A Therapeutic Journey of Semicarbazide and Thio Semicarbazide Derivatives and their Transition Metals Complexes: Mini Review

Abstract

Semicarbazide and Thiosemicarbazide are classes of Schiff bases prepared by condensation between aldehydes / ketones with amines, they are belongs to urea and thiourea derivatives whose pharmacological activities are a function of attached aldehydes or ketones moiety. Semicarbazide and thiosemicarbazide have potential pharmacological activities including antifungal, anticancer, antibacterial, antimalarial, anticonvulsant, antitubercular, anti-proliferative, anti-inflammatory, antimicrobial, analgesic, antioxidant, radical scavenging, antiviral, and antipyretic properties. Thiosemicarbazides derivatives are of great interest not only in pharmacological activities, but also as the starting material for the preparation of different Schiff base derivatives, metal chelating complexes and anticorrosion agents. This review aim to evaluate the different biological activities of synthesized semicarbazide and thiosemicarbazide derivatives.

Keywords

Semicarbazide, Thiosemicarbazide, Biological activity, Transition metal complexes

Introduction

The chelating chemistry has been widely enriched due to the preparation of transition metal complexes, in which the Lewis acid is coordinated through hetero atoms containing free lone pairs of electrons. Metal complexes with Lewis bases containing nitrogen, sulfur and phosphorous donors have been found to be have potential pharmacological activities [1,2]. The semicarbazones and thiosemicarbazones usually behave as chelating ligands containing donor imines groups which react with transition metal vacant d-orbital giving complexes. These are multifunction ligands in both neutral and anionic forms [3]. The complexes can exhibit bioactivities which are not shown by the free ligands. The main interest to prepare and elucidate the structure transition metal complexes of these ligands is due to their pharmacological activities. Some transition metals complexes have different applications such as chemical sensor [4-7], antiviral [8-11] agent and catalyst [12-16]. In addition, they have also been used as antifungal, anticancer, antibacterial, antimalarial, anticonvulsant, antitubercular and anti-proliferative agent. The transition metal complexes based on titanium, gold, cobalt and platinum are used as chemotherapy agents in modern researches [17,18]. Additionally, several nickel (II) complexes with octadiensemicarbazones exhibit strong inhibitory activity against Staphylococcus aureus and Eschericia coli. In vitro anticancer studies of several nickel(II) complexes with naphthoquinone semicarbazone and thiosemicarbazone on MCF-7 human breast cancer cells reveal that semicarbazone derivate with nickel(II) complexes is more actively inhibiting cell proliferation than thiosemicarbazone analogues.

Biological Activities of Different Semicarbazide and Thiosemicarbazide Derivatives

Saddam et al. [19] synthesized Cu(II) complexes with two new Schiff base ligands derived from reaction of salicylaldehyde with semicarbazide (HL₁) and thiosemicarbazide (HL₂) respectively. The synthesized complexes are characterized by IR, UV-Visible, 1HNMR and thermal analysis. The structure of the synthesized complexes was distorted square planar (Figure 1) and the biological activity revealed that the Cu- HL₂ complex had more antibacterial activity as compared to Cu- HL₁ complex. The metal complexes were more antibacterial activity than its free Schiff base ligand.

Figure 1: Schemes 1, 2, 3 and 4 summarizes the synthesis of HL1 and HL2 ligands and their corresponding Cu(II) complexes.

Sulekh et al. [20] synthesized Cu(II) complexes containing 2-formyl pyridine semicarbazone (L₁), 2-formyl pyridine thiosemicarbazone (L₂), 5-methyl-2-formyl pyridine semicarbazone (L₃) and 5-methyl 2-formyl pyridine thiosemicarbazone (L₄). The synthesized complexes were characterized by elemental analysis, FT-IR, ¹HNMR, molar conductance, magnetic moment, EPR spectral studies and mass spectrometry. The complexes were found to have general composition [Cu(L)₂X₂] (where L=L₁, L₂, L₃ and L₄, X = Cl^–] ½SO₄^2–, NO₃^- (Figure 2). On the basis of IR, electronic and EPR spectra of complexes, tetragonal distorted octahedral geometries were found with planar coordination of the ligand around Cu²⁺ ion and the anions occupies axial position.

Figure 2: Synthesis of ligands and structure of their corresponding Cu(II) complexes.

Samy et al. [21] applied Vilsmier-Haack formylation of 5-bromo-2,3-diphenyl indole afforded 6- formyl derivative which was subjected to various condensation reactions that finally gave heterocyclic rings bounded to the starting compound at position 6 in Figure 3. The biological activity for the synthesized compounds revealed that they have antibacterial activity. They have been tested against two types of Bactria (Bacillus subtilis and Escherichia coli).

Figure 3: Scheme for condensation reactions of synthesized ligands.

