Study On The Design,Synthesis And Optical Property Of EV71 And Coxa16 Hand-Foot-Mouth Virus Inhibitors

Hand-foot-mouth disease?HMFD?is an acute infectious disease caused by enteroviruses.The prevalence of the disease is mainly in children under 5 years old.In China,Coxsackie virus 16?CVA16?and Enterovirus 71?EV71?are the main viruses leading to the disease,and the incidence rate is extremely high.Severely children who suffered this disease may be lead to death.At present,there are no specific drugs or vaccines in clinical practice.Therefore,it is very important to develop drugs for the treatment of HMFD.In this study,the proteins 3N6M and 5ABJ are selected as target using rational drug design method to develop anti-HMFD drugs.Using computer-aided drug design software of Discovery Studio 2017 as a tool,there are more than 600,000 small-molecule compounds docked with 3N6M and 5ABJ proteins to carry out virtual screen.The lead compound was selected with the highest score.After analyzing the screening results,it was found that the common characteristics of the compounds with better comprehensive evaluation were the combination mode of A+Link+B.Part A contained the active structure of the pepper ring,the alkyl chain was the main basis of Link,and Part B was mainly based on aromatic and non-aromatic heterocycles.Based on this patten,we designed a series of compounds for structural modification of leading compounds.The new designed compounds were further docked with the CADD tool of Discovery Studio 2017,and it is found that 20 compounds were superior to the leading compounds.The 20compounds were then conducted ADMET's forecast and also showed a good result.The piperazine was reacted with adipoyl chloride and oxalyl chloride to give the target compound of the leading compound.The structure of the leading compound was determined by the single crystal X-ray determination method.The target compounds were synthesized by the reaction of piperonylamine and the pepper benzylamine with the cis-butadiene anhydride to obtain the corresponding carboxylic acid and then with different heterocyclic aniline or benzylamine with regular amide synthetic mothod.Some of the target compounds were obtained is to obtain by reaction of adipoyl chloride or oxalyl with the piperonylamine and the pepper benzylamine.We studied the optical properties of these compounds and found that some of them have good optical activity,which facilitates future targeted therapies.In this study,dozens of compounds were designed according to the leading compounds.There were 20 compounds chosen to synthesis by further simulation and ADMET prediction.The structure of 20 synthesized compounds were identified by¹H-NMR?¹³C-NMR?IR.All the structures of 20 compounds are correct.The bio-activity study for HFMD viruses is on processing.Our objective is developing the specific anti-virus drug for enterovirus EV71 and CVA16 type.And it is also study the relationship of protein and small molecule compounds.It is expected that the specific and effective compounds can be developed out to relieve the infant patients suffering of HFMD disease.