Studies on the synthesis, characterization and antimicrobial and antifertility aspects of sulfur donor ligands and their Al(III) and Ga(III) complexes

Sunita Yadav 1 , Suresh Chand Joshi 2  and Ran Vir Singh 1
  • 1 Department of Chemistry, University of Rajasthan, Jaipur, India
  • 2 Department of Zoology, University of Rajasthan, Jaipur, India
Sunita Yadav, Suresh Chand Joshi and Ran Vir Singh

Abstract

The biologically important complexes of aluminium(III) and gallium(III) derived from 1-acetylferrocenehydrazinecarbothioamide (L1H) and 1-acetylferrocene carbodithioic acid (L2H) were prepared and investigated using a combination of microanalytical analysis, melting point, electronic, infrared, 1H NMR and 13C NMR spectral studies along with X-ray powder diffraction studies. Aluminium and gallium isopropoxides interact with the ligands in molar ratios of 1:1, 1:2 and 1:3 (metal:ligand), resulting in the formation of coloured products. The ligands are coordinated to aluminium(III) and gallium(III) via the azomethine nitrogen atom and the thiolic sulfur atom. On the basis of X-ray powder diffraction study, one of the representative gallium(III) complexes was found to have orthorhombic lattice, having the following lattice parameters: a=8.9200, b=14.6000 and c=7.0000. On the basis of the above studies, for the aluminium(III) and gallium(III) complexes, pentacoordinated structure for 1:1 complex and hexacoordinated structure for 1:2 and 1:3 complexes were assigned. The antimicrobial activities of the ligands and complexes were screened in vitro against bacteria Pseudomonas cepacicola and Bacillus substilis and fungi Collectatrichum capsici and Fusarium oxysporum. The complexes have higher activities than the free ligands do. In vivo studies of the ligands and their corresponding complexes have also been carried out to assess their antifertility activity. The results of these activities indicate the antiandrogenic nature of these complexes.

Introduction

The coordination chemistry involving ferrocene has attracted great interest since it was discovered by Kealy and Pauson 50 years ago. The large amount of applications of ferrocene derivatives in fields, ranging from non-linear optical materials, electrochemical sensors, liquid crystals, catalysis and nanoparticles, has contributed to the high interest in their chemistry (Ingram et al., 1997; Togni and Halterman, 1998). In addition, the introduction of groups with coordinating capabilities further allows the ferrocenyl moiety to become an organometallic ligand, which can bind with other metal centres in order to enhance their properties. Some antitumor activity has been detected in ferrocenium ion, and although the results were not outstanding, they were promising enough to be extended to specially designed systems (Snegur et al., 2004). As a matter of fact, when ferrocene was introduced in certain molecules, their cytotoxic activity was enhanced (Quintal et al., 2008). The versatility of the ferrocenyl unit, allowing for relatively easy functionalization of one or two rings, as well as the redox capability of the iron centre, explains this success, making possible the tuning of the same basic unit to different challenges. The chemistry of ferrocenyl amides containing amino acids and peptides has been developed to include the introduction of groups able to bind to biological targets in attempts to improve biological applications (Van Staveren and Metzler-Nolte, 2004). The synthesis of ferrocene-labelled amino acids has been carried out (Chowdhury et al., 2005), and the ligand capability of new ferrocenyl moieties toward several metal fragments has been analysed (Appoh et al., 2005). Many reports (Edwards et al., 1975) have shown that replacement of an aromatic group by ferrocenyl moiety in penicillins and cephalosporins improves their medicinal properties. New species and their properties (Heinze and Beckmann, 2005) have been studied in detail, namely as sensors (Suksai et al., 2005).

Aluminium is the third most abundant element in the earth, inferior to oxygen and silicon, and it is widely used as building material for water purification, food additives and clinical drug (Wang et al., 2008). Aluminium, a well-known and commonly exposed neurotoxin, was found to alter glutamate and c-aminobutyrate levels as well as activities of the associated enzymes with regional specificity (Nayak and Chatterjee, 2003; Yang et al., 2007). Aluminium(III) [Al(III)] also inhibits glutamate dehydrogenase, a central enzyme in glutamate metabolism (Zatta et al., 2000). Gallium plays an important role as antitumor (Foster et al., 1986), antiviral (Kratz et al., 1992) and anticoagulant agents, and thallium, as a probe for K+in biological systems (Cox et al., 1988). The trivalent gallium cation is capable of inhibiting tumour growth, mainly because of its resemblance to ferric ion (Jakupec and Keppler, 2004). Gallium(III) [Ga(III)] complexes of an aminophenol ligand are active against chloroquine and Plasmodium falsiparum strains (Ocheskey et al., 2003). In view of these findings, in the present study, we have selected two sulfur donor ligands and studied their Al(III) and Ga(III) complexes. These studies of Schiff base complexes of metals have considerable interest in the spectral structure correlations and mechanism of inorganic reactions. The biochemical, pharmacological and industrial applications of hydrazinecarbothioamides and S-benzyldithiocarbazates and their metal complexes have stimulated us to compare the NS donor system from the structural and biochemical points of view. That is why some imine and their metal complexes were prepared.

Experimental

All the chemicals used in the synthesis of the complexes were of AR grade and supplied by Sisco, Lancaster, and Loachemie. All the solvents were dried and distilled before use. Aluminium and gallium isopropoxides were prepared following methods described in the literature (Belwal et al., 1999; Saini et al., 2009).

Analytical methods and physical measurements

Molecular weights were determined using the Rast camphor method (Barrow, 2004). The infrared (IR) spectra of the ligands and their metal complexes were recorded with the help of a Nicolet Megna FT IR 550 spectrophotometer using KBr pellets. The purity of these ligands and their metal complexes was checked using TLC on silica Gel-G using anhydrous dimethyl sulphoxide and benzene (1:1) as solvent. 1H NMR and 13C NMR spectra were recorded in deuterated dimethyl sulphoxide (DMSO-d6) using tetramethylsilane as standard on a JEOL AL 300 FT NMR spectrometer. Electronic spectra of the complexes were recorded in DMF on a UV-160 Shimadzu spectrophotometer in the range of 200–600 nm. X-ray powder diffractograms of the compounds were obtained on a Philip Model PW 1840 automatic diffractogram using a Cu(Kα) target with Mg filter. The wavelength used was 1.540598 Å. Nitrogen and sulfur were estimated by the Kjeldahl and Messenger methods, respectively (Makode and Aswar, 2004). Carbon and hydrogen analyses were performed at the CDRI, Lucknow.

