Design, Synthesis And Antiviral Activities Of A Novel Series Of Triazole Derivatives As Potential Anti-Enterovirus Agent

Enteroviruses belong to the picornavirus family, which associatedwith several human and mammalian diseases. It is estimated thatenteroviruses cause10-15billion (or more) enteroviral infections annuallyworldwide. In the spring of2008, a large HFMD (hand-foot&monthdisease) outbreak caused by EV71(Enterovirus71) in China resulted in ahigh aggregation of fatal cases. HFMD outbreaks caused by CVA16(Coxsachievirus A16) also occurred in Asia and all over the world.Currently, as no efficient drug was found for the clinical treatment ofenteroviruses, there is a tremendous clinical need to develop novel classesof antiviral agents for the treatment of enterovirus infection.In our previouswork, a series of benzimidazole-4-carboxamide derivatives weresynthesized and screened, and these compounds were indentified asmodest inhibitors of EV71, CAV24, CVB3(Coxsachievirus B3) andCVB6(Coxsachievirus B6). Most of the benzimidazole-4-carboxamidederivatives were proved to have strong antiviral activities against CVB3，especially those2-pyridyl-1H-benzimidazole-4-carboxamide derivatives.CVB3is a virus that belongs to a family of non-enveloped linearsingle-stranded positive-sense ssRNA viruses, picornaviridae and thegenus enterovirus, tending to cause myocarditis. In recent years, the triazole compounds have gained significantinterest in drug discovery due to their wide range of biological activitiessince the first synthetic nucleoside drug, ribavirin, showed a broadspectrum of antiviral activity against many RNA and DNA viruses.In ourprevious work, a series of2-pyridyl-1H-benzimidazole-4-carboxamidederivatives were synthesized, screened and indentified as modest inhibitorsof CVB3. In view of its novel structural template, which differed fromthose of all reported anti-enterovirus agents, we were interested tointroduce1,2,4-triazoles moiety. A series of amide derivatives containing1,2,4-triazole ring were synthesized, screened and indentified as modestinhibitors of coxsackie viruses. It was believed that one compound couldbe found effective against enterovirus as a leading compound.In this work, a series of novel1,2,4-triazole derivatives weresynthesized through multiple steps of reactions, based on different types oftriazole as material. The structure of these compounds were verified by1HNMR and the inhibitory activities were tested against CVB3/B6. Thesecompounds were found to exhibit good inhibitory