Sulfurdonor ligands

Thiosemicarbazones

Thiosemicarbazones have anti-viral, -malarial, -fungal, -microbial and -tumor activity.5 Their Pd(II) complexes are expected to enhance the properties of these ligands. The ligands used are included in Figure 21.1.

Thus, Pd(II) complexes of general formula [PdLCl2] (L is a thiosemicarbazone derivative) (Figure 21.1a) were prepared and screened in vitro against HK-9 strain of Entamoeba histolytica and found active. All complexes were more

(L) is 5-nitrothiophene-2-carboxaldehyde-fl-thiosemicarbazone

R = o-toludine (5-N-2-TCA-o-TolTSCN) R = m-toludine (5-N-2-TCA-m-TolTSCN) R = p-toludine (5-N-2-TCA-p-TolTSCN) R = n-methylbutyl (5-N-2-TCA-NMBuTSCN) R = n-methylbenzyl (5-N-2-TCA-NMBzTSCN) R = cyclooctyl (5-N-2-TCA-COTSCN) R = admantamine (5-N-2-TCA-AdmTSCN) (a)

R2= H, R-, = H, 2-acetylpyridine thiosemicarbazone (HAcTsc)

R2= H, R1 = piperazinyl (HAc4PiPizTsc)

R2 = formyl, R1= piperazinyl (HFo4PiPizTsc)

thiophene-2-carboxaldehyde-pyrrolidine thiosemicarbazone (2-TCA-PYRTSC)

thiophene-2-carboxaldehyde-1,2,3,4-tetrahydroquinoline thiosemicarbazone (2-TCA-1,2,3,4THQTSC)

R = 2-chlorobenzyl (2-TCA-2-CBTSC) R = 2,4-difluoroaniline (2-TCA-2,4-DFATSC) R = 2,6-difluoroaniline (2-TCA-2,6-DFATSc) (b)

CHOH

CHOH

3-deoxy-D-erythro-hexos-2-ulose bis(thiosemicarbazone) (d)

Figure 21.1

active than the free ligands themselves. The complexes [Pd(5-N-2-TCA-COTSCN)Cl2] and [Pd(5-N-2-TCA-AdmTSCDN)Cl2] displayed activities higher than that of the drug metronidazole (2-methyl-5-nitro-1H-imidazole-1-ethanol) with IC50 values of 0.81 ± 0.22 and 0.73 ± 0.18 mM, 2.05 ± 0.33 mM, respectively.7

More thiosemicarbazone derivative complexes of Pd(II) (Figure 21.1b) of related formulae were also screened for anti-amoebic activity against strain of

E. histolytica (HM-1:1 MSS).8 The best results were found with [Pd(2-TCA-1,2,3,4-THQTSCD)Cl2] (IC50 = 1.15 ± 0.34 mM).

Complexes of formulae [Pd(AcTSC)Cl], [Pd(HAcTSCD)2]Cl2 and [Pd(AcTsc)2] (HAcTsc is 2-acetylpyridine thiosemicarbazone, Figure 21.1c) showed a completely lethal effect on Gram(+) bacteria (Staphylococcus aureus, Bacillus cereus) but no effect against Gram(—) bacteria (E. coli, P. aeruginoza).9

Another series of Pd(II) complexes with 2-acetylpyridine N(4)-ethyl-thio-semicarbazones (HAc4EtTSCD), 2-acetylpyridine N(4)-1-(2-pyridyl)-piperazinyl thiosemicarbazones (HAc4PiPizTSCD) and 2-formylpyridine N(4)-1-(2-pyridyl)-piperazinyl thiosemicarbazone (HFo4PiPizTSCD) of various formulae were tested for anti-bacterial activity against Gram(—) E. coli and B. subtilis, and Gram(+) B. cereus and S. aureus. Complexes Pd(Ac4EtTSCD), Pd(HAc4Pi-PizTSCD)2Cl2, Pd(Ac4EtTSCD)2 and Pd(Fo4PiPizTSCD)2 were more effective, with maximum inhibitory concentration (MIC) values of 6-12 mg/ml but not one affected E. coli growth, at a concentration of 100 mg/ml.10

3-Deoxy-D-erythro-hexos-2-ulose bis(thiosemicarbazone) (Figure 21.1d) acts as a tetradentate N2S2-donor ligand. Its complex of Pd(II) has shown anti-viral activity against poliovirus type I.11

The ligand pyridine-2-carbaldehyde thiosemicarbazone (HFo4TSCD) and its three complexes with Pd(II) were studied for their activity against herpes simplex virus 1 (HSV-1) infection in cultured cells.12 [Pd(HFo4TSCD)2]Cl2, [Pd(Fo4TSCD)2] and [Pd(Fo4TSCD)Cl] complexes were cytotoxic, with a maximum non-toxic concentration (MNC) of 1-10 mmol/l and a 50% cytotoxic concentration (CC50) of 60-100 mmol/l after 72 h, for all.