Preparation of the ligands

The ligands (L1H) and (L2H) were prepared by the condensation of 1-acetylferrocene with hydrazinecarbothioamides and S-benzyldithiocarbazate, respectively, in a 1:1 molar ratio as reported earlier (Yadav and Singh, 2011).

Preparation of Al(III) and Ga(III) complexes

Al(III) and Ga(III) isopropoxide and ligands were dissolved in dry benzene in molar ratios of 1:1, 1:2 and 1:3. The resulting mixture was refluxed for 16–20 h. The progress of the reaction was checked by measuring the amount of isopropanol in the azeotrope. After completion of the reaction, the excess of the solvent was removed under reduced pressure and was dried in vacuo. The physical properties and analytical data of these complexes are listed in Table 1.

Table 1

Physico-chemical properties and analytical data of the ligands and corresponding metal complexes.

S. noCompoundProduct and colourMP (oC)Analyses (%) found (calcd.)Mol. Wt. found (calcd.)
CHNSM
1C13H15N3SFe (L1H)Light brown17451.76 (51.84)4.94 (5.02)13.87 (13.95)10.77 (10.65)314 (301.19)
2C20H20N2S2Fe (L2H)Black22058.72 (58.82)4.82 (4.94)6.81 (6.86)15.63 (15.70)390.41 (408.37)
3[Al(OPri)2(L1)}2Brown232–23451.14 (51.25)6.26 (6.34)9.32 (9.45)7.12 (7.21)5.94 (6.06)898.53 (890.64)
4[Al(OPri)(L1)2}2Dark brown230–23250.66 (50.75)5.06 (5.14)12.12 (12.25)9.21 (9.35)3.82 (3.94)1380.54 (1372.80)
5[Al(L1)3}Black210–21250.40 (50.51)4.49 (4.58)13.52 (13.60)10.24 (10.38)2.80 (2.92)932.56 (927.55)
6[Ga(OPri)2(L1)}2Brown80–8246.66 (46.76)5.69 (5.78)8.50 (8.61)6.46 (6.57)14.16 (14.29)984.56 (976.15)
7[Ga(OPri)(L1)2}2Brown78–8047.68 (47.77)4.72 (4.84)11.42 (11.53)8.71 (8.80)9.45 (9.56)1467.54 (1458.36)
8[Ga(L1)3}Black72–7448.16 (48.28)4.28 (4.36)12.88 (12.99)9.82 (9.91)7.08 (7.19)979.58 (970.28)
9[Al(OPri)2(L2)}2Coffee138–14056.42 (56.53)5.93 (6.03)4.92 (5.07)11.50 (11.62)4.72 (4.89)1112.34 (1105.02)
10[Al(OPri)(L2)2}2Coffee140–14257.24 (57.35)4.92 (5.04)6.12 (6.23)14.12 (14.25)2.83 (2.99)1812.36 (1801.62)
11[Al(L2)3}Brown148–15057.60 (57.70)4.59 (4.60)6.62 (6.74)15.30 (15.41)2.02 (2.16)1258.65 (1249.07)
12[Ga(OPri)2(L2)}2Brick90–9252.36 (52.46)5.50 (5.59)4.62 (4.71)10.68 (10.77)11.64 (11.72)1200.20 (1190.50)
13[Ga(OPri)(L2)2}2Red86–8854.62 (54.74)4.70 (4.81)5.82 (5.94)13.48 (13.59)7.23 (7.39)1894.72 (1887.05)
14[Ga(L2)3}Red88–9055.70 (55.79)4.36 (4.45)6.40 (6.51)14.79 (14.90)5.32 (5.40)1299.94 (1291.81)

Pharmacology

In vitro antifungal and antibacterial assay

  • Antifungal activity: The antifungal activity of the ligands and their complexes was evaluated using the Radial Growth Method using Czapek’s agar medium with the following composition: glucose 20 g, starch 20 g, agar-agar 20 g and distilled water 1000 mL. Solutions of the test compound in dimethylformamide at concentrations of 50, 100 and 200 ppm were prepared. The medium was then poured onto Petri plates and the spores of fungi were placed on the medium with the help of an inoculum needle. The Petri plates were wrapped in polythene bags containing a few drops of alcohol and were placed in an incubator at 30±1°C. The controls were also run, and three replicates were used in each case. The linear growth of the fungus was obtained by measuring the fungal colony diameter after 4 days, and percentage inhibition was calculated as 100(dC-dT)/dC, where dC and dT are the diameters of the fungus colony in the control and test plates, respectively. The organisms used in these investigations included Collectatrichum capsici and Fusarium oxysporum.
  • Antibacterial activity: Activity against bacteria was evaluated using the Inhibition Zone Technique. A nutrient agar medium having the composition peptone 5 g, beef extract 5 g, NaCl 5 g, agar-agar 20 g and distilled water 1000 mL was pipetted into a Petri dish. When it solidified, 5 mL of warm seeded agar was applied. The seeded agar was prepared by cooling the molten agar to 40°C and then adding the amount of bacterial suspension. The compounds were dissolved in dimethylformamide in concentrations of 250, 500 and 1000 ppm. Paper discs of Whatmann No. 1 filter paper with a diameter of 5 mm were soaked in these solutions of varied concentrations. The discs were dried and placed on the medium previously seeded with organisms in Petri plates at suitable distance. The Petri plates were stored in an incubator at 28±2°C for 24 h. The zone of inhibition thus formed around each disc containing the test compounds was measured accurately in millimetres. The organisms used in these investigations included Pseudomonas cepacicola and Bacillus substilis.

