Studies On The Synthesis And Bioactivities Of Novel Pyrrolidone Fused Heterocyclic Compounds

Tetramic acid (2,4-pyrrolidinedione) and its derivatives have been found to be a key substructure in many natural products. The naturally occurring tetramic acids have attracted a great deal of interest. The majority of the tetramic acid derivatives to date exhibit good biological activity, such as antibiotic, antineoplastic, anti-tumor, and antiviral activity. The multi reactive center containing structure of tetramic acid has caused researchers to study a large number of total synthesis, structural modification and structure-activity relationship.Multicomponent reactions (MCRs) is the ’one-pot’ method for the synthesis of compounds by taking more than three substrates into a reactor without separating intermediate products. The strategies of MCRs offer significant advantages over conventional linear-type syntheses for their high degree of atom economy, ease of execution, and broad applications characters, which are particularly useful to generate diverse chemical libraries of’drug like’ molecules for biological screening.In this dissertation, much attention has been focused on the MCRs in the synthesis of pyrrolidinone-containing spirooxindole heterocycles, including 1,4-dihydropyridine derivatives and 4H-pyran derivatives, pyrrolidinone fused benzodiazepine derivatives and parazole fused pyrrolidinone derivatives. All the new compounds synthesized were characterized by IR, NMR, HRMS, as well as X-ray single crystal diffraction. The biological activities of some of the synthesized compounds and structure-activity relationship were evaluated. The whole work is mainly composed of the following five parts:Part Ⅰ:A simple and efficient ’one-pot’ three-component reaction for assembling novel spirooxindole 4H-pyran derivatives was developed and used to prepare a series of biologically important compounds. We attempted a ’one-pot’ reaction of tetramic acid, isatin, and malononitrile without any catalysts. The cytotoxic activities of these new pyrans derivatives were evaluated in vitro. Most of the tested compounds exhibited significant cytotoxicities to Raji cell lines.Part Ⅱ:A series of novel spirooxindole 1,4-dihydropyridine compounds were synthesized via’one-pot’ four-component reactions of substituted aniline, tetramic acid, isatin, and malononitrile. The reaction could be easily performed in aqueous ethanol with 4-DMAP as catalyst. Particularly valuable features of this method include environmentally benign character, high yields processing and straightforward procedure. Plausible mechanism of the reaction is also presented.Part Ⅲ:A series of novel pyrazole fused heterocyclic derivatives were synthesized and their catalytic DNA cleavage abilities and anti-BVDV activities were also evaluated. The interaction of plasmid pUC19 DNA with ligands in the presence of Cu2+ complexes respectively was monitored by Agarose gel electrophoresis and UV-Visible spectroscopy. The studies on anti-viral activities against bovine viral diarrhea virus (BVDV) demonstrated that some of the pyrazole derivatives showed pronounced anti-BVDV activity.Part IV:An efficient and clean three-component ’one-pot’ reaction was developed for the convenient and cheap synthesis of benzodiazepine derivatives. Both sets of reaction were conducted in the presence of acetic acid catalyst in ethanol. The present new synthesis method shows attractive green chemistry characteristics, such as concise’one-pot’conditions, easy work-up/purification. The studies on anti-viral activities against bovine viral diarrhea virus (BVDV) demonstrated that some of the benzodiazepine derivatives showed pronounced anti-BVDV activity.Part V:A fast and convenient protocol for the diasteroselective synthesis of novel spirooxindoles 4H-pyran derivatives was developed by the three-component reactions of isatin, malononitrile or ethyl cyanoacetate, and chiral 5-substituted tetramic acid in water in absence of catalyst. The present new synthesis shows attractive green chemistry characteristics, such as the use of water as reaction media, short reaction periods, easy work-up/purification, and reduced waste production. At the same time, the effects of different substituents on the diastereoselectivity and the isolation of the two diasteromers were also studied.