Design And Synthesis Of Benzofuran Benzothiazole Derivatives

In recent years,although the survival rate of cancer has improved,it is still a worldwide problem to be solved urgently.Because of the shortcomings of poor selectivity,drug resistance and toxicity of current anti-cancer drugs,the development of targeted and highly selective anti-cancer drugs has been the focus of attention and research in recent years.Among them,molecular targeting drugs targeting vascular endothelial growth factor receptor(VEGFR-2)have become a research hotspot.Benzofuran structure exists widely in a large number of natural products and synthetic drugs.As the core of a new type of selective angiogenesis inhibitor,it caused widespread concern.The antitumor activity of benzothiazole derivatives has been deeply studied in recent years.Based on this,a new potential inhibitor of VEGFR-2 PTK was screened by means of Computer-assisted Drugs Design(CADD)and skeleton transition,electronic isosteric arrangement and molecular docking.The synthesis was the mainly explored in this paper.The main contents are as follows:1.The intermediate benzofuran compounds were synthesized.In this paper,the synthesis of benzofuran-2-carboxylic acid and its derivatives was the main method.Benzofuran-2-carboxylic acid and its derivatives were synthesized from salicylaldehyde and substituted salicylaldehyde by S_N2 nucleophilic substitution reaction,nucleophilic addition reaction and ester hydrolysis reaction;3-aminobenzfuran-2-carboxylic acid ester and its derivatives were dehydrated by nucleophilic addition of aldehyde and ammonia derivatives,nucleophilic substitution of S_N2 and nucleophilic addition of cyano group.The synthesis of benzofuran-3-carboxylic acid was completely different from the above two reactions,which underwent Sonogashira coupling reaction and ester hydrolysis reaction.2.The synthesis of intermediate benzothiazole compounds was explored and synthesized.2-aminobenzothiazole derivatives were synthesized from p-toluidine(m-toluidine)by nucleophilic addition and cyclization.2-hydroxymethyl benzothiazole was synthesized from o-aminobenzothiophenol by two steps nucleophilic addition and dehydration.3.Two kinds of target compounds were synthesized,N-(5-methylbenzo[d]thiazole-2-yl)benzofuran-2-formamide and its derivatives,N-(4-methylbenzo[d]thiazole-2-yl)benzofuran-2-formamide and its derivatives with amide bonds as connecting groups;2-(benzofuran-3-yl)benzo[d]thiazole and 2-(5-bromobenzofuran-2-yl)benzo[d]thiazole with carbon-carbon single bond as connecting group.4 N-(5-methylbenzothiazole-2-yl)benzofuran-2-formamide and its derivatives,N-(4-methylbenzothiazole-2-yl)benzofuran-2-formamide and its derivatives were molecularly docked with VEGFR-2.The toxic activity of the compounds on Human orthotopic pancreatic cancer cell BXPC-3 was roughly determined.