Antifertility activity

In view of the potential interest in biologically active compounds, the antifertility activity of selected compounds was studied in male albino rats. Healthy adult male rats (Rattus norvegicus, Wistar strain) weighing between 160 and 180 g were chosen for the experiment. The animals were housed in clean plastic cages covered with chrome plate grills at room temperature (20C±5°C) and uniform light (14:10 light:dark). The animals were maintained mostly on standard rat feed procured from Ashirwad Food Industries Ltd. (Chandigarh, India) and were occasionally on germinated/sprouted gram and wheat seeds as an alternative feed and fresh water ad libitum.

The animals were divided into six groups containing six animals in each group. The animals of group A served as vehicle-treated controls. Groups B, C, D and E animals were administered the ligand L2H (50 mg/kg b.wt. for 60 days in 0.5 mL olive oil orally), whereas the animals of groups C, D and E received [Al(OPri)(L2)2}2, [Al(L2)3} and [Ga(L2)3} complexes, respectively, dissolved in olive oil at a dose level of 50 mg/kg b.wt./day for 60 days. These animals were screened for fertility and were autopsied for determination of detailed biochemical estimations. The sperm motility in cauda epididymis, sperm density in testes and cauda epididymis, protein, sialic acid, glycogen, cholesterol contents of reproductive tissues and serum testosterone were determined by standard laboratory methods. For the histopathological examination, testes were fixed in Bouin’s fluid, and several sections of the testes were prepared with hematoxylin and eosin. The evaluation of cell population dynamics was based on the counts of each cell type per cross-tubular sections. Various cell components were quantitatively analysed using spherically appearing sections. Abercrombie’s correcting factor was introduced (Bernston, 1977). Student’s t-test was used for assessment and significance of variation. Data are presented as mean±SEM.

Results and discussion

The reactions of aluminium and gallium isopropoxides with monobasic bidentate ligands were carried out in molar ratios of 1:1, 1:2 and 1:3 in dry benzene, followed by heating at reflux for 16–20 h. This resulted in the successive replacement of isopropoxy groups according to the following equations (1–3). These compound numbers, which are used in the following equations, are given in Table 1.

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The resulting complexes are coloured solids, soluble in alcohol, benzene, THF, DMF and DMSO. All the reactions could be completed within 16–20 h. The alkoxy derivatives are moisture sensitive, while the 1:3 metal:ligand complexes are quite stable. Molecular weight determinations reveal the dimeric nature of the mono- and bis-alkoxy metal complexes and the monomeric nature of the tris (ligand) metal derivatives. It was observed that the order of the rate of reaction in (metal:ligand) complexes is 1:1>1:2>1:3. However, there is no correlation between the coordination numbers and the melting points of the resulting complexes, particularly in the present case.

Electronic spectra

The electronic spectra of the ligands (L1H and L2H) show broad maxima in the range of 370–360 nm due to the n-π* electronic transitions of the azomethine group. The bands in the region 285–280 nm due to π-π* electronic transitions of the ligands undergoes a blue shift in the metal complexes due to the polarisation within the >C=N chromophore caused by the metal ligand interactions.

IR spectra

The IR spectra of the free ligands L1H and L2H display absorption bands at 2910–3000, 1610–1620 and 1030 cm-1 assigned to ν(N-H), ν(C=N) and ν(C=S), respectively. The broad band due to ν(N-H) vibrations disappears in the spectra of the complexes, indicating the deprotonation of this group on coordination with the metal atom. The negative shift (10–20 cm-1) of the ν(C=N) band observed in all complexes indicates the involvement of azomethine nitrogen upon complexation. The bands due to ν(C=S) shifted towards lower frequencies in the complexes, indicating coordination of sulfur to the central metal atom. The coordination through the azomethine nitrogen atom and the thiol sulfur is further substantiated by the appearance of new bands in the regions 590–460 and 430–300 cm-1, which may be attributed to the different vibrational modes of Al←N and Al-S, respectively. The gallium complexes exhibit new bands in the region 480–350 and 320–280 cm-1, which may be attributed to the different vibrational modes of Ga←N and Ga-S frequencies, respectively. The characteristic bands of the ferrocenyl group appear at 3080–3070, 1450–1445, 1120–1110, 829–825 and 480–470 cm-1 arising from ν(C-H), ν(C=C), δ(C-H), π(C-H) and (Fe-ring), respectively.

1H NMR spectra

The proposed bonding pattern in the newly synthesized complexes is further supported by the 1H NMR spectral studies. The 1H NMR spectra of the ligands and their aluminium and gallium complexes were recorded in DMSO-d6, and the chemical shift values (δ, ppm) are listed in Table 2. The disappearance of the -NH proton signal (δ=8.92–8.96 ppm) of the ligands (L1H and L2H) in their respective metal complexes indicates the removal of a proton from the -NH group and the coordination of nitrogen with simultaneous covalent bond formation by sulfur with the metal. A signal at δ=1.86 ppm due to the -SCH2 and aromatic protons in the complexes appears in almost the same positions as in the respective free ligands. In addition, there appears a sharp singlet (δ=6.22–6.62 ppm), giving evidence for the presence of π-C5H5 group in all the complexes. The spectra of 1:1 complexes display two doublets, which may be assigned to the gem-dimethyl protons of the terminal and bridging isopropoxy groups, respectively. Moreover, the spectra of the bis-isopropoxy metal(III) complexes exhibit two fused spectrums due to methane protons of the terminal and bridging isopropoxy groups, respectively. On the other hand, the spectra of 1:2 complexes exhibit only one singlet and one septate due to methyl protons and methane group of bridging isopropoxy. The spectra of 1:3 complexes show the absence of isopropoxy signals.

Table 2

1H NMR spectral data (δ, ppm) of the ligands and corresponding metal complexes.