Dithiocarbazates

The ligands S-acetyl N^-acetyldithiocarbazate (aadt) (Figure 21.2a), S-methyl-N^-[5-nitrothiophene-2-yl) methylene]dithiocarbazate (mndt) (Figure 21.2b) and S-benzyl N^-[5-nitrothiophene-2-yl) methylene]dithiocarbazate (bntdt) (Figure 21.2c) afforded complexes of formulae [Pd(L)Cl2]13 (L are ligands Figure 21.2a-c) with Pd(II). Ligand (Figure 21.2a) coordinates with the thioxo S-atom and the carbazate N(/3)-atom while ligands (Figure 21.2b) and (Figure 21.2c) use the thioxo S-atom and the azomethine N-atom.13

Screening for anti-amebic activity of these compounds against the HK-9 strain showed all to be more active than their respective free ligands and comparable to the activity of metronidazole, a highly effective drug against the acute disease, with an IC50 value of 0.33 mg/ml, compared with those for the complexes [Pd(aadt)Cl2], [Pd(mntdt)Cl2] and [Pd(bntdt)Cl2] of 0.53 ± 0.09, 0.32 ± 0.08 and 0.28 ± 0.07, respectively. These results indicate that complex-ation to Pd(II) increases the activities of the free ligands and modifies them from amebostatic to amebicidal.13

o2n xs iS

o2n xs iS

Figure 21.2

Complexes of formulae [Pd(L)2]Cl2 and [Pd(L)2]14 with L = o-FC6H4C-(H)NNC(SH)SCH2Ph or o-FC6H4C(Me)NNC(SH)SCH2Ph (Figure 21.3) were synthesized and tested against selected fungi and bacteria. The results have shown that the Pd(II) complexes exhibit higher inhibitory effects than the free ligands.

The synthesis, characterization and biochemical behavior of Pd(II) complexes of benzylidenehydrazinecarboxamide and -carbothiamide have been described.15 Complexes correspond to the formulae [Pd(RN—XH)2]Cl2 and [Pd(RN—X)2] (X is O or S). Against selected pathogenic fungi and bacteria, the complexes showed higher inhibitory effects than the free ligands. This observation was attributed to the inherent properties of metal ions to denaturate proteins.15

It is noteworthy that the complex [Pd(H2Cu)ClPy] (H2Cu is 5-carboxyuracil (isoorotic acid)), prepared amongst a series of Ag(I), Pt(II) and Pt(IV) complexes of isoorotic and thioisoorotic acid, was found active against Pseudomonas sp. and Microcus sp. at MIC values lower than 50 mg/cm3.16

The mixed ligand complexes involving methionine (meth), 2-mercaptopyr-imidine (2-Spym) and 2-aminopyrimidine (2-Spym) of formulae [Pd(meth)-Cl2], [Pd(meth)(2-pymerpy)Cl]Cl and [Pd(meth)(2ampy)Cl]Cl, and those of ethionine (ethio), cytosine (cyt) and guanosine (guo) of formulae [Pd(ethio)Cl2], [Pd(ethio)(cyt)Cl]Cl and [Pd(ethio)(guo)Cl]Cl were tested for anti-microbial activity against various bacteria (Klebsiella pneumoniae, Vibrio cholerae, etc.) and showed a broad spectrum of activity. It was shown that [Pd(meth)(2merpy)Cl]Cl eliminated plasmids from various human microbial pathogens with a 100% frequency.17 The above complexes were also screened in vitro for anti-tumor activity against Hela (Epidermoid Carcinoma Cervix) and CHO (Chinese hamster ovary) cell lines. An excellent correlation between the anti-tumor activity of the complexes and their ability to cure plasmids was found.

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