Synthesis Of (Indazole) Benzothiazole Derivatives As Tyrosine Kinase Inhibitors

As the incidence of cancer appears an upward trend significantly,more and more funds and personnel are devoted to the huge field of anticancer drugs.Starting from the different targets of anticancer drugs,a brief review of all kinds of anticancer drugs is given and the new target anticancer drugs are introduced in detail.The target of protein tyrosine kinase is the most widely studied.With tyrosine kinase as the target,a series of potentially anticancer compounds(Series I-V)which contain indazole,indole and benzothiazole as the nuclear structure were designed by computer-aided drug design(CADD).In this paper,we mainly focused on the synthesis of intermediate compounds and target compounds,and supported by molecular docking studies in order to find more active compounds which would get into preclinical studies.The paper was divided into the following three parts:(1)Synthesis of indazole derivatives: Using Indole,isatin and o-halobenzonitrile as the raw materials,1H-indazole-3-carbaldehyde,1H-indazole-3-carboxylic acid and 1H-indazole-3-amine derivatives were successively synthesized.In addition,there were an optimization of the intermediate compounds' yields from a series of single factor test.(2)Synthesis of 2-substituted benzothiazoles derivatives: 2-aminobenzothiazole derivatives and benzothiazole-2-carboxylic acid were synthesized from and substituted aniline o-aminothiophenol.In addition,there were an optimization of the intermediate compounds' yields 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,five synthetic routes had been designed for the experimental investigation,and eventually we successfully synthesized(3-amino-4-chloro-1H-indazol-1-yl)(benzothiazol-2-yl)methanone,(3-amino-4-fluoro-1H-indazol-1-yl)(benzothiazol-2-yl)methanone,2-(1H-indol-3-yl)benzothiazole,and 2-(5-bromo-1H-indol-3-yl)benzothiazole.Molecular docking research mainly based on the four compounds synthesized.The docking results of the molecules indicated that they had hydrogen bonds and ?-hydrogen bonds between them and the target protein,providing theoretical reference and support for the subsequent activity determination of the target compounds.