Masoumeh et al. [22] synthesized a series of nine new semicarbazone (12a-i) and six new thiosemicarbazone (14a-c, 14f-h) of isatin which is considered as a vital class of bioactive compounds exhibiting different biological activities. This study showed the synthesis and In vitro determination of the cytotoxic and antimicrobial activities of nine new isatin semicarbazones (12a-i) and six new reported thiosemicarbazones (14a-c, 14f-h) (Figure 4). They showed that complexes of isatin thiocarbazone with metals such as Pd(II), Zn(II) and Hg(II) had enhanced their antimicrobial activities in comparison to their respective ligands [23].

Figure 4: Scheme for condensation reactions of semicarbazide and thiosemicarbazide with isatin.

Božidar et al. [24] synthesized Schiff base complexes based on reaction of 3-acetylpyridine with semicarbazide as well as the corresponding tetrahedral Zn(II). The synthesized complexes were characterized by X-ray crystal structure (Figure 5) and spectroscopic methods. The computational studies showed that the ligand coordinated as monodentate although there are several donor atoms. The complex exhibited moderate antibacterial, antifungal and cytotoxic activities while the ligand was mostly inactive. The complex strongly induced formation of reactive oxygen species in tumor cell lines It also influenced cell cycle progression in tumor cell lines, and induced autophagy.

Figure 5: Scheme of reactions of semicarbazide and thiosemicarbazide with acetylpyridine and their corresponding complexes.

Junming et al. [25] synthesized a series of N,N-disubstituted salicylaldehyde semicarbazones (SSCs) and their corresponding rhenium (I) tricarbonyl complexes (Figure 6). The synthesized compounds were characterized by IR and 1HNMR spectroscopy. Crystallographic studies showed that ligands acts as bidentate via its imino nitrogen and carbonyl oxygen atoms. The [ReBr(CO)₃(SSC)] complexes exhibit moderate to high cytotoxicities towards MOLT^-4 cells.

Figure 6: Synthesized ligands and their corresponding complexes X-ray crystal structure.

Chandra et al. [26] synthesized a novel Anthraquinone N⁴ benzyl- thiosemicarbazone Cr (III) complex with a potential to act as an anti-cancer drug and characterized by spectral methods (Figure 7). Effect of N⁴-substitution, additional donor sites and complexation on the biological activity of the ligand has been studied. The prepared complexes constituted a new family of antibacterial compounds for controlling the growth of at least 1-10 bacterial species. The effect of additional binding sites, N4 substitution and complexation with metal ion on biological activity has been given importance.

Figure 7: Proposed structure of synthesized ligand and its corresponding complex with Cr(III).

Verma [27] synthesized Mn(II) complexes with four semicarbazide and thiosemicarbazide based ligands such as 2-formyl pyridine semicarbazone (L₁), 2-formyl pyridine thiosemicarbazone (L₂), 5-methyl 2-formyl pyridine semicarbazone (L₃) and 5-methyl 2-formyl pyridine thiosemicarbazone (L₄). The prepared ligands and complexes were characterized by elemental analyses, IR, ¹HNMR, mass spectral studies, molar conductance, magnetic susceptibility measurements and spectral studies such as IR, UVvisible and EPR. On the basis of IR electronic and EPR spectral data distorted octahedral geometry of complexes has been suggested (Figure 8).

Figure 8. Scheme of synthesized ligands and structure of their corresponding complexes.

Krishna et al. [28] synthesized a new heterocyclic ketimines, 3-acetyl-2,5-dimethylthiophene thiosemicarbazone (C₉H₁₃N₃OS₂ or L1H) and 3-acetyl-2,5- dimethylthiophene semicarbazone (C₉H₁₃N₃OS or L2H), by reaction of 3-acetyl-2,5-dimthylthiophene with thiosemicarbazide and semicarbazide hydrochloride. The Pd(II) and Pt(II) complexes have been synthesized by mixing metal salts in 1:2 molar ratios with these ligands by using microwave as well as conventional heating method. The structure of these ligands (Figure 9) and their complexes has been established on the basis of elemental analysis, melting point determinations, molecular weight determinations, IR, 1H NMR and UV spectral studies. These studies showed that the ligands coordinate to the metal atom in a monobasic bidentate manner and square planar environment around the metal atoms has been proposed to the complexes. The anti-amoebic activity of both the ligands and their palladium compounds against the protozoan parasite Entamoeba histolytica has been tested.

Figure 9: Scheme of synthesized ligands and structure of their corresponding complexes.

Conclusion

Semicarbazide and thiosemicarbazide derivatives are related to some necessary biological activities like antitubercular, fungicidal, anthelmintic, antitumor, antibacterial and antimalarial activity. They are found to be physiologically and pharmacologically active. The difficulty of treating microorganism diseases induced to assess the biological activities of metal complexes with different transition metals like Ni(II), Cu(II) and Pd(II). This approach would possibly give compounds with greater biological activity in pharmacological research.

