Antibacterial Co(II), Cu(II), Ni(II) and Zn(II) Complexes of Thiadiazoles Schiff Bases

Schiff bases were obtained by condensation of 2-amino-l,3,4-thiadiazole with 5-substituted-salicylaldehydes which were further used to obtain complexes of the type [M(L)2]Cl2, where M=Co(II), Cu(II), Ni(II) or Zn(II). The new compounds described here have been characterized by physical, spectral and analytical data, and have been screened for antibacterial activity against several bacterial strains such as Escherichia coli, Staphylococcus aureus, and Pseudomonas aeruginosa. The antibacterial potency of these Schiff bases increased upon chelation/complexation, against the tested bacterial species, opening new aproaches in the fight against antibiotic resistant strains.


INTRODUCTION
Many studies stressed the role of metal ions in important biological processes, whereas the inorganic pharmacology started to be an important field per se .with more than 25 inorganic compounds, being used in therapy as antibacterial, antiviral and antieaneer drugs''. Kirsebmer et al have suggested* that the transfer of the metal ion from the ligand to the cancer-associated viruses was an important mechanism for designing new anticancer therapies. The inverse process, i.e., coordinating a metal ion from an important biomolecule, such as for instance a zinc finger protein, has recently been used to design novel antiviral therapies, targeted against human immunodeficiency (HIV) and human papilloma virus (HPV')ilffeetions. 9 Palladium and platinum complexes of 6-mercaptopurine have already been shown to destroy 0 the adenoearcinomas, whereas the complexes of dialkyldithiophosphate , cisplatin and carboplatin are potent antineoplastic drugs used in chemotherapy2. They show their best results in the treatment of testicular and ovarian carcinoma and are also effective against bladder tumors and tumors of head and neck. 12 It has also been demonstrated that chelation/complexation tend to make biologically inactive compounds active 3q6. All these evidences however, need to highlight more th,%b,ioologieal application of qhe.,lation in the.ate, utic potentials. For.sthis purpose, keeping in view the antibacterial'''', antiviral', antiftmgal"-'', antiturnoF and antileukemia properties of some thiadiazole derivatives, we report here some new Sehfff bases, obtained by the condensation reaction of 2-3 ammo-1,3,4-thiadiazole with 5-substituted salieyloaldehydes (I -HL ) (Fig. 1). These newly prepared Schiff bases were used to synthesize their Co(II), Cu(II), Ni(II) and Zn(II) complexes. In order to evaluate and establish the role of metal ions on the antibacterial activity, these Schiff bases in comparison to their metal(II) complexes were screened for antibacterial activity against bacterial species such as Escherichia coB,  30) gave the desired metal complex (1) (0.5 g, 68 %). All other metal complexes were formed respectively following the same method.

Antibacterial Studies
The synthesized metal complexes, in comparison to the uncomplexed Schiff bases were screened for their antibacterial activity against pathogenic bacterial species, Escherichia coli, Staphylococcus aureus and Pseudomonas aeruginosa. The paper disc diffusion method 6"2 was adopted for the determination of antibacterial activity.

Physical Properties
The Schiff bases (HL-HL3) (    Of Thiadiazoles Schiff Bases Infrared spectra IR spectra of the Schiff bases showed the absence of bands at 1735 and 3420 cm "1 due to c_a-bonyl v(C=O) and v(NH2) stretching vibrations and, instead, appearance of a strong new band at --1635 eraassigned 3 to the azomethine v(HC=N) linkage. The comparison of the infrared tra of the Schiff bases with their metal chelates indicated that the Schiff bases were principally coordinated to the metal atom in three ways, thus representing the ligands as acting tridcntatc.ly: a) The band .appearing at 1635 cm " duc to the azomethine, shifted to lower frequency by -10-15 cm " indicating 31 participation of the azomethine nitrogen in complexation. b) The band at 1620 assigned to thiadiazole ring v(C=N) nitrogen also shifted to lower frequency by -10 cm -I which was indicative of the involvement of thiadiazole ring nitrogen in chelation. c) A band appearing at 3425 em " assigned to v(OH) in the Sehiff base compounds was not found in the spectra of their metal complexes indicating dcprotonation and coordination of the hydroxyl oxygen to the metal ion.

d)
Further evidence of the coordination of these Schiff base compounds with the metal ions, was shown by the appearance of weak low frequency new bands at 525-530 and 455-460 em (Table 3). These were, assigned 2 to the metal-nitrogen v(M-N) and metal-oxygen v0Vl-O) respectively. These new bands were observable only in the Slctra of the metal complexes and not in the spectra of its uncomplcxcd Sehiff base compounds thus confnaning participation of these hetero groups (O or N) in the coordination.

NMR Spectra
The NMR spectral data of Schiff bases as well as some of their Zn(II) complexes taken in DMSO-ds arc listed in Tables and 4. The Schiff bases exhibited signals duc to all the expected protons in their expected region and have bccn identified from the integration curves found to bc equivalent to the total nurnbcr of protons deduced from their proposed structures. These were compared with the reportexP 3 signals of the known identical compounds and give further support for the compositions of these new Schiff bases as well as their complexes suggested by their IR and elemental analyses data. Comparison of the chemical shifts of the uncomplcxcd Schiff bases with those of the corresponding complexes show that some of the resonances arc shifted upon complcxation. In each case, the protons assigned duc to hcteroaromatic (HC=N), azomcthinc (HC=N), hydroxyl group (OH) and substituted aromatic were found at around 6 8.8, 7.4, 9.9 and 6.8-7.7 ppm in the spectra of the Schiff bases. The protons duc to heteroaromatic, azomethine and substituted aromalac undergo shift towards downficld in the complexes indicating coordination of these groups with the metal atom. Also, protons duc to hydroxyl oup (OH) were found absent in the spectra of the complexes. The absence of these signals suggested the deprotonation of the hydroxyl oxygen atom of the Schiff base on complcxation. The same shifts were observed in the 3C NMR spectral data of the Sehiff bases and their complexes. The electronic sp,ectra of the Co01) chelates sowed ree bartds obsqrved at 878(]-8815, 417560-18425 and 30210-30575 cm" which may, be assigned to -'Tg "T_g(F), 'T,s ----A,(F) and "T,s Ts(P) transitions respectively and are suggestive 37'38 of the octahedral geometry around the colSalt ions.
The Cu(II) comolexes showed three 2 absotion bands tmtween 10 Dq band for a distorted octedral gometry corresponding a' to the transitions E T2. The bands at 22152-22355 and 30550-30545 cm" may be due to intra-ligand charge transfer transitions.
The diamagnetic zinc(II) complexes did not show any d-d bands and their spectra are dominated only by charge transfer bands. The charge transfer band at 28450-28510 cm q was assigned 43 Table III). The compounds were tested at a concentration of 30 g/0.01 mL in DMF solution using the paper disc diffusion method. The diameter of the susceptibility zones were measured in (ram). The results of which are shown in Table 4. The susceptibility zones measured were the clear zones around the discs killing the bacteria. All the Schiff bases and their complexes individually exhibited varying degrees of inhibitory effects on the growth of the tested bacterial species. The antibacterial results evidently show that the activity of the Sehiff base compounds became more pronounced when coordinated to the metal ions. On the basis of these observations, it is claimed that chelation dominantly affects the biological behavior of the compounds that are potent against some bacterial strains. It is however, suspected that factors such as solubility, dipole moment and cell permeability mechanisms are certainly influenced by the presence of the metal ions. Table III. Antibacterial Activity Data of the Schiff bases and its Metal(II) chelates