Design,Synthesis And Properties Of Azole-containing Compounds

The azole-containing fused heterocycles by combining of imidazole with benzene,pyri-dine,pyrimidine,thiazole or other rings always possess abundant biological activities.With their advantages of good biocompatibility and excellent controllability in binding with active targets of organisms,the imidazole-fused heterocycles have been widely utilized as the core active centers for the development of new medicines in the past decades.Besides the pharma-ceutic values,the fluorescence of imidazole-fused heterocycles has also received considerable attention with their easily adjustable emission wavelength and biological safety in biomedical imaging field.The typical structures,imidazopyridine,imidazolopyrimidine,imidazothiazole and imidazothiadiazole are often acted as important candidates in the researches of new drug.Thus,they are spontaneously selected as targeting fragments in the design of high-performance targeted fluorescence molecular.In recent years,with the rapid development of interdisciplinary subjects among organic synthetic chemistry,chemical biology and medicinal chemistry,novel organic fluorescent molecules with imidazole-fused heterocycles have gradually demonstrated their values especially in the field of fluorescence imaging as well as fluorophore-assisted di-agnosis and treatment.However,most of the reported fluorescent dyes based on imidazopyridine,imidazothia-zole or imidazothiadiazole still suffer from some shortcomings as following:(1)complicated synthesis process;(2)short emission wavelength and unsatisfactory quantum yield;(3)serious fluorescence quenching in aqueous media or solid state.In order to overcome above shortcom-ings and further excavates their application value of fluorescence,this thesis has reported sev-eral new methods to synthesize functional imidazopyridines,imidazothiazoles and imidazothi-adiazoles.With the introducing carbonyl to above skeletons in situ,the aggregation-induced emission(AIE)performances of these three fused heterocycles have been greatly improved.Furthermore,their fluorescent performance and biological application performance were stud-ied.The specific researches consisted of following four aspects:(1)Using alkyne and aminomethylpyridine/pyrimidine derivatives as raw materials,this thesis developed an both iodine-promoted tandem Kornblum oxidation and C-N bond coupling reaction to construct imidazole[1,5-a]pyridine/pyrimidine bearing carbonyl.Under optimal conditions,40 desirable compounds were successfully obtained from terminal alkynes or ter-minal alkenes under mild condition.As the presence of carbonyl,steric distortion and hydrogen bonds of imidazole[1,5-a]pyridine/pyrimidine was achieved,exhibiting excellent wavelength-tunable AIE properties.Several compounds were successfully used for imaging of He La cell,showing high biocompatibility.According to the molecular docking results of the compound with the cannabinoid receptor subtype 2(CB₂),this scaffold possesses potential anti-inflamma-tory activity.In addition,the obtained imidazo[1,5-a]pyrimidine derivates shown significant inhibitory effect on inflammation by mouse ear swelling experiments.(2)Researches on the cyclization of enaminone with thiocyanate were conducted to con-struct imidazole-containing multi-ring.Under the guidance of theoretical calculations,using the reaction of N-phenyl-enamine and potassium thiocanate as a template,a selective synthesis of carbonyl-containing benzimidazo[2,1-b]thiazole was achieved with the promotion of Cu Br/KBr.After slightly changing the reaction conditions,the reaction can also be used to syn-thesize thiazolimide.The results of optical studies showed that the obtained benzimidazo[2,1-b]thiazoles exhibited wavelength-tunable solid-state fluorescence and typical AIE properties with the introduction of carbonyl.(3)A novel type of donor-acceptor-donor conjugated AIE molecule was designed using imidazo[2,1-b][1,3,4]thiadiazole ring as the charge acceptor,and carbonyl as AIE rotor.To achieve the construction of desired compounds,an comprehensive investigation was conducted for the Cu(I)/Cu(II)-mediated cyclization of N-toluenesulfonyl hydrazide,chalcone and potas-sium thiocyanate.Under the optimal reaction conditions,45 carbonyl-containing imidazo[2,1-b][1,3,4]thiadiazoles(selenodiazole)were obtained.Among them,imidazo[2,1-b][1,3,4]thiadi-azole bearing strong electron-donating group exhibited excellent solid fluorescence and AIE properties.These compounds were successfully applied to cell imaging of HEPG2,A549 and He La cells,achieving the selective recognition of different organelles.(4)A donor-?-donor type fluorophore based on multi-substituted thiazole was designed using thiazole ring as a?-electron bridge.In order to construct the target molecule,a study conducted and concentrated on the C-S bond formation in the reaction of the enamine and xan-thate mediated by iodine catalysts.After systemically investigation,an I₂/K₂S₂O₈ promoted cy-clization of N-benzyl-substituted enaminone analogs and potassium xanthate were developed affording 47 desired products successfully.Comparing to the existing methods,this synthetic approach features the advantages of mild conditions,rapid reaction and high yield.The reaction can also be applied to gram scale synthesis with excellent yield.Fluorescence studies indicated that these products possessed excellent AIE performance.In addition,several products with high quantum yield had been successfully used to the imaging HEPG2,A549 and He La cells.The accomplishment of this thesis can not only enrich the types of fluorescent dyes,but also provide some alternatives for the construction of related containing hovercycles.