Synthesis and Structure-Activity Correlation Studies of Metal Complexes of α-N-heterocyclic Carboxaldehyde Thiosemicarbazones in Shewanella oneidensis

This investigation involved the synthesis of metal complexes to test the hypothesis that structural changesand metal coordination in pyridine thiosemicarbazones affect cell growth and cell proliferation in vitro. Thiosemicarbazones are well known to possess antitumor, antiviral, antibacterial, antimalarial, and other activities. Extensive research has been carried out on aliphatic, aromatic, heterocyclic and other types of thiosemicarbazones and their metal complexes. Due to the pronounced reactivity exhibited by metal complexes of heterocyclic thiosemicarbazones, synthesis and structural characterization of di-2-pyridylketone 4N-phenyl thiosemicarbazone and diphenyl tin (Sn) and platinum (Pt) complexes were undertaken. Shewanella oneidensis MR-1, a metal ion-reducing bacterium, was used as a model organism to explore the biological activity under aerobic conditions. A comparision of the cytotoxic potential of selected ligand and metal-complex thiosemicarbazones on cell growth in wild type MR-1 and mutant DSP-010 Shewanella oneidensis strains at various concentrations (0, 5, 10, 15, 20 or 25 ppm) was performed. The wild type (MR-1) grown in the presence of increasing concentrations of Sn- thiosemicarbazone complexes was comparatively more sensitive (mean cell number = 4.8 X 10(8) +/- 4.3 X 10(7) SD) than the DSP-010, a spontaneous rifampicillin derivative of the parent strain (mean cell number = 5.6 x 10(8) +/- 6.4 X 10(7) SD) under comparable aerobic conditions (p = 0.0004). No differences were observed in the sensitivity of the wild and mutant types when exposed to various concentrations of diphenyl Pt- thiosemicarbazone complex (p = 0.425) or the thiosemicarbazone ligand (p = 0.313). Growth of MR-1 in the presence of diphenyl Sn-thiosemicarbazone was significantly different among treatment groups (p = 0.012). MR-1 cell numbers were significantly higher at 5ppm than at 10 to 20ppm (p = 0.05). The mean number of DSP-010 variant strain cells also differed among diphenyl Sn- thiosemicarbazone complex treated groups (p = 0.051). In general, there was an increasing trend in the number of cells from about 5.0 X 10(8) cells (methanol control group) to about 6.0 X 10(8) cells (25ppm). The number of cells in methanol control group was significantly lower than cell numbers at 20ppm and 25ppm (p = 0.05), and numbers at 5ppm treatment were lower than at 20 and 25ppm (p = 0.05). Furthermore, a marginally significant difference in the number of MR-1 cells was observed among diphenyl Pt- thiosemicarbazone complex treatment groups (p = 0.077), and an increasing trend in the number of cells was noted from approximately 5.0 X 10(8) cells (methanol control group) to approximately 5.8 X 10(8) cells (20ppm). In contrast, the DSP-010 variant strain showed no significant differences in cell numbers when treated with various concentrations of diphenyl Pt- thiosemicarbazone complex (p = 0.251). Differences in response to Sn- metal complex between MR-1 and DSP-010 growing cultures indicate that biological activity to thiosemicarbazone metal complexes may be strain specific.