Synthesis, Crystal Structure And Biological Activity Of A-N-heterocyclic Thiosemicarbazones And Their Main Group Metal Complexes

Heterocyclic thiosemicarbazones and their metal complexes have generated considerable interest dueto varied coordination environments and marked biological activities, notable for antibacterial, antifungaland antitumor activities. In many cases, their biological properties are often related to the donor sequenceof the ligands and metal ion coordination. The widespread use of bismuth compounds in the medicinalrealm for centuries is coming from their high effectiveness and low toxicity in the therapy of diversemicrobial infections, involving syphilis, diarrhea, gastritis and colitis. In addition to antimicrobial activity,bismuth compounds revealed anticancer activities, Radioisotope212Bi and213Bi compounds have beenapplied as targeted radio-therapeutic agents for cancer therapy, and furthermore they have the ability toreduce the side-effects of cisplatin （cis DDP） in carcinoma treatment. Bismuth is also considerednowadays as the least toxic heavy metal and the bismuth （III） atom with a larger ionic radius has one inertelectron pair （6s2） and forms the complexes of the non-transition metal center with higher coordinationnumbers. Tin complexes are known for their multiple applications as antimicrobials and biocides.Moreover, organotin （IV） compounds are known to exhibit important cytotoxic effects against tumor celllines. Heterocyclic thiosemicarbazones and their main group metal bismuth （III） and gallium （III）complexes are scarce. Although heterocyclic thiosemicarbazones and its organotin （IV） complexes arenumerous, the syntheses of tin complexes with thiosemicarbazones could be a strategy of preparation ofnew drug candidates in which the metal and ligand could act synergistically. The chemists and medicalscientists always devote themself to synthesis and biological evaluation of the better and more practicalthiosemicarbazones and its organotin （IV） complexes. So it is important to study the synthesis, crystalstructures and biological activities of heterocyclic thiosemicarbazones and their main group metal bismuth （III）、 gallium （III） and organotin （IV） complexes in the finding of new drugs against bacteria and cancer.In this paper, we studied the synthesis, single-crystal structures and biological activities ofbis（2acetylpyrazine） thiocarbonohydrazone （H₂L1）、2-acetylpyrazine N（4） phenylthiosemicarbazones（HL2）、2-acetylpyrazine N（4）-pyridylthiosemicarbazones （HL3）、2-acetylpyridine N（4）pyridylthiosemicarbazone （HL4）、2-acetylpyridine N（4） pyridylthiosemicarbazones （HL5） and2.6-diacetylpyidine bis（N（4）-methylthiosemicarbazones）（HL6） and their main group metal complexes.Main group metal complexs [Bi（HL1）（NO3）2（H₂O）]（1）、[Ga（L1）（HL1）]（2） and[（Ph）2Sn（HL1）（CH3COO）] CH3CH₂OH （3） where H12L=bis（2-acetylpyrazine） thiocarbohydrazones;Bismuth（III） complex [Bi（L2）（NO3）2（CH3OH）]（4） and gallium（III） complex [Ga（L2）2]·（NO3）·（H₂O）（5）derived from2-acetylpyrazine N（4）-phenylthiosemicarbazones （HL2）; Bismuth（III） complex[Bi（HL3）·（NO₃）₃]（6）,[Bi（L4）·（NO3）2·（CH3CH₂OH）]（7） and [Bi（HL5）·（NO₃）₃]（8） derived from2acetylpyrazine N（4）-pyridylthiosemicarbazones （HL3）,2acetylpyridine N（4）-phenylthiosemicarbazones（HL4）,2-acetylpyridine N（4）-pyridylthiosemicarbazones （HL5）, respectively, and Bismuth（III） complex[Bi（H₂L6）（NO3）2] NO3（9） derived from2.6-diacetylpyidine bis（N（4）-methylthiosemicarbazones）（H₂L6）have been synthesized and characterized by elemental analysis, MS, IR spectra and single-crystal X-raydiffraction studies. Biological studies, carried out in vitro against selected bacterias and different cancercell lines, respectively, have shown that the free ligands and theirs corresponding complexes show distinctdifferences in the biological properties.Bismuth （III） complexes show higher activities against Gram positive bacteria Bacillus cereus andGram negative bacteria Salmonella typhimurium than positive control antibiotics ampicillin （Amp）,chloramphenicol （Cm）, kanamycin sulfate （Kan）, respectively. Gallium （III） complexes2、5are inactiveagainst the tested microorganisms. Organotin （IV） complex3only shows excellent activity against Staphylococcus aureus （MIC=15.6μg/mL）.The comparison of cytotoxic activity of the free ligands and their complexes indicates that bismuth （III）complexes1、7、8and9show much lower IC50value than the other compounds. Its possible apoptoticmechanism of complexes1、7、8was evaluated in HepG2cells. For morphologic observation, cells werestained with acridine orange （AO） and ethylene dibromide （EB） and assessed by fluorescence microscopy.For detecting the change of the mitochondria membrane potential （MMP）, Rhodamine123dye combinedthe high content live cell imaging system was used. For analysis of intracellular ROS, theoxidation-sensitive fluorescent probe DCFH DA was used for complexes1and7.Effect of the complex8on Annexin-V FITC/PI double staining and caspase activation was measuredin HepG2cells by indirect immunofluorescence.The acute toxicity and antitumor activity of complex9were evaluated on leukemia P388-bearing mice.The LD50of9is44.7mg/kg in Kunming mice by caudal vein injection （95%confidence interval39～51.2mg/kg）. The tumor inhibition ratio of the complex9is61.6%.