Synthesis, Characterization And Pharmacological Activity Of N(4)-substituted Thiosemicarbazones And Their Metal Complexes

Heterocyclic thiosemicarbazones containing N, S, etc miscellaneous atoms and C=N, C=Sgroups are easy to form stable complexes with a variety of metal ions, and many complexes obtained havegenerated considerable interests due to higher biological activities, notable for antibacterial, antifungal andantitumor activities. In many cases, their biological properties are often related to type of metal ions and thedonor sequence of the ligands. So it is important to further study the synthesis, crystal structures andbiological activities of heterocyclic thiosemicarbazones and their metal complexes in the finding of newdrugs against bacteria and cancer.Heterocyclic thiosemicarbazone Schiff bases and their metal complexes have importantpharmacological activities, and become a research hotspot in recent years. In this paper, we studied thesynthesis, characterization, and biological activities of2-acetylpyridine-N（4）-pyridylthiosemicarbazone（HL¹）,2-benzoylpyridine-N（4）-pyridylthiosemicarbazone （HL²）,2-acetylpyridine-N（4）-phenylthiosemicarbazone （HL³） and2-benzoylpyridine-N,N-dimethylthiosemicarbazone （HL⁴） and their metal complexes113.The results of cytotoxicity test in vitro have indicated that the complexes [（Ph）₂Sn（L¹）（CH₃COO）]（4）,[（Ph）₂Sn（L²）（CH₃COO）]（7） and [Ga（L³）₂] NO₃·2H₂O （9） show better cytotoxicity against humanhepatocellular carcinoma HepG2cells. In order to further understand their mechanisms of action, we havedone the mechanism tests of inducting HepG2cells apoptosis for complexes4,7and9. In the process, weadopted the Acridine Orange （AO）/Ethidium Bromide （EB） fluorescent staining, using the high contentscreening （HCS） to observe the apoptosis morphology of human hepatocellular carcinoma HepG2cells,using Rh123/Hoechst33342dyeing, and adopting the HCS to determine the change of mitochondrial membrane potential in the cells. Besides, we have used PI/Hoechst33342fluorescence double staining toobserve the cells apoptosis, and analyzed them. The major research contents are as follows:Chapter1Synthesis, characterization and pharmacological activity of4-（2-pyridyl）-3-thiosemicarbazones and their metal complexesThe ligands were prepared by boiling an ethanolic solution of4-（2-pyridyl）-3-thiosemicarbazideand2-acetylpyridine or2-phenylpyridine. Reactions of2-acetylpyridine-N（4）-pyridylthiosemicarbazones（HL¹） with some metal-salts formed the title complexes [In（HL¹）（NO13）₂（NO₃）（H₂O）]·CH₃OH （1）,[Mn（L）₂]（2）,[（CH₃）₂Sn（L1）（CH₃COO）]（3） and [（Ph）12Sn（L）（CH₃COO）]（4）. Other metal complexes[Mn（L²）₂]·DMF （5）,[（CH₃）₂Sn（L²）（CH₃COO）]（6） and [（Ph）₂2Sn（L）（CH₃COO）]（7） where HL²=2-phenylpyridine-N（4）-pyridylthiosemicarbazones, have also been synthesized. Schiff base in itsdeprotonated forms coordinate to center metal ion via pyridine nitrogen atom and its imine nitrogen atomand sulfur atoms of the thiosemicarbazone moiety. The free ligands （HL¹, HL²） and all of their metalcomplexes have been characterized by elemental analysis, FT-IR spectroscopy, UV-vis spectroscopy, MSand single-crystal X-ray diffraction studies. Effect on the antibacterial activity of the ligand and itscorresponding complexes against selected bacterias was measured by the disk difusion method. Evaluationon the cytotoxicity of the ligand and its corresponding complexes was measured in human hepatocellularcarcinoma HepG2and human normal heptical QSG7701cells. Pharmacological studies, carried out in vitroagainst eight selected bacterias, HepG2cells and QSG7701cells, respectively, have shown that the freeligands （HL¹and HL²） and their corresponding complexes show differences in the antibacterial propertiesand cytotoxicities.Chapter2Synthesis, characterization and pharmacological activity of2-acetylpyridine-4-（2-phenyl）-3-thiosemicarbazone and its copper（II）, gallium（III） and indium（III） complexes The ligand was prepared by boiling a methanolic solution of4-（2-phenyl）-3-thiosemicarbazideand2-acetylpyridine. Three metal complexes [Cu2（L³）3_]ClO₄（8）,[Ga（L³）₂]NO₃·2H₂O （9） and[In（L³）₂]NO₃·H₂O （10） where HL³=2-acetylpyridine-N（4）-phenylthiosemicarbazone have beensynthesized. HL³and all of its metal complexes have been characterized by elemental analysis, FT-IRspectroscopy, UV-vis spectroscopy, MS and single-crystal X-ray diffraction studies. Effect on theantibacterial activity of the ligand and its corresponding complexes against selected bacterias was measuredby the disk difusion method. Evaluation on the cytotoxicity in vitro of the ligand and its correspondingcomplexes was measured against HepG2cells and QSG7701cells. In vitro pharmacological studies haveindicated that the free ligand （HL³） and its corresponding complexes show differences in the antibacterialproperties and cytotoxicities.Chapter3Synthesis, characterization and pharmacological activity of2-phenylpyridine-N,N-dimethyl-3-thiosemicarbazone and its metal complexesThe ligand was prepared by boiling a methanolic solution of4,4-dimethyl3-thiosemicarbazideand2-phenylpyridine. The free ligand （HL⁴） and its three metal complexes [Ga（L⁴）₂]NO₃（11）,[Zn（L⁴）₂]（12） and [Sn（ph）₂（L⁴）（CH₃COO）]（13） where HL⁴=2-phenylpyridine-N,N-dimethylthiosemicarbazonehave been synthesized. HL⁴and all of its metal complexes have been characterized by elemental analysis,FT-IR spectroscopy, UV-vis spectroscopy, MS and single-crystal X-ray diffraction studies. Effect on theantibacterial activity of the ligand and its corresponding complexes against selected bacterias was measuredby the disk difusion method. Evaluation on the cytotoxicity in vitro of the ligand and its correspondingcomplexes was measured in HepG2cells and QSG7701cells. In vitro pharmacological studies have indicated that the free ligand （HL4） and its corresponding complexes show differences in the antibacterialproperties and cytotoxicities.