Compound-NH (s)-NH2 (s)-S-CH2 (s)-CH3 (s)Isopropoxy groups
Gem-dimethyl (d)Methine (septet)
L1H8.922.292.10
L2H8.961.862.10
[Al(OPri)2(L1)}22.302.441.05 (terminal)4.10 (terminal)
1.22 (bridging)4.46 (bridging)
[Al(OPri)(L1)2}22.312.461.24 (bridging)4.50 (bridging)
[Al(L1)3}2.322.43
[Ga(OPri)2(L1)}22.302.441.05 (terminal)4.10 (terminal)
1.22 (bridging)4.46 (bridging)
[Ga(OPri)(L1)2}22.312.461.24 (bridging)4.50 (bridging)
[Ga(L1)3}2.322.43
[Al(OPri)2(L2)}21.882.431.06 (terminal)4.11 (terminal)
1.22 (bridging)4.42 (bridging)
[Al(OPri)(L2)2}21.902.461.25 (bridging)4.51 (bridging)
[Al(L2)3}1.922.42
[Ga(OPri)2(L2)}21.882.431.06 (terminal)4.11 (terminal)
1.22 (bridging)4.42 (bridging)
[Ga(OPri)(L2)2}21.902.461.25 (bridging)4.51 (bridging)
[Ga(L2)3}1.922.42

13C NMR spectra

The 13C NMR spectra of L1H and L2H and their Al(III) and Ga(III) complexes show the shifting of thiolic and azomethine carbons, further confirming the coordination of sulfur and azomethine nitrogen to the metal atom (Table 3). The spectra of 1:1 complexes exhibit signals due to terminal and bridging isopropoxy, while the spectra of 1:2 complexes show signals only due to bridging isopropoxy. For Al(III) and Ga(III) complexes, a pentacoordinated structure for 1:1 complex and hexacoordinated for 1:2 and 1:3 complexes were assigned (Figure 1).

Table 3

13C NMR spectral data (δ, ppm) of the ligands and corresponding metal complexes.

CompoundChemical shift valuesIsopropoxy group
>C=O/>C=S>C=N/>C-N-CH3Ferrocenyl carbonsα-carbonβ-carbon
L1H192.24179.3011.5969.89, 71.26, 73.07, 77.86
L2H177.46168.9711.5469.96, 71.20, 73.13, 77.39
[Al(OPri)2(L1)}2193.56180.9311.6469.97, 71.19, 73.25, 77.4871.94 (terminal)22.82 (terminal)
73.79 (bridging)23.38 (bridging)
[Al(OPri)(L1)2}2194.12182.2011.6269.98, 71.18, 73.19, 77.5173.19 (bridging)23.06 (bridging)
[Al(L1)3}196.10183.8611.6069.91, 71.18, 72.99, 77.45
[Ga(OPri)2(L1)}2193.56180.9311.6469.97, 71.19, 73.25, 77.4871.94 (terminal)22.82 (terminal)
73.79 (bridging)23.38 (bridging)
[Ga(OPri)(L1)2}2194.12182.2011.6269.98, 71.18, 73.19, 77.5173.19 (bridging)23.06 (bridging)
[Ga(L1)3}196.10183.8611.6069.91, 71.18, 72.99, 77.45
[Al(OPri)2(L2)}2179.24170.2411.6069.89, 71.26, 73.07, 77.8673.95 (terminal)22.57 (terminal)
75.89 (bridging)24.25 (bridging)
[Al(OPri)(L2)2}2180.56171.8211.5869.96, 71.20, 73.13, 77.3975.15 (bridging)23.26 (bridging)
[Al(L2)3}182.48173.2811.5669.95, 71.16, 72.89, 77.49
[Ga(OPri)2(L2)}2179.24170.2411.6069.89, 71.26, 73.07, 77.8673.95 (terminal)22.57 (terminal)
75.89 (bridging)24.25 (bridging)
[Ga(OPri)(L2)2}2180.56171.8211.5869.96, 71.20, 73.13, 77.3975.15 (bridging)23.26 (bridging)
[Ga(L2)3}182.48173.2811.5669.95, 71.16, 72.89, 77.49
Figure 1
Figure 1

Proposed structures of the synthesized metal complexes.

Citation: Main Group Metal Chemistry 36, 3-4; 10.1515/mgmc-2012-0072

27Al NMR spectra

The 27Al NMR spectra of these compounds were recorded in CDCl3 solution with reference to Al(NO3)3. The 27Al NMR spectra of metal complexes have a sharp signal at δ=11.97–14.90 ppm assigned to five-coordinated aluminium complexes.

X-ray powder diffraction

The X-ray powder diffraction of one powdered sample was recorded in order to determine the lattice of the complexes. The observed interplanar spacing values d(A0) were measured from the diffractogram of the complex [Ga(L2)3} in Figure 2, and the Miller indices h, k and l were assigned to each d value. The data suggest an orthorhombic lattice to this derivative, having unit cell dimensions of a=8.9200, b=14.6000 and c=7.0000; the Miller indices h, k and l are recorded in Table 4 and α=β=γ=90°.

Table 4

X-ray powder diffraction data of [Al(L1)3}.

hkl2Θ (exp.)2Θ (calc.)2Θ (diff.)d (exp.)d (calc.)Intensity (exp.)
20123.62023.634-0.0143.763633.761402.35
13124.38624.389-0.0033.647143.646672.75
02228.20628.254-0.0483.161283.15600120.62
14129.30929.333-0.0233.044743.042382.99
05030.62230.5910.0302.917182.920001.94
05030.57330.591-0.0182.921702.920001.97
22234.82134.7950.0262.574392.576242.01
33137.72637.6800.0462.382602.385401.46
16038.31238.3100.0022.347462.347558.92
40040.42840.4160.0122.229362.23000110.36
34141.22641.1950.0302.188042.189581.76
15241.45841.494-0.0362.176292.174513.63
42042.33642.346-0.0102.133172.132713.43
41142.97542.981-0.0062.102912.102632.80
43044.64744.663-0.0162.027972.0273052.32
07145.28545.333-0.0482.000881.9988721.86
14347.26947.309-0.0411.921441.919872.20
41248.76048.782-0.0221.866101.865291.87
36150.08650.124-0.0381.819751.8184646.11
07250.90050.926-0.0261.792561.791703.38
50051.20851.1610.0471.782481.784002.09
17251.99352.018-0.0261.757421.756623.77
43252.09952.0930.0061.754071.754273.97
01452.60652.632-0.0261.738371.737565.45
37053.65153.6320.0191.706951.707503.06
28054.26354.265-0.0021.689121.689064.92
28054.23654.265-0.0291.689901.689064.92
12454.89954.8780.0211.671051.671633.14
03455.77455.779-0.0051.646891.646773.43
40357.06857.085-0.0171.612591.612143.41
26358.52158.537-0.0161.575951.5755720.58
52259.47059.4700.0001.553051.553053.07
17360.33760.375-0.0381.532801.531922.85
17360.40860.3750.0331.531171.531922.79
28260.87960.8460.0331.520441.521192.19
09263.15463.1170.0381.471031.471821.74
60163.98963.9700.0191.453841.454232.33
56166.28366.2660.0161.408981.4092950.28
21067.44567.4420.0031.387501.387552.68
28368.57168.5270.0451.367431.368211.93
Figure 2
Figure 2

X-ray powder diffraction of the complex {Ga (L2)3}.

