Design,Synthesis And Biological Activities Of Diazo Fused Ring Derivatives

Diazo-fused ring derivatives have many biological activities,such as bactericidal,insecticidal,antitumor and antimalarial activities.The important representative skeletons of these compounds include quinazoline ring,quinazolinone ring,azaindole ring and so on.These dinitrogen fused ring compounds are bioelectronic isomers,which can be replaced by each other in the optimization of lead compounds,so as to improve the pharmacokinetic properties of technical drug.Therefore,diazonium fused ring compounds are important heterocyclic molecules and play an important role in the field of chemical biology.Quinazolinone and 7-azaindole are new compounds in diazolid fused ring compounds,which have good inhibitory activities against Streptococcus pneumoniae,drug-resistant staphylococcus aureus and other animal pathogens.However,there are few studies on the control of plant pathogens.Chemical biology-oriented pesticide molecular design has become an important model for the creation of new pesticides.Constructing a large number of dinitrogen fused ring compounds library with various structures,and using multi-level screening models such as enzyme and cell level and computer virtual model to study the activity of compounds,is of great significance to find active lead compounds and verify and discover new targets or mechanisms of action.This dissertation is focused on two types of diaza-fused ring compounds,quinazolinone and 7-azaindole,which have a variety of biological activities and targets.Two compound libraries were designed and constructed.The activity of these compounds was carried out withing a multi-level screening model at the enzyme and cell in vitro level.The targets and mechanisms of the compounds were explored by combining theoretical analysis and experimental research.The dissertation is divided into five chapters.The first chapter summarizes the literature and puts forward the research ideas and research contents of the paper.The second chapter to the fourth chapter respectively describes the synthesis of compounds,antibacterial activity test,tumor cell inhibition activity test,and the mechanism of action.The completed works are as following:(1)4 series of quinazolinone compounds(series A,B,C and D,82 in total)were designed and synthesized;The structures of these compounds was characterized by ¹H NMR,¹³C NMR and HRMS.(2)A series of azaindole compounds(series E,29 in total)were synthesized using the self-developed microwave-assisted iron-catalyzed cyclization method;the structures of these compounds was characterized by ¹H NMR,¹³C NMR and HRMS.(3)We tested these compounds in vitro antimicrobial activity assay.The results showed that:A series compounds had poor solubilities and low antibacterial activities;the activities of series B and C compounds have been improved.They had moderate antibacterial effects against Rhizoctonia solani(Rs)and Xanthomonas oryzae pv.Oryzae(Xoo).They also had a good inhibitory effect against Pseudomonas syringae pv.Actinidae(Psa).Among them,25 compounds have an inhibition rate of more than70%against Rs,which is equivalent to the control agent bismerthiazol.The inhibitory activities of series D compounds against Rs are greatly improved.The EC₅₀ value of II-14p against Rs can reach 75.3?g/m L.The E series compounds had high inhibitory activities against Rs.The EC₅₀ value of compound IV-3o against Rs is 2.4?g/m L,which is equivalent to Boscalid.(4)We also tested these compounds in vitro anti-tumor activity assay and the inhibitory activity assay on EGFR^wt-TK.The results showed that:series B and C compounds have poor inhibitory activities on A549 and NCI-H1975 tumor cells;series D compounds have certain inhibitory activity on A549,PC-3 and SMMC-7721tumor cells,better inhibitory activities on EGFR^wt-TK.Among them,The IC₅₀ value of compound II-14k against EGFR^wt-TK could reach 10 n M.(5)At last,we studied the mechanism of action and binding mode.The results showed that compound II-14k can induce early transformation of A549 cells and block the cell cycle in G2/M phase;the compound may be combined with EGFR^wt-TK in an inactive state.