Design,Synthesis And Biological Evaluation Of Broad-spectrum Antiviral Drug Targeting Host Cell

Viruses seriously threat human's health and life.The conventional antiviral drugs mainly targeting the protein of virus.However,viruses had produced resistance agaist these drugs,in the long-term course of treatment.What's more,few drugs are currently available to treat epidemic viral diseases efficiently.Since the 1970 s,looking for safe and effective broad-spectrum antiviral drugs gradually become a hot topic in the field of anti-virus.The mammalian target of rapamycin(mTOR),comprise various proteins that drive diverse cellular processes,such as growth,proliferation,apoptosis and autophagy.Moreover,it plays an significant role in replication of virus in cells.mTOR can be activated by virus,and then promote the replication of virus through promoting the translation of mRNAs that contain 5? cap group and synthesis of proteins,and also inhibiting autophagy of cell.Numerous studies have showed that,mTOR inhibitors have anti-tumor and broad-spectrum antiviral activity,have a good prospect.This paper has carried on the research from the following aspects:Firstly,based on the reported complex crystal of mTOR and existing research on the applications of PI3K-Akt-mTOR channel inhibitors in anti-viral fields,two classes of mTOR inhibitors were designed and selected through molecular docking software—SYBYL and DS.Secondly,Nine pyrazolopyrimidine derivatives were designed and synthesized from barbituric acid through a nine-step reaction including Vilsmeier-Haack formylation,SN2 substitution reaction,Suzuki coupling etc.Then,three of these compounds were coupled with D-biotin to improve their targeting property and binding stability.Additionally,four benzothiazole derivatives were prepared via 6-step reaction,such as SN2 substitution reaction,Suzuki coupling,esterfication etc,with 2,4-dibromoaniline or 4-amino-3-bromobenzoic acid as raw materials respectively.All the compounds were characterized by NMR and MS spectra.Thirdly,all the synthesized compounds were evaluated for their bioactivities.The results demonstrated that 10 of these compounds showed obvious inhibitory activities against isolate of enterovirus type 71(E71)from thevesicle fluid.According to the evaluation result of bioactivities,preliminary discussions on the structure-activity relationship of the compounds were carried out to offer a guide to the development ofthis type of the compounds as mTOR inhibitors.