Design, Sythesis And Evaluation Of EV71 VP1 Inhibitors

Enterovirus EV71 is not only a main pathogen for hand-foot-mouth disease, but also causes virus infection related complications like myocarditis, respiratory infection pulmonary edema, aseptic meningitis, brainstem encephalitis and Poliomyelitis like paralysis. So disovering effective anti-EV71 drugs is necessarily urgent.EV71 falls into the group of Picornaviridae virus. Several drug targets have been discovered as the study for EV71 keeps going further. Among them, Protein VP1 that positions at the virus capsid closely correlates the virus absorption and uncoating, and have become one of the major drug targets for EV71 anti-virus agents. A hydrophobic pocket lays at the bottom of "valley" constitutes of the VP1 protein surface, and serves as the binding site of the anti-virus drugs. Drug binding to the hydrophobic pocket results in the increase of virion rigidity and the decrease of virion flexibility, so that the absorption and uncoating for the virus turns into a much harder process.Human Rhinovirus (HRV) is another member from Picornaviridae virus. HRV VP1 is also a capsid protein and has a high homology with EV71 VP1 protein. Our research group has previously synthesized a series of highly active HRV VP1 inhibitor. Thus, based on the stereochemical analysis of the binding sites in EV71 VP1 and HRV VP1 and comparison bwtween the pharmacophores respectively generated by EV71 and HRV inhibitors, a series of novo EV71 anti-virus inhibitors have been designed based on the strucuture of the HRV VP1 inhibitor Mc1041116, which was sythesized in our research group as well.It has been reported that VP1 targeting pyridyl imidazolidin compounds are of great anti-EV 71 virus potency. Using the pyridyl imidazolidin compounds as lead compounds, bioisosterism, one of the classical drug design methods, was adopted for the design of the novo EV 71 inhibitors. So far,46 target compounds have been synthesized, among which 44 has not been reported. The structures of all the 46 compounds were identified by methods of MS,1H-NMR; one target compound was cultured for single crystal and the absolute configurations were determined by X-ray diffraction. Pharmacodynamic evaluation of the synthesized target compounds was conducted at cellular level through Reed-Muench method, to assess their activity to inhibit EV71, Cox A16 and HRV-3, their toxocity was evaluated as well. Based on results as above, pyridazines and thiazoles possess anti-EV71, Cox A16 and HRV-3 avtivities at the different extents. According to the anti-EV71 results, D-17, D-18, SY-04, SY-05 and SY-06 are outstandingly active, which means promising prospect of them as anti-EV71 agents. Based on the discussion above, compound D-18 displayed excellent in vitro inhibition of EV71, Cox A16 and HRV-3; compound SY-06 could inhibit EV71 and Cox A 16. These results indicated that the two compounds can be used for the further study as the broad-spectrum antivirus agents.Primary structure-activity relationships of these target compounds was identified based on the biological activity assessment. The influence of the number of carbon atoms between the piperazine and benzene ring and the substituent group of the benzene ring in the hydrophobic region on the activity were respectively discussed.