Design And Synthesis Of Indozale-linked Benzoxazole Derivatives

As the population grows and ages,the incidence of cancer and the mortality rate of cancer patients are increasing;and smoking,obesity,lack of exercise and other unhealthy lifestyles also increase the risk of cancer.Cancer not only seriously harms human health,but also imposes a huge burden on society.Vascular endothelial growth factor(VEGF)is closely related to angiogenesis.Studies have shown that blocking the interaction of VEGF with vascular endothelial growth factor receptor-2(VEGFR-2)tyrosine kinase inhibits cancer cell proliferation.A series of potential anticancer active compounds with indazole and benzoxazole as the core structure were designed by computer-aided drug design(CADD)targeted by tyrosine kinase.we mainly focuses on the synthesis of intermediate compounds and target compounds,supported by molecular docking studies,in the hope of finding more active compounds into preclinical studies.The paper was divided into the following three parts:1.Synthesis of 1H-indazole-3-carboxylic acid derivatives: 1H-indazole-3-carboxylic acid and its derivatives were obtained by nucleophilic addition,acylation,Friede-Crafts acylation,rearrangement and cyclocondensation obtain reaction by using phenylhydrazine hydrochloride derivatives and benzaldehyde as raw materials.Then more 1H-indazole-3-carboxylic acid derivatives were obtained by Bromination,nitration and N-methylation obtain reaction by using 1H-indazole-3-carboxylic as raw materials.There was an optimization of the yield of the intermediate compounds from a series of single factor test.2.Synthesis of 2-(1H-indazol-3-yl)acetic acid derivatives: 2-(1H-indazol-3-yl)acetic acid and its derivatives were obtained by nucleophilic addition,reduction and cyclocondensation obtain reaction by using propanedioic acid,ammonium acetate and 2-nitrobenzaldehyde derivatives as raw materials.Then N-substituted indazole-3-acetic acid and its derivatives were obtained by N-methylation by using 2-(1H-indazol-3-yl)acetic acid derivatives as raw materials.There was an optimization of the yield of the intermediate compounds from a series of single factor test.3.Synthesis of target compounds and molecular docking studies: For the synthesis of a series of target compounds,with the indazole carboxylic acid derivative and the substituted 2-aminophenol as raw materials,PPA as dehydrating agentand,2-(1H-carbazol-3-yl)benzoxazole and 2-((1H-indazol-3-yl)methyl)benzoxazole derivatives were obtained.Molecular docking research mainly based on the thirteen compounds synthesized.The docking results of the molecules indicated that they had hydrogen bonds and π-hydrogen bonds between them and the target protein,providing theoretical reference and support for the subsequent activity determination of the target compounds.