Citation: Main Group Metal Chemistry 36, 3-4; 10.1515/mgmc-2012-0072

Bioassay

The antimicrobial activity of the synthesized ligands and their corresponding metal complexes on selected bacteria, P. cepacicola and B. substilis, and two fungi, C. capsici and F. oxysporum, was carried out (Tables 5 and 6). Biological activities were compared with the conventional fungicide bavistin and the conventional bactericide streptomycin. The metal chelates are more active than the ligands for antimicrobial activity. Increased biocidal properties after complexation can be explained by the chelation theory (Chohan et al., 2006).

Table 5

Fugicidal screening data for the ligands and their complexes [inhibition after 96 h (%) (conc. in ppm)].

CompoundCollectatrichum capsiciFusarium oxysporum
5010020050100200
L1H435159414450
L2H455462454552
[Al(OPri)2(L1)}2455262424655
[Al(OPri)(L1)2}2475363464856
[Al(L1)3}485465485058
[Ga(OPri)2(L1)}2505463475261
[Ga(OPri)(L1)2}2525665505562
[Ga(L1)3}555867525767
[Al(OPri)2(L2)}2575860474962
[Al(OPri)(L2)2}2606168525469
[Al(L2)3}636470575972
[Ga(OPri)2(L2)}2596062495762
[Ga(OPri)(L2)2}2616265536167
[Ga(L2)3}656667586470
Standard (Bavistin)971001009195100
Table 6

Antibacterial screening data for the ligands and their metal complexes [diameter of inhibition zone (mm) (conc. in ppm)].

CompoundPseudomonas cepacicolaBacillus substilis
25050010002505001000
L1H469358
L2H5710469
[Al(OPri)2(L1)}25710469
[Al(OPri)(L1)2}268115710
[Al(L1)3}710127812
[Ga(OPri)2(L1)}279116710
[Ga(OPri)(L1)2}2810127911
[Ga(L1)3}9111481012
[Al(OPri)2(L2)}25810568
[Al(OPri)(L2)2}29111381012
[Al(L2)3}10121491114
[Ga(OPri)2(L2)}2710116810
[Ga(OPri)(L2)2}2811127911
[Ga(L2)3}10121491014
Standard (Streptomycin)151617141516

Antifertility activity

Body and organ weights

There were no significant differences in body weights observed at the end of the experimental period among the treated groups as compared with the control (Table 7). However, the weights of the testes, epididymis, ventral prostate and seminal vesicle were decreased significantly after treatment with ligand (L2H) and its [Al(OPri)(L2)2}2, [Al(L2)3} and [Ga(L2)3} complexes.

Table 7

Effect of the ligand (L2H) and its corresponding complexes on the reproductive organ weight of male rats.

GroupTreatmentBody weight (g)Organ weight (mg/100 g body weight)
InitialFinalTestesEpididymisSeminal vesicleVentral prostate
AControl185.0±10.0210.0±8.01310.0±25.0470.0±15.8480.0±10.9395.0±9.7
BL2H175.0±9.0205.0±10.0ns1120.0±18.0a390.0±13.8a340.0±10.2b330.0±10.1a
C[Al(OPri)(L2)2}180.0±10.0200.0±9.0ns820.0±24.0b320.0±19.5b325.0±9.7b270.0±13.5b
D[Al(L2)3}190.0±8.0215.0±10.0ns790.0±29.0b290.0±20.2b290.0±10.7b285.0±11.9b
E[Ga(L2)3}2178.0±11.0192.0±8.0ns740.0±20.0b270.0±10.4b270.0±12.4b240.0±10.8b

ns, nonsignificant, group B compared with group A.

aSignificant for groups C, D, E and F compared with group A, p<0.01.

bHighly significant, p<0.001.

Sperm dynamics

The sperm motility in the cauda epididymis was decreased significantly after treatment with ligand (L2H) and its [Al(OPri)(L2)2}2, [Al(L2)3} and [Ga(L2)3} complexes. In addition, significant decreases in fertility and sperm density in the cauda epididymis and testes were observed (p≤0.1–0.001) with ligand (L2H) and its [Al(OPri)(L2)2}2, [Al(L2)3} and [Ga(L2)3} complexes (Table 8).

Table 8

Sperm dynamics and fertility after the administration of the ligand (L2H) and its corresponding complexes.

GroupTreatmentSperm motility%

(cauda epididymis)
Sperm density (million/mL)Fertility (%)Testosterone
TestesCauda epididymis
AControl75.0±2.34.50±0.248.5±4.7100 (+ve)4.9±0.3
BL2H63.0±1.5a3.60±0.1a38.0±5.3a65 (-ve)3.1±0.1a
C[Al(OPri)(L2)2}35.0±1.4b2.4±0.2b20.0±2.5b80 (-ve)1.8±0.4b
D[Al(L2)3}30.0±1.7b1.8±0.3b15.0±1.5b90 (-ve)1.9±0.3b
E[Ga(L2)3}2]28.0±1.6b1.6±0.2b12.0±1.1b95 (-ve)1.68±0.2b

ns, nonsignificant, group B compared with group A.

aSignificant for groups C, D, E and F compared with group A, p<0.01.

bHighly significant, p<0.001.

