against its cytotoxicity and reported that compounds show significant activity against K562 leucocythemia cancel cell line [86].

2-Pyridineformamide thiosemicarbazones, 2-formyl and 2-acetyl acetyl pyridine thiosemicarbazones and its complexes of Ga(III) antiproliferative activity were evaluated against human cancer cell lines (MCF-7, T24, A549 and mouse L-929). 2-acetyl pyridine thiosemicarbazone shows higher activity than others against all cancer cell lines [87]. Kowol et al. [72] studied the anticancer activity of 2-Acetylpyridine N, N-dimethyl TSC, 2-acetyl pyridine N-pyrrolidinyl TSC, acetyl pyrazine N, N-dimethyl TSC, acetyl pyrazine N-pyrrolidinyl and acetyl pyrazine-N-piperidinyl TSC and its complexes of Ga(III), Fe(III). Cytotoxic activity of the ligands was enhanced by the chelation with Ga(III) while weakening with Fe(III). Noblia et al. [88] reported cytotoxic activity of 5-Bromo salicylaldehyde semicarbazone; 2-Hydroxy-naphtalen-1-carboxaldehyde semicarbazone and their vanadium complexes. The results indicate that the complexes had selective activity against TK-10 cell line. Anticancer activity of ortho-Naphthaquinone thiosemicarbazone and its Cu(II),Ni(II), Pd(II) and Pt(II) complexes were tested against MCF7 human breast cancer cell lines and results revealed that chelation of metal ion into ligand was enhanced its activity [89]. Casas et al. reported the cytotoxic activity of Formylferrocene thiosemicarbazones and their Au(III) complexes were evaluated against HeLa cell lines and found that antiproliferative activity was similar to cisplatin, a commercial drug.

Arion et al. [90] reported cytotoxic activity of 2-Acetylpyridine 4 N-dimethyl TSC and its Ga(III) complex against human cancer cell lines SW480, SK-BR-3, and 41 M were tested and results revealed that complexes show slightly higher activity than ligand. Antiproliferative activity of Acenaphthenequinone thiosemicarbazone and its Ni(II), Fe(II), Cu(II), Zn(II)were reported and found that Cu(II) complex shows better antiproliferative activity than others. Perez et al. [91] tested the cytotoxic activity of p-Isopropyl benzaldehyde and methyl 2-pyridyl ketone thiosemicarbazones and their Zn(II), Cd(II) against various cell lines. Results indicate that zinc complex was proven as a more potent antitumor agent. Jayasree and Araindakshan [92] reported the antitumor activity of Acetoacetanilide thiosemicarbazone and its Mn(II), Zn(II), Cd(II), Co(II), Fe (IIII) complexes against Ehrlich Ascites tumor cells and found that metal complexes were more active than free ligand. Mohan et al. [93] studied the antitumor activity of 2,6-Diacetylpyridine bis(N4-azacyclic thio semicarbazones) and their Mn(II), Fe(III), Fe(II), Co(II), Ni(II), Cu(II), Zn(II), Pt(II) complexes against P 388 lymphocytic leukemia test system in mice shows that copper complex shows better activity than others.

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4. Conclusions

From the above discussion it is concluded that in most of the studies the metal complexes show greater cytotoxic activity than the free ligands. In metal complexes most of the researchers found the activity of palladium and platinum complexes than other metal complexes. There is a gap between structure activity relationship between metal complexes and their activity towards specific species. Metal complexes of thiosemicarbazones shows great antiproliferative activity and destroys cell completely. Several derivatives of TSC and its metal complexes such as Pt(II), Pd(II), Cu(II), Fe(II), Ni(II), etc., shows excellent cytotoxic activity.

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Written By

Narjala Rama Jyothi and Snehalatha Pulivarthi

Submitted: October 6th, 2022 Reviewed: October 12th, 2022 Published: November 27th, 2022