Synthesis, Characterization and Electrochemical Behavior of Transition Metal (II) Complexes from 2, 6-Diphenyl-Piperidin-4-Thiosemicarbazone and their Antimicrobial Studies

 

A. Jamal Abdul Nasser¹*, A. Pasupathy ², R. Surendra Kumar¹ and A. Idhayadhulla¹

¹P.G. and Research Dept. of Chemistry, Jamal Mohamed College, Tiruchirappalli-620020, Tamil Nadu, India

² Department of Chemistry, Urumu Dhanalakshmi College, Tiruchirappalli - 620 019. Tamil Nadu, India

*Corresponding Author E-mail: jamal_abdulchem@ymail.com

ABSTRACT:

2,6-dipheyl–piperidin-4-thiosemicarbazone (DPPTSC) ligand and their metal (Co^II,  Ni^II , Cu^II, Cd^II ) complexes have been synthesized and characterized by IR, ¹H NMR, elemental analysis, molar conductance, magnetic susceptibility measurements. The electrochemical property was studied by cyclic voltammeter. All the metal complexes are [ML₂Cl₂] type, where M= Co, Ni Cu, Cd and L = DPPTSC act as a bidentate ligand in all the complexes. Distorted octahedral geometry for Cu complex and octahedral geometries for all other complexes are proposed. The newly synthesized metal complexes have been screened at in vitro for their antimicrobial activity against five bacterial strains and five fungai strains, all the complexes and ligand CPPTSC possess strong inhibitory action against bacteria and fungi, the antimicrobial activities of the complexes are stronger than those of ligand CPPTSC itself.

 

 

 

INTRODUCTION:

The study of thiosemicarbazone compounds has received great impetus in recent years due to their remarkable potential of tumours¹, antitubercular², antimalarial³, antileishmanial^4­ and antifungal activities⁵, the biological activities of the thiosemicarbazone ligands have been attributed to their transition metal complex abilities and the metal compounds have been generally found to possess enhanced therapeutic properties⁶. Thiosemicarbazone also active potential of anticancer activity⁷, it have been noted in case of several copper thiosemicarbazone⁸. Thiosemicarbazone active against protozoa, small box, certain kind of tumors, it was found that the drugs when administered as metal chelates increased their activity⁹ and number of metal chelates were found to inhibit tumor growth¹⁰.Copper complexes of bis(thiosemicarbazones) was found by antitumor activity¹¹ and Compound containing –SO₂-NH – group have been found to display antifungal¹², and antibacterial¹³, similarly some thiosemicarbazones of some ketones exhibit antibacterial activities and also fungi toxicity¹⁴.

 

Thiosemicarbazones are biologically active pharmacophores besides having good complexing ability enhances on complexion with metal ion¹⁵. Metal complexes of ligand’s containing thiosemicarbazone’s are pharmacophores much less investigates recently; we have investigated the nuclease activity of copper complexes of hetero aromatic thiosemicarbazone¹⁶. Thiosemicarbazone derivatives of shift base compounds contain N,S-donor chromophores and metal complexes exhibit non-linear optical properties¹⁷, and  wide range of biological activities such as antitumour, antilenkemic¹⁸, antibacterial, antiviral activities¹⁹ and antimalarial activity²⁰. Prepared many thiosemicarbazones (TSC’s) derivatives and found that all the tumor inhibitions potentially act as N-N-S type ligands in general, the N,S- types tridentate donor ligands of substituted thiosemicarbazones and thiosemicarbazide are attributed to their ability to chelate and form as metal complexes²¹ . Thiosemicarbazone derivatives exhibit a wide spectrum of biological activities, such as antitumour²², antimalarial²³, antileuhemic properties²⁴, antiviral activity²⁵, antibacterial²⁶, and antifertility properties²⁷. Metal complexes with ligands contains N, O and S donor atoms are useful as potential drugs²⁸, fungicidal²⁹ and antibacterial³⁰ agents. The biological properties of thiosemicarbazone are often related to the metal ion coordination. Thiosemicarbazone derivatives of various aldehydes and their transition metal complexes present wide biological activities^31,32, copper complexes with thiosemicarbazone derivatives are found to be potent of cytotoxic^33,34, antifungal and antibacterial activities^35,36, antiviral activity³⁷, and the coordinating properties of some thiosemicarbazone metallic complexes have also been studied^38-41. Piperidine were reported to possess analgesic, anti-inflammatory, central nervous system (CNS)^42,43, synthesis of 2,6-diaryl-3-methyl-piperidin-4-thiosemicarbazone and biological activity have reported the literature⁴⁴. Through literature survey indicates that 2,6-diphenyl–piperidine-4-thiosemicarbazone have not been used as a ligand for transition metal complexes but only report on copper(II) piperidine-4-one complexes⁴⁵. As part of our study, 2,6-diphenyl-piperidine-4-thiosemicarbazone derivatives and their metal complexes were prepared and studied their biological, and electrochemical behavior.