Biochemical changes

A marked reduction in the protein and sialic acid contents of the testes, epididymis, ventral prostate and seminal vesicle and in glycogen contents in the testes was observed. However, testicular cholesterol contents were increased after treatment with ligands and its various complexes (Table 9). Serum testosterone levels declined significantly after treatment with ligand (L2H) and its [Al(OPri)(L2)2}2, [Al(L2)3} and [Ga(L2)3} complexes.

Table 9

Effect of the ligand (L2H) and its corresponding complexes on tissue biochemistry.

GroupTreatmentSialic acid (mg/g)Protein (mg/g)Testicular cholesterol (mg/g)Testicular glycogen (mg/g)
TestesEpididymisSeminal vesicleVentral prostateTestesEpididymisSeminal vesicleVentral prostate
AControl5.70±0.36.20±0.26.35±0.46.50±0.7250.0±10.5245.0±9.7235.0±10.3247.0±19.64.8±0.73.15±0.17
BL2H4.30±0.4a4.7±0.3a4.9±0.3a5.1±0.1a290.0±9.7a200.0±7.4a195.0±8.4a200.0±5.0a6.5±0.9a2.40±0.2a
C[Al(OPri)(L2)2}2.9±0.2b3.1±0.3b3.7±0.3b4.1±0.2b150.0±9.3b156.0±9.1b170.0±3.9a171.0±4.7b8.20±0.7b1.75±0.4b
D[Al(L2)3}2.5±0.7b2.7±0.4b3.3±0.2b3.7±0.2b155.0±9.7b140.0±3.5b148.0±4.5b142.0±7.5b8.5±0.3b1.30±0.3b
E[Ga(L2)3}2]2.1±0.5b2.3±0.3b2.6±0.1b3.3±0.1b140.0±8.6b138.0±7.5b120.0±9.4b118.0±6.7b8.9±0.4b1.10±0.2b

ns, nonsignificant, group B compared with group A.

aSignificant for groups C, D, E and F compared with group A, p<0.01.

bHighly significant, p<0.001.

Testicular cell population dynamics

A significant reduction in the seminiferous tubular diameter was observed after administration of ligand (L2H) and its [Al(OPri)(L2)2}2, [Al(L2)3} and [Ga(L2)3} complexes. The number of spermatogonia, proleptotene, pachytene and secondary spermatocytes decreased significantly after treatment with ligand (L2H) and its [Al(OPri)(L2)2}2, [Al(L2)3} and [Ga(L2)3} complexes (Table 10).

Table 10

Effect of the ligand (L2H) and its corresponding complexes on testicular cell population and seminiferous tubule diameter of experimental rats (mean±SEM of six animals).

GroupTreatmentTesticular cell count (number/10 cross-sections)
Sertoli cellsSpermatogoniaProleptotene spermatocytePachytene spermatocyteSecondary spermatocyteSeminiferous tubule diameter (mm)
AControl2.90±0.077.1±0.725.0±1.1037.5±1.6048.6±2.80272.0±8.7
BL2H2.42±0.03a5.8±10.5b17.0±1.30a28.0±1.90a37.0±2.10b238.0±7.3a
C[Al(OPri)(L2)2}2.12±0.01a4.90±0.2b14.1±1.50a18.0±1.30b27.0±1.30b180.0±7.4a
D[Al(L2)3}1.90±0.02b4.7±0.3b12.2±1.12b16.0±1.40b22.0±1.90b170.0±6.9b
E[Ga(L2)3}2]1.95±0.03b4.8±0.1b11.3±1.35b12.3±1.70b20.0±1.71b150.0±7.5b

ns, nonsignificant, group B compared with group A.

aSignificant for groups C, D, E and F compared with group A, p<0.01.

bHighly significant, p<0.001.

Discussion

The present study shows that administration of the ligand (L2H) and its [Al(OPri)(L2)2}2, [Al(L2)3} and [Ga(L2)3} complexes at the dose level of 50 mg/kg b.wt. for 60 days resulted in many degenerative changes in the reproductive organs. The decrease in testicular weight may be due to reduced tubular size, spermatogenic arrest and inhibition of steroid biosynthesis (Verma et al., 2005). The reduction in the weight of accessory reproductive organs directly supports the reduced availability of androgen (Joshi et al., 2003). Suppression of gonadotropins might have caused the decrease in sperm density in the testes. The decreased sperm density after oral administration may be due to androgen insufficiency (Sujatha et al., 2001), which caused the impairment in testicular function by altering the activities of the enzymes responsible for spermatogenesis (Sharma et al., 2003), suggesting the antiandrogenic nature of the compounds. It is supported by the reduction in serum testosterone, which clearly demonstrated the inhibitory effects of these compounds on testosterone biosynthesis (Wango et al., 1997).

In the present study, protein content in the testes and other sex organs significantly decreased following the administration of ligand (L2H) and its [Al(OPri)(L2)2}2, [Al(L2)3} and [Ga(L2)3} complexes probably be due to the absence of spermatogenic stages in the testes (Chinoy and Bhattacharya, 1997). Reduced sialic acid level in the testes, epididymis, seminal vesicle and ventral prostates in treated rats may be correlated with loss of androgen (Gupta et al., 2001). Reduced glycogen levels may be due to interference in glucose metabolism. The absence of carbohydrate also suppresses Leydig cell function, and the increase in accumulation of cholesterol in the testes is a direct evidence of the antiandrogenic nature of the complexes (Joshi et al., 2006). The number of proleptotene, pachytene and secondary spermatocytes decreased after administration of ligand (L2H) and its [Al(OPri)(L2)2}2, [Al(L2)3} and [Ga(L2)3} complexes. The reduction might be due to the antiandrogenic nature of the compounds as these stages are completely androgen dependent.

Conclusions

The ligands L1H and L2H coordinate in 1:1, 1:2 and 1:3 metal:ligand ratios as monobasic bidentate. For the Al(III) and Ga(III) complexes, the analytical and spectral studies suggested a pentacoordinated structure for 1:1 complex and hexacoordinated for 1:2 and 1:3 complexes. From the present study, it can be concluded that these complexes are capable of suppressing male fertility and that the addition of Al(III) and Ga(III) moiety further enhances their activity by interfering in the process of spermatogenesis. The antimicrobial and antifertility activities of the complexes are higher than those of the parent ligands.

