Design,synthesis And Anti-coronavirus Activity Of Nucleoside Drugs And Oligosyltransferase Inhibitors

Coronaviruses are ubiquitous in nature and it does harm to humans,livestock,and poultry in different degrees.Up to now,Seven coronaviruses that are pathogenic to humans have been found.Among them,"SARS-Co V" and "MERS-Co V" have had a great impact on human being,which appeared in2003 and 2012,respectively.Since the end of 2019,the novel coronavirus epidemic caused by "SARS-Co V-2" is still spreading all over the world.To deal with this epidemic,"reuse of old drugs" has become a fast and effective response method in the initial stage.However,in the face of repeated outbreaks and constant mutations of the new coronavirus,the rapid research and development of new drugs is still imminent.In this study,we started with two different antiviral mechanisms.On the one hand,we continued the research of nucleoside antiviral drugs targeting the virus itself,and on the other hand,we focused on the antiviral mechanism targeting host oligosaccharide transferases,and synthesized 38 target compounds.EIDD-1931(NHC)is the in vivo metabolite of molnupiravir,a new drug for the treatment of coronavirus pneumonia.It is the core structure that plays an antiviral role.Due to the strong polarity and poor bioavailability of NHC,14 target compounds were synthesized by introducing carbon chains in this study,aiming to reduce its polarity and improve its cell permeability.All compounds showed antiviral activity to HCo V-OC43 and HCo V-229 E in vitro.Among them,there are three compounds whose activity is better than that of NHC,which can be further studied.NGI-1 is a reported oligosaccharide transferase inhibitor found by high-throughput screening,which has been confirmed to be active against dengue fever,Zika,new coronavirus and other viruses in vitro studies,however its activity needs to be enhanced.Therefore,in this study,the active group of NGI-1 compound was derivatized at the 5-methyl-thiazole position,and a total of 24 target compounds were synthesized to enhance the antiviral activity.In vitro evaluation of anti-HCo V-OC43 and HCo V-229 E showed that three of them had good activity which was worthy of further study.