 

MATERIAL AND METHODS:

All the reagents were used for merk products. The IR Spectra were recorded on a Nicoler Mgna 550 FTIR Spectrophotometer in the range 4000-200 cm^-1 employing KBr Pellets. Electronic spectra were recorded with a Lambda 35 Uv/Vis spectrophotometer from DMSO (10^-3 mol.dm^-3) and  ¹H NMR Spectra were recorded on a Bruker DRX-300Mhz. Magnetic Susceptibility measurement of the complexes were done using a Guy balance.  Elemental analysis (C, H, N, S) were taken using on Elementer analyzer model vario EL IIIS. Cyclic voltogram of the complexes were recorded in dichloride methane solution at 300k using a three electrode cell comprising reference Ag /AgCl auxiliary Pt and working glassy carbon electrodes. Motor conductivity was measured on a synchronic conductivity bridge with a dip-type cell using 10^-3 M solution of complexes in DMSO.

 

Synthesis of DPPTSC:

A mixture of 2,6-diphenyl-piperidine-4-one( 0.1mol) and   thiosemicarbazide (0.1mol) dissolved in ethanol (30 mL) and add few drops of DMSO, the reaction mixture was refluxed on a steam bath for 3h with continuous stirring. The reaction mixture were cooled and poured into crushed ice, the precipitate was obtained was filtered, washed with water, dried and recrystallized by absolute alcohol.

 

Synthesis of Metal complexes

All the complexes were prepared in anhydrous ethanol. (0.02 mol) DPPTSC in ethanol solution was added (drop wise with continuous stirring) to an ethanolic solution of the corresponding metal (II) Chloride (0.01mol) 1: 2 molar ratio. The mixture was gently stirred and refluxed for 2h, and then refluxed on water bath for 3-4 h. The precipitated metal complexes were washed with ethanol and dried under reduced pressure.

 

Antimicrobial Activity:

In vitro Antibacterial screening:

The compound DPPTSC and its metal complexes were evaluated for their In vitro antibacterial activity against S.aureus (MTCC 96), E. faecalis (MTCC 439), E. coli (MTCC 739), and P. aeruginosa (MTCC-2453) by agar dilution method⁴⁶, was performed using Mueller–Hinton agar (Hi-Media) medium. Each compound was tested at a concentration of 100μg/mL in DMSO. The zone of inhibition was measured after 24h incubation at 37ºC, Norfloxacin used as a standard. The results are summarized in Table 3.

 

In vitro antifungal screening :

The compound DPPTSC and its metal complexes were evaluated for their In vitro antifungal activity of A. niger (MTCC-282), C. albicans (MTCC-227), A. fumigatus (MTCC1811), Cr. neoformans (Clinical isolate) using an agar dilution method⁴⁷ with sabouraud’s dextrose agar (Hi-Media). Each compound was tested at a concentration of 100μg/mL in DMSO. The zone of inhibition (mm) were measured incubated at 37°C for 24h, Ketoconazole used as a standard. The results are summarized in Table 4.

 

RESULTS AND DISCUSSION:

The reaction of metal chloride with (DPPTSC) (I) (Figure1) in 1:2 molar ratio results in the formation of complex (ll) (Figure 2). All the metal complexes are non- hygroscopic in nature, stable at room temperature, insoluble in water and slightly soluble in common organic solvents but fully soluble in DMSO. The Molar conductivity shows that all the complexes are non- electrolyte with   l= 0.88 -1.97 Ω^-1 mol^-1 in DMF (10^-4 M) solution at room temperature. A comparative interpretation of the IR spectral data Table 2 suggests the DPPTSC acts as a bi-dentate ligand in the complexes, using both sulphur and nitrogen as donor atoms. Physicochemical characterization data summarized in Table 1.