References

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  • Saini, M. K.; Swami, M.; Fahmi, N.; Jain, K.; Singh, R. V. Antimicrobial, antifertility, and antiradiation studies of Ga(III) and Tl(I) complexes with NS and NO donor systems. J. Coord. Chem. 2009, 62, 3986–3996.

  • Sharma, A.; Verma, P. K.; Dixit, V. P. Effect of Semecarpus anacardium fruits on reproductive function of male albino rats. Asian J. Androl. 2003, 5, 121–124.

  • Snegur, L. V.; Simenel, A. A.; Nekrasov, Y. S.; Morozova, E. A.; Starikova, Z. A.; Peregudova, S. M.; Kuzmenko, Y. V.; Babin, V. N.; Ostrovskaya, L. A.; Bluchterova, N. V.; et al. Synthesis, structure and redox potentials of biologically active ferrocenylalkyl azoles. J. Organomet. Chem. 2004, 689, 2473–2479.

  • Sujatha, R.; Chitra, K. C.; Latchoumycandane, C.; Mathur, P. P. Effect of lindane on testicular antioxidant system and steroidogenic enzymes in adult rats. Asian J. Androl. 2001, 3, 135–138.

  • Suksai, C.; Leeladee, P.; Jainuknan, D.; Tuntulani, T.; Muangsin, N.; Chailapakul, O.; Kongsaeree, P.; Pakavatchai, C. A new heteroditopic receptor and sensor highly selective for bromide in the presence of a bound cation. Tet. Lett. 2005, 46, 2765–2769.

  • Togni, A.; Halterman, R. L. Metallocenes; Wiley-VCH: New York, 1998, pp. 455–544.

  • Van Staveren, D. R.; Metzler-Nolte, N. The bioorganometallic chemistry of ferrocene. Chem. Rev. 2004, 104, 5931–5985.

  • Verma, P. K.; Sharma, A.; Joshi, S. C.; Gupta, R. S.; Dixit, V.P. Effect of isolated fractions of Barleria prionitis root methanolic extract on reproductive function of male rats: preliminary study. Fitoterapia 2005, 76, 428–432.

  • Wang, J.-Q.; Huang, L.; Gao, L.; Zhu, J. H.; Wang, Y.; Fan, X.; Zou, Z. A small and robust Al(III)-chemosensor based on bis-Schiff base N,N′-(1,4-phenylenedimethylidyne)bis-1,4-benzene diamine. Inorg. Chem. Commun. 2008, 11, 203–206.

  • Wango, E. O.; Onyango, D. W.; Odongo, H.; Okindo Mugweru, E. In vitro production of testosterone and plasma levels of luteinising hormone, testosterone and cortisol in male rats treated with heptachlor. J. Pharmacol. Toxicol. Endocrinol. 1997, 118, 381–386

  • Yadav, S.; Singh, R. V. Ferrocenyl-substituted Schiff base complexes of boron: Synthesis, structural, physico-chemical and biochemical aspects. Spectrochim. Acta Part A 2011, 78, 298–306.

  • Yang, X.; Zhang, Q.; Li, L.; Shen, R. Structural features of aluminium(III) complexes with bioligands in glutamate dehydrogenase reaction system – a review. J. Inorg. Biochem. 2007, 101, 1242–1250.

  • Zatta, P.; Lain, E.; Cagnolini, C. Effects of aluminum on activity of Krebs cycle enzymes and glutamate dehydrogenase in rat brain homogenate. Eur. J. Biochem. 2000, 267, 3049–3055.

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  • Appoh, F. E.; Sutherland, T. C.; Kraatz, H.-B. Ferrocenoyl-amino acids: redox response towards di- and trivalent metal ions. J. Organomet. Chem. 2005, 690, 1209–1217.

  • Barrow, G. M. Physical Chemistry; Tata McGraw Hill, 2004, pp. 291–292.

  • Belwal, S.; Fahmi, N.; Singh, R. V. Synthesis and structural aspects of aluminium (III) imine complexes. Indian J. Chem. 1999, 38, 596–600.

  • Bernston, W. E. Methods of quantification of mammalian spermatogenesis – a review paper. J. Anim. Sci. 1977, 44, 818–833.

  • Chinoy, N. J.; Bhattacharya, S. Effects of chronic administration of aluminium chloride on reproductive function of testes and some accessory sex organs of male mice. Indian J. Environ. Toxicol. 1997, 7, 12–15.

  • Chohan, Z. H.; Arif, M.; Shafiq, Z.; Yaqub, M.; Supuran, C. T. In vitro antibacterial, antifungal & cytotoxic activity of some isonicotinoylhydrazide Schiff’s bases and their cobalt (II), copper (II), nickel (II) and zinc (II) complexes. J. Enzyme Inhibit. Med. Chem. 2006, 21, 95–103.

  • Chowdhury, S.; Mahmoud, K. A.; Schatte, G.; Kraatz, H.-B. Amino acid conjugates of 1,1′-diaminoferrocene. Synthesis and chiral organization. Org. Biomol. Chem. 2005, 3, 3018–3023.

  • Cox, B. G.; Troka, J. S.; Schneider, I.; Scheider, H. Kinetic studies and thermodynamic results for complex formation and solvation of thallium(I) cryptates in acetonitrile and in acetonitrile-water mixtures. Inorg. Chim. Acta 1988, 147, 9–15.

  • Edwards, E. I.; Epton, R.; Marr, G. Organometallic derivatives of penicillins and cephalosporins a new class of semi-synthetic antibiotics. J. Organomet. Chem. 1975, 85, C23–C25.

  • Foster, B. J.; Leyland-Jones, B. Gallium nitrate: the second metal with clinical activity. Cancer Treat. Rep. 1986, 70, 1311–1319.

  • Gupta, R. S.; Yadav, R.; Dixit, V. P.; Dobal, M. P. Antifertility studies of Colebrookia oppositifolia leaf extract in male rats with special reference to testicular cell population dynamics. Fitoterapia 2001, 72, 236–245.