References

1. Chandra S and Gupta LK. Electronic, EPR, magnetic and mass spectral studies of mono and homo-binuclear Co(II) and Cu(II) complexes with a novel macrocyclic ligand. Spectrochim Acta A 2005; 62:1102.
2. Siji VL, et al. Synthesis, characterization and physiochemical information, along with antimicrobial studies of some metal complexes derived from an ON donor semicarbazone ligand. Spectrochim Acta A 2010;76:22.
3. Kumar DR and Ayesha M. Preparation and Characterization of Ni(II) and Mn(II) Complexes of Semicarbazone and Thiosemicarbazone of m- Hydroxy Benzaldehyde and p- Hydroxy Benzaldehyde. Res J Chem Environ 2011;15:5.
4. Ott I and Gust R. Non Platinum Metal Complexes as Anti-cancer Drugs. Arch Pharm Chem Life 2007;340:117.
5. Singh K, et al. Synthesis and characterization of cobalt(II), nickel(II), copper(II) and zinc(II) complexes with Schiff base derived from 4-amino-3-mercapto-6-methyl-5-oxo-1,2,4-triazine Eur J Med Chem 2008;42:394.
6. Shahab SK, et al. Spectrochim Acta A 2009;72:229.
7. Ade B, et al. Synthesis and Spectral Studies of some Novel Schiff Base derived with Pyrimidines. J Chem Pharm Res 2012;4:105.
8. Yildirim LT, et al. Polyhedron 2007;26:4187.
9. Echegoyen Y, et al. Sol–gel synthesis of Ni and Ni supported catalysts for hydrogen production by methane decomposition. Appl Cat A 2007;333:229.
10. Wang XJ, et al. J Mol Cat A 2007;278:12.
11. Lambert S, et al. Synthesis, characterisation and biological activities of copper(II) complexes with semicarbazones and thiosemicarbazones. Cat Commun 2007;8:2032.
12. Jakupec MA. Antitumour metal compounds: more than theme and variations, Dalton Trans. 2008; p: 183.
13. Yang P and Guo M. Interactions of organo-metallic anticancer agents with nucleotides and DNA. Coord Chem Rev 1999;185:189.
14. Hadjikakou SK and Hadjiliadis N. Antiproliferative and antitumor activity of organotin compounds. Coord Chem Rev 2009;253:235.
15. Strohfeldt M and Tacke M. Bioorganometallic fulvene- derived titanocene anticancer drugs. Chem Soc Rev 2008;37:1174.
16. Abeysinghe PM and Harding MM. Antitumour bis (cyclopentadienyl) metal complexes: titanocene and molybdocene dichloride and derivatives. Dalton Trans 2007; p: 3474.
17. Gust R, et al. Development of Cobalt (3,4-diarylsalen) Complexes as Tumor Therapeutics. J Med Chem 2004;47:5837.
18. Hartinger CG and Dyson PJ. Bioorgano-metallic chemistry from teaching paradigms to medicinal applications. Chem Soc Rev 2009;38:391.
19. Saddam H, et al. Synthesis, Spectral and Thermal Characterization of Cu(II) Complexes with two New Schiff Base Ligand towards Potential Biological Applications. Pelagia Research Library 2017;8:380-392.
20. Sulekh C, et al. Synthesis, characterisation and biological activities of copper(II) complexes with semicarbazones and thiosemicarbazones. Journal of Chemical and Pharmaceutical Research 2012;4:1612-1618.
21. Samy BS, et al. Synthesis and Biological Activity of Some 2,3- Diphenylindole derivatives. Research & Reviews: Journal of Chemistry 2015;4:1-5.
22. Masoumeh D, et al. Journal of Pharmaceutical Research International 2017;17:1-13.
23. Konstantinović SS, et al. Antimicrobial activity of some isatin-3- thiosemicarbazone complexes. Journal of the Serbian Chemical Society 2008;73:7-13.
24. Božidar CO, et al. Crystal Structure of C10H16ClN3O3. Inorganica Chimica Acta 2013;404:5-12.
25. Junming H, et al. Journal of Inorganic Biochemistry 2013;119:10-20.
26. Chandraa JS, et al. Indian Journal of Advances in Chemical Science 2013;2:32-37.
27. Verma R. Synthesis and characterisation of manganese(ii) complexes with semicarbazide and thiosemicarbazide based ligands. IJPSR 2017;8:1504-1513.
28. Afrasiabi Z, et al. Nickel (II) complexes of naphthaquinone thiosemicarbazone and semicarbazone: Synthesis, structure, spectroscopy, and biological activity. J Inorg Biochem 2005;9:1526.