Copper-catalyzed Tandem Cyclization Strategy For Efficient Construction Of N-containing Heterocycles And Bioactivity Study

Nitrogen-containing heterocycle is one of the most important basic skeletons of natural products and drug molecules.According to research statistics,59%of small molecule drugs contain N-heterocycles.During the development of new,highly effective,and low-toxic plant virus inhibitors,we found that the nitrogen-containing heterocyclic alkaloids such as Antofine,Cryptopleurine,Harmine,Lycorine and Nortopsentins,showed excellent antiviral activity against tobacco mosaic virus?TMV?.To this end,the development of new methodologies for the efficient construction of N-heterocyclic skeletons and the studies of their biological activities have been a research hotspot and of great significance.This dissertation first focuses on the efficient construction of N-heterocyclic skeletons,by using copper-catalyzed tandem cyclization as the synthetic strategy.In this dissertation,this dissertation developed a new methodology for the efficient construction of tetra-substituted4,5-dicarbonyl imidazole and N-thiazoline indole;furthermore,a series of ring-turned indole diketopiperazine acylhydrazones were designed,synthesized,and their biological activity were studied.?1?The imidazole ring is one of the basic skeletons of the natural products,among which tetra-substituted 4,5-biscarbonyl imidazole moiety is important,it constitutes the core skeleton of some bioactive compounds and the carbonyl group can serve as a versatile handle for the preparation of different imidazole derivatives.Various approaches to the synthesis of fully substituted imidazoles have recently been developed,such as condensation reactions between diketones,aldehydes and amines?ammonia?ans such as transition-metal-catalyzed direct N–H or C–H functionalization.However,few of these methods can be used to synthesize tetra-substituted 4,5-biscarbonyl imidazoles in one step.To this end,This dissertation developed a methodology for the efficient construction of such imidazoles via copper-catalyzed aerobic oxidative[2+3]tandem cyclization reaction.This method has the following advantages:high atomic economy,broad substrate scope,O₂ as a co-oxidant,with water as the only side-product,easy operation,high yields and mild reaction conditions.On the results of the control experiments,this dissertation proposed the plausible mechanism.First,glycine derivative was oxidized to produce imine under the synergistic effect of copper salt and O₂;then the electron-rich carbon nucleophile at the 4-position of 5-alkoxyoxazoles attacked imine,which was activated by the copper salt;subsequent intramolecular cyclization,ring opening reaction and oxidation aromatization produced the target product.?2?Although in the past century,a large number of methods for the construction of indole derivatives have been reported,the methods for constructing N-thiazoline indole skeletons have not been reported yet.Considering the indole ring and the thiazoline ring are the important moieties in pharmaceutical and materials field,this dissertation have developed a methodology for the efficient construction of N-thiazoline indole skeletons by the copper catalyzed tandem cyclization strategy,which was used to efficiently build tetra-substituted 4,5-dicarbonyl imidazoles in our previous work.Based on the mechanism study experiments,this dissertation proposed that the reaction process included the nucleophilic addition of propargylamine to alkynyl isothiocyanate,the copper-catalyzed 5-exo-dig cyclization of the alkynes,and the copper catalytic intramolecular hydrogenation cyclization.This method is characterized by is easy operation,mild conditions,100%atomic economy,broad substrate,and selective Z-configuration products selectivity.?3?Inourpreviouswork,wefoundthatthecompound?3S?-N'-?4-chlorobenzylidene?-1-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-3-carbohydrazide?NK0209?exhibited an excellent anti-TMV activity.Further antiviral mechanism studies revealed that NK0209 binds with several residues of the four-layer CP aggregate.This binding leads to the disassembly of the CP discs into monomers.As a result,the protective effect of internal viral RNA is almost completely lost and the pathogenicity is almost complete lost.It is also found that acylhydrazone bond is a flexible group that can rotate to bind with the residues of the TMV CP in the most favorable spatial configuration,thereby increasing the antiviral activity of the molecule.Although the structure-activity relationship?SAR?of acylhydrazone structure on C₃ position and the substituent on C₁ of the tetrahydro-?-carboline acylhydrazone compounds has been studied and summarized,these modifications do not have much effect on the spatial configuration of the molecule.However,the latter usually plays a more important role in adjusting the interaction between molecules and target proteins.In order to further systematically study the effect of the spatial configuration of tetrahydro-?-carboline acylhydrazone compounds on the antiviral activity,this dissertation designed and synthesized a series of chiral indole diketopiperazine acylhydrazone compounds with optically active C₆ and C_12a.Their anti-TMV activity and the SAR were studied.In particular,the effects of different spatial configurations of C₆ and C_12a on the anti-TMV activity.The bioactive data indicated that most of these new compounds displayed good to excellent anti-TMV activity,among which compounds V-4,V-5,V-8,V-14,V-18,V-19,V-23,V-25,V-27,V-28,V-31,and V-37 showed higher activities than that of commercial anti-virus reagent ribavirin.It was noteworthy that trans-compound V-5,which derived from D-tryptophan,exhibited the best anti-TMV activity among the four stereoisomers?V-2–V-5?.Given its special trans-configuration,compound V-5is of certain value for further study.At the same time,it also profoundly summarized the structure-activity relationship of these new compounds.?1?The chirality at C-12a significantly affected antiviral activity and the chirality of the methyl group at C-6had little effect on the activity,these stereoisomers followed this sequence:C-12a R>S,and trans>cis.?2?As a whole,when introducing an electron withdrawing group to the benzene ring of aromatic aldehyde hydrazones,the anti-TMV activity was higher than that of the compound with an electron donating group.?3?The antiviral activity was significantly increased when the phenyl ring had tert-butyl or the benzene ring was replaced by a naphthyl.?4?The greater of the electronegativity of atoms in the five-membered heteroaryl ring,the better its antiviral activity.?5?Compared with aldehyde hydrazone,ketone hydrazone compounds exhibited a slightly higher antiviral activity.In addition,these derivatives also exhibited broad-spectrum fungicidal activities.Among them,aromatic-aldehyde hydrazones exhibited a certain fungicidal selectivity,and they had excellent fungicidal activity against several plant pathogenic fungi such as Physalospora piricola,Bipolaris maydis,and Sclerotiia sclerotiorum.It is noteworthy that the chlorine-substituted compounds V-13 and V-15 had relatively poor antiviral activity,but they exhibited excellent fungicidal activity against Sclerotinia sclerotioru,85.2%and 93.4%at 50 mg/L),respectively.The tert-butylethanone hydrazone V-32 exhibited 91.2%fungicidal activity against Phytophthora capsici at 50 mg/L.In addition,the N-benzyl hydrazide compound V-37 showed even 100%inhibition at 50 mg/L against Phytophthora capsici.