  • Heinze, K.; Beckmann, M. Conformational analysis of chiral ferrocene-peptides. Eur. J. Inorg. Chem. 2005, 17, 3450–3457.

  • Ingram, R. S.; Hostetler, M. J.; Murray, R. W. Poly-hetero-ω-functionalized alkanethiolate-stabilized gold cluster compounds. J. Am. Chem. Soc. 1997, 119, 9175–9178.

  • Jakupec, M. A.; Keppler, B. K. Gallium in cancer treatment. Curr. Top. Med. Chem. 2004, 4, 1575–1583.

  • Joshi, S. C.; Mathur, R.; Gajraj, A.; Sharma, T. Influence of methyl parathion on reproductive parameters in male rats. Environ. Toxicol. Pharmacol. 2003, 14, 91–97.

  • Joshi, S. C.; Goyal, R.; Choudhary, N.; Jain, S. Effect of lindane on fertility and biochemical markers of male rats. Asian J. Microbiol. Biotechnol. Environ. Exp. Sci. 2006, 8, 755–758.

  • Kratz, F.; Nuber, B.; Weiss, J. Keppler, B. K. Synthesis and characterization of potential antitumour and antiviral gallium(III) complexes of N-heterocycles. Polyhedron 1992, 11, 487–498.

  • Makode, J. T.; Aswar, A. S. Synthesis, characterization, biological and thermal properties of some new Schiff base complexes derived from 2-hydroxy-5-chloroacetophenone and S-methyldithiocarbazate. Indian J. Chem. 2004, 43, 2120–2125.

  • Nayak, P.; Chatterjee, A. K. Dietary protein restriction causes modification in aluminum-induced alteration in glutamate and GABA system of rat brain. BMC Neurosci. 2003, 4, 1–14.

  • Ocheskey, J. A.; Polyakov, V. R.; Harpstrite, S. E.; Oksman, A.; Goldberg, D. E.; Piwnica-Warms, D.; Sharma, V. Synthesis, characterization, and molecular structure of a gallium(III) complex of an amine-phenol ligand with activity against chloroquine-sensitive Plasmodium falciparum strains. J. Inorg. Biochem. 2003, 93, 265–269.

  • Quintal, S.; Matos, J.; Fonseca, I.; Fe’lix, V.; Michael, G. B. D.; Trindade, N.; Meireles, M.; Calhorda, M. J. Synthesis and properties of new trinuclear Mo(II) complexes containing imidazole and benzimidazole ferrocene units. Inorg. Chim. Acta 2008, 361, 1584–1596.

  • Saini, M. K.; Swami, M.; Fahmi, N.; Jain, K.; Singh, R. V. Antimicrobial, antifertility, and antiradiation studies of Ga(III) and Tl(I) complexes with NS and NO donor systems. J. Coord. Chem. 2009, 62, 3986–3996.

  • Sharma, A.; Verma, P. K.; Dixit, V. P. Effect of Semecarpus anacardium fruits on reproductive function of male albino rats. Asian J. Androl. 2003, 5, 121–124.

  • Snegur, L. V.; Simenel, A. A.; Nekrasov, Y. S.; Morozova, E. A.; Starikova, Z. A.; Peregudova, S. M.; Kuzmenko, Y. V.; Babin, V. N.; Ostrovskaya, L. A.; Bluchterova, N. V.; et al. Synthesis, structure and redox potentials of biologically active ferrocenylalkyl azoles. J. Organomet. Chem. 2004, 689, 2473–2479.

  • Sujatha, R.; Chitra, K. C.; Latchoumycandane, C.; Mathur, P. P. Effect of lindane on testicular antioxidant system and steroidogenic enzymes in adult rats. Asian J. Androl. 2001, 3, 135–138.

  • Suksai, C.; Leeladee, P.; Jainuknan, D.; Tuntulani, T.; Muangsin, N.; Chailapakul, O.; Kongsaeree, P.; Pakavatchai, C. A new heteroditopic receptor and sensor highly selective for bromide in the presence of a bound cation. Tet. Lett. 2005, 46, 2765–2769.

  • Togni, A.; Halterman, R. L. Metallocenes; Wiley-VCH: New York, 1998, pp. 455–544.

  • Van Staveren, D. R.; Metzler-Nolte, N. The bioorganometallic chemistry of ferrocene. Chem. Rev. 2004, 104, 5931–5985.

  • Verma, P. K.; Sharma, A.; Joshi, S. C.; Gupta, R. S.; Dixit, V.P. Effect of isolated fractions of Barleria prionitis root methanolic extract on reproductive function of male rats: preliminary study. Fitoterapia 2005, 76, 428–432.

  • Wang, J.-Q.; Huang, L.; Gao, L.; Zhu, J. H.; Wang, Y.; Fan, X.; Zou, Z. A small and robust Al(III)-chemosensor based on bis-Schiff base N,N′-(1,4-phenylenedimethylidyne)bis-1,4-benzene diamine. Inorg. Chem. Commun. 2008, 11, 203–206.

  • Wango, E. O.; Onyango, D. W.; Odongo, H.; Okindo Mugweru, E. In vitro production of testosterone and plasma levels of luteinising hormone, testosterone and cortisol in male rats treated with heptachlor. J. Pharmacol. Toxicol. Endocrinol. 1997, 118, 381–386

  • Yadav, S.; Singh, R. V. Ferrocenyl-substituted Schiff base complexes of boron: Synthesis, structural, physico-chemical and biochemical aspects. Spectrochim. Acta Part A 2011, 78, 298–306.

  • Yang, X.; Zhang, Q.; Li, L.; Shen, R. Structural features of aluminium(III) complexes with bioligands in glutamate dehydrogenase reaction system – a review. J. Inorg. Biochem. 2007, 101, 1242–1250.

  • Zatta, P.; Lain, E.; Cagnolini, C. Effects of aluminum on activity of Krebs cycle enzymes and glutamate dehydrogenase in rat brain homogenate. Eur. J. Biochem. 2000, 267, 3049–3055.

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