Synthesis And Activity Determination Of Benzothiazole Derivatives

At present,cancer is still a malignant disease with high mortality in developed countries and developing countries.Molecular targeted therapy has many advantages,such as strong specificity,obvious therapeutic effect and less normal tissue damage,so it has become a new way of tumor treatment.Among the known molecular targeted therapies,the molecular targeted drugs developed by targeting VEGF and its receptor VEGFR-2 have become the research focus.Studies have shown that blocking or interfering the signaling pathways mediated by VEGF/VEGFR-2 can inhibit angiogenesis and achieve the purpose of treating tumors.Protein tyrosine kinases are key protein kinases in cell signal transduction pathways.Cell growth,proliferation and differentiation are closely linked to protein tyrosine kinases.Therefore,developing new VEGFR-2 tyrosine kinase inhibitors is of great significance.Benzothiazole compounds are potential VEGFR-2 PTK inhibitors,the synthesis and biological activity of three kinds of compounds are explored in this paper,main contents are as follows:1 The intermediate 2-substituted benzothiazole compounds were synthesized.First,benzothiazol-2-amine and its derivatives were obtained by nucleophilic substitution and cyclocondensation reaction by using aniline and its derivatives as raw materials,and then benzothiazol-2-ylmethanol,benzothiazole-2-carbaldehyde,2-chlorobenzothiazole and 2-bromobenzothiazole were obtained by using o-aminothiophenol as raw material.2 The intermediate 3-substituted-N-methyl-indoles were synthesized.First of all,N-methyl-indole-3-carbaldehyde was synthesized from N-methyl-indole by electrophilic substitution reaction,next,N-methyl-indole-3-carbaldehyde oxime and Nmethyl-indole-3-carbonitrile were obtained by nucleophilic addition and elimination reaction,and then,N-methyl-indole-3-carboxamide was obtained by hydrolysis,finally,N-methyl-indole-3-carbonyl isocyanate was obtained by the nucleophilic substitution reaction.3 The intermediate indole-2-ones were synthesized.Partial N-ethyl-substituted isatins were synthesized from some substituted isatins by alkylation,and then indole-2-ones were reduced by isatin and its derivatives via Wolff-Kishner reaction.4 Three kinds of target compounds were synthesized.Respectively for(E)-3-(benzothiazol-2-ylmethylene)indolin-2-ones,N-(benzothiazol-2-ylcarbamoyl)-1-methyl-1H-indole-3-carboxamide and its derivatives and N-(benzothiazol-2-yl)-1-methyl-1H-indole-3-carboxamide.5 The inhibitory activity of(E)-3-(benzothiazol-2-ylmethylene)indolin-2-ones to two kinds of tumor cells and its molecular docking with VEGFR-2 were evaluated.