 

Figure 1. Ligant  (DPPTSC) (I)

 

Figure 2. Ligant  (DPPTSC) and their metal complexes (M = Co^ll  , Ni ^ll , Cu ^ll, Cd ^ll  ) (II)

Table 1.  Physical characterization of ligand and complexes

Compounds	Colour	Yield (%)	B.M. µ eff	Mol.Cond (Ω-1cm-2 mol-1)	Found (Calculated) (%)
					C	H	N	S	M
DPPTSC	Colourless	82	-	-	58.52 (58.57)	8.41 (8.43)	18.52 (18.63)	14.18 (14.22)	-
[CoCl2(DPPTSC)2]	Brown	64	4.6	0.28	55.20 (55.47)	5.28 (5.1)	14.65 (14.38)	8.54   (8.23)	7.41 (7.56)
[NiCl2(DPPTSC)2]	Green	72	2.7	1.29	55.32 (55.49)	4.78 (4.88)	14.24 (14.38)	8.17 (8.23)	7.21 (7.53)
[CuCl2(DPPTSC)2]	Brown	68	1.9	1.59	55.48 (55.19)	5.64 (5.10)	14.27 (14.30)	8.64 (8.18)	8.42 (8.11)
[CdCl2(DPPTSC)2]	Yellow	78	diam	1.08	52.87 (52.71)	4.74 (4.87)	13.54 (13.66)	7.52 (7.81)	13.65 (13.70)

 

Table 2.  IR Spectra Values  for DPPTSC and its complexes

Compound	υ (NH2)	υ (NH)	υ (C=S)	υ (C=N)	υ (N-H)	υ ( Ar-H)	υ (M-N)	υ (M-S)	υ (m-Cl )
DPPTSC	3470as 3301s	3075	1081	1687	948	828	-	-	-
[CoCl2 (DPPTSC)2 ]	3421as 3329s	3162	1024	1654	921	832	425-470	322	303
[NiCl2(DPPTSC)2]	3465as 3302s	3029	1042	1663	962	301	432	330	301
[CuCl2(DPPTSC)2]	3432as 3249s	3026	1062	1672	981	366	457	326	361
[CdCl2(DPPTSC)2]	3401as 3332s	3077	1087	1681	976	857	446	341	358

 

Table 3. Antibacterial activity of DPPTSC and its metal complexes zone of inhibition

Compounds	S. aureus	E. feacalis	E.coli	P. aeruginosa
DPPTSC	12	14	16	8
[CoCl2 (DPPTSC)2]	23	17	12	6
[NiCl2(DPPTSC)2]	18	8	23	8
[CuCl2(DPPTSC)2]	22	20	24	21
[CdCl2(DPPTSC)2]	21	10	21	15
Norfloxacin	22	15	24	21

Indicates bacteria are resistant to the compound 100μg/mL

Norfloxacin is used as the standard drug

Resistance             < 10mm

Slightly active       > 10 to 15 mm

Moderately active > 15 to 20 mm

Highly active        > 20 to 25 mm

 

Table 4. Antifungal activity of DPPTSC and its metal complexes zone of inhibition (mm)

Compounds	A. niger,	C. albicans,	A. fumigatus	C. neoformans
DPPTSC	12	10	12	13
[CoCl2 (DPPTSC)2]	16	16	16	16
[NiCl2(DPPTSC)2]	20	19	20	18
[CuCl2(DPPTSC)2]	22	21	23	19
[CdCl2(DPPTSC)2]	8	10	16	8
Ketoconazole	22	24	16	18

Indicates fungal are resistant to the compound 100μg/mL, ketoconazole is used as the standard

Resistance               < 10mm

Slightly active         > 10 to 15 mm

Moderately active   > 15 to 20

Highly active           > 20 to 25

 

IR spectra:

The IR Spectra of DPPTSC shows two strong band at 3470 and 3301 cm^-1 attributed respectively to n(N-H) asymmetric and n (N-H) symmetric vibration of the terminal NH₂ group. A Medium intensity band at 3075 is attributed to the N-H Stretching vibration of the imino group the band at 1687 cm^-1 is due to n(C=N) while the order at 948 cm^-1 is assigned to n (N-N). The ligand DPPTSC shows strong band at 1081 cm^-1 assigned to n(C=S). A comparison of the spectra of DPPTSC to these of its metal complexes Table 2 allows as determining the coordinating atom in all species.

 

DPPTSC act as a bidentate ligand having the azomethine nitrogen C=N and the sulfur atom as C=S group. This mode of complexation is supported by the following observation, the n(C=N) moved to lower wave number and down ward shift of n (C=S); the appearance of new bands in the regions 425-470, 322-349 and 303-388 cm^-¹ relative to n (M-N), n (M-S) and n (M-Cl) respectively. This indicates that the sulfur atom of C=S group and azomethine nitrogen atom are involved in coordination.The values are summarized in Table 2 .

ELECTRONIC SPECTRA:

The Electronic spectra of the cobalt (II) complex exhibit bands at 14677, 16328, 38403 cm ^-1 which were assigned to ⁴T1g®⁴T2g (F), ⁴T1g ® ⁴T1g (p), ⁴T1g® ⁴T2g and change transfer transitions of the d⁷ system. Therefore octahedral geometry was proposed for (Co (II)) Complex. The electronic spectra of nickel (II) Complex exhibit multiple bands at 14769, 23838, 37627 cm^-1 which are assigned to    ³A2g ®³T2g, ³A2g ®³T1g (F), ³A2g ^®3T1g (P) and change transfer transition of d⁸ system. Hence octahedral geometry was proposed for Ni complex. The electronic spectrum of Cu (II) Complexes show that 1400, 20500, and 34800 cm^-1 which were assigned to ²B1g ®²A1g, ²B1g®²Eg and change transfer transition of d⁹ system. Hence a distorted octahedral geometry was proposed for the Cu complex. The UV electronic spectra of Cd Complex show the occurrence of an absorption characteristics of p- p* transition shifted by hypsochromic effect.

 

¹H NMR Spectra:

¹H NMR Spectra of a ligand and its metal complexes were recorded in DMSO-d₆ solution. The ligand shows a multiplet between d 7.06 and 7.88 d which is due to aromatic protons. In the spectrum of DPPTSC following signals were observed at d 9.76 (s, IH, NH), 8.15 (s, 1H, N-NH), 7.01-7.98 (m, 5H, Ph-H), 6.73 (s, 2H, NH₂), 3.61-3.74 (d, 2H, 2,6-H). The ¹H spectra did not show significant differences between the ligand and its metal complexes. The spectral data reveal formation of [MCl₂ (DPPTSC)₂] type complexes.

 

Figure 3. Cyclic voltammogram of [CuCl₂ (DPPTSC)₂] at 300 Kk in DMSO solution; Scan rate 100 mVs^-1

 

Cyclic voltammetry:

Cyclic voltamogram of the copper complex in CH₂Cl₂ solution using tetra ethyl ammonium-tetra fluoro borate as supporting electrolyte (1.1 to - 0.8V potential range) shows a well defined redox process corresponding to the formation of the Cu (II)/ Cu(III) couple at Epa=0.64V and the associate cathode peak at Epc= 0.19V .This couple is found to be reversible with DEp = 0.45V and  the ratio of cathodic to anodic peak current (IPc / IPa~I) corresponding to a simple one electron process. This couple is found to be quasi-reversible as the peak separation between the anodic and cathode potential is very high. But the ratio between the anodic and cathodic currents suggests that the process is simple one-electron transfer, quasi-reversible process. The reversibility of the Cu(II)/Cu(III) couple of the complex was unaffected by varying the scan rates ranging from 50 mVs^-¹ with peak potential. (Figure 3) indicated that cyclicvoltammogram graph of [CuCl₂(DPPTSC)₂] at 300 Kk in DMSO solution; Scan rate 100 mVs^-1

 

Antimicrobial activities:

In vitro antibacterial activity of ligand (I) and its metal complex (II), the results showed that ligant low activity compared with metal complexes. Cupper containing complex has highly active against E. coli compared with other complex and compared with standard equipotent activity. In vitro antifungal studies of Cupper containing complex has highly active against A .fumigatus compared with other complex and standard.

 

CONCLUSION:

A new serious of 2,6-diphenyl-piperidin-4-thiosemicarbazone and their metal (II) complexes have been synthesized and characterized by spectral, electrochemical behavior and antimicrobial activity.

 

ACKNOWLEDGMENT:

We wish to thank Dr. J. Selvin Department of Microbiology Bharathidasan University, for their help in microbial activities. We sincerely thank Principal and management committee of Jamal Mohamed College, for providing Laboratory and financial support.

 

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Received on 04.06.2010        Modified on 22.06.2010

Accepted on 01.07.2010        © AJRC All right reserved