Design, Synthesis And Activity Evaluation Of New Anti-EV71 Inhibitor

Hand, foot, and mouth disease (HFMD) is a epidemical disease resulting from infecting with Enterovirus 71 and Coxsackievirus A16. The HFMD caused by EV71 is a global disease, several epidemic outbreaks have occurred since 1970s. To date, no antiviral agents have been approved to enter into clinical trail. Thus, it is still an arduous task to discover and develop new anti-EV71 agents with novel structure type.The VP1 is a structural protein of EV71, which is an impom.p.ant target for anti-EV71 drug design. The aim of the dissem.p.ation is to design and synthesize some new anti-EV71 small molecule inhibitors with novel structure on the basis of VP1 protein target.Pyridyl imidazolidinones compounds and another compound with benzocy- cloheptene anhydride structure as lead compounds, using the classical drug design theory and analyses of the structure-activity relationship(SAR) of compounds with high activities in recent literatures, we designed and synthesized three series of compounds consist of 3-(pyridine-4-yl)-tetrahydropyrimidin-2(1H)-one structure, benzocyclohepetene anhydride structure, 5-phenyl-1,3,4-oxadiazole-2-thiol structure and N-(3-chloro-4-methylphenyl)-N-(3-substitution)-propyl benzamide. All synthesiz- ed compounds were confirmed by MS and 1H-NMR.All the target compounds were evaluated for their in vitro antiviral activity against EV71 BrCr TR strain infection in RD cells and cell cytotoxicity. The results showed that the compounds with 3-(pyridine-4-yl)-tetrahydropyrimidin-2-(1H)-one and benzocyclohepetene anhydride structure have no significant bioactivity against EV71 BrCr TR strain. The compounds with 5-phenyl-1,3,4-oxadiazole-2-thiol structure exhibited potent anti-EV71 activity, especially compounds M7, which IC50 is 0.74μg/mL and CC50 is 44.14μg/mL.The SAR of three series compounds were discussed based on the effects of substitution and configurational changes, position isomerism, the results are as follows: (1) The target compounds get better activities when the left structures are five- membered rigid rings. (2) The right structures of the target compounds are effect with its cell cytotoxicity, the compounds exhibited high cell cytotoxity when the right structures are benzyl piperizine. (3) The carbon chain length of the compounds with 5-phenyl-1,3,4-oxadiazole-2-thiol structure has no notable effect on anti-virus activities. All the conclusions provided a theoretical basis for the next round new anti-EV71 inhibitors design.