Heterocyclic Compounds Containing The Pyrazole Structure, Structure And Antibacterial Activity

Three classes, forty-eight in total, of pyrazole compounds, imidazolo[1,2-b] pyrazoles, dipyrazolylmethanones and pyrazolyloxadiazoles, have been synthesized, and they have been fully characterized by modern spectroscopic methods, two of which were further confirmed by X-ray diffraction. Most of these compounds have been evaluated for the inhibitions of Gram-positive bacterium represented by Staphylococcus aureus and Gram-negative bacterium represented by Klebsiella pneumoniae.In the first part of this thesis is presented the synthesis of twenty-eight imidazolo[1,2-b]pyrazoles, including seven bis(imidazolo[1,2-b]pyrazol-3-yl)-methanes.Starting with two reactive methylene compounds, ethyl cyanoacetate and malononitrile, two 5-amino-1H-pyrazoles were prepared through the intermediates ketene dithioacetal. Reactions of 5-amino-lH-pyrazoles with aromatic and aliphaticα-bromoacetophenones, followed by acid-mediated iminative cyclization and the ensuing tautomerization, produced methylthio-imidazolo[1,2-b]pyrazoles 6a-6g. methylthio-imidazolo[1,2-b]pyrazoles 6a-6g were mildly oxidized with H₂O₂/acetic acid at room temperature to yield methylsulfinyl-imidazolo[1,2-b]pyrazoles 7a-7g and violently oxidized with H₂O₂/acetic acid at 50℃to afford methylsulfonyl-imidazolo[1,2-b]pyrazoles 8a-8g.Methylthio-imidazolo[1,2-b]pyrazoles 6a-6g were refluxed in freshly distilled formamide to generate structurally novel bis(imidazolo[1,2-b]pyrazol-3-yl)methanes 9a-9g. Given the structural novelty of 9a-9g, they were fully and unambiguously characterized by IR, ¹H NMR, ¹³C NMR, elemental analyses and ESI-MS.The region-selectivity involved in the construction of imidazolo[1,2-b]pyrazole skeleton was fully investigated and discussed, and the X-ray diffraction of 6a and 6b unequivocally supported the precise structure of imidazolo[1,2-b]pyrazole skeleton.In the second part is described the synthesis of ten dipyrazolylmethanones. The intermediate 5-amino-1H-pyrazole-4-carboxylic acid ethyl ester prepared in the first part underwent successively hydrazinolysis, condensations with ketene dithioacetals and alkylations to give rise to the dipyrazolyhnethanes. The chemo-selectivity and regio-selectivity were also discussed. In the final part is reported the synthesis of ten pyrazolyloxadiazoles. The same intermediate 5-amino-1H-pyrazole-4-carboxylic acid ethyl ester underwent in turn alkylations, mild oxidation with H₂O₂/acetic acid, hydrazinolysis and formation of potassium xanthate followed by desulfurization to give the pyrazolyloxadiazoles. The effect of the order of alkylations, oxidation to form sulfoxides and cyclizations to form oxadiazoles involved in the synthetic route on the synthesis of final pyrazolyloxadiazoles 18a-18e was also investigated and discussed.Part of the final compounds, along with a small amount of intermediates, were tested for the inhibition of Staphylococcus aureus and Klebsiella pneumoniae, and all the tested imidazolo[1,2- b]pyrazoles and dipyrazolylmethanones showed regular structure-activity relationship (SAR) in the inhibition of both standard and clinical Staphylococcus aureus, while neither imidazolo[1,2-b]pyrazoles nor dipyrazolylmethanones displayed noticeably regular SAR in the inhibition of both standard and clinical Klebsiella pneumoniae. The bioactivities in the inhibition of Staphylococcus aureus were more potent than those in the inhibition of Klebsiella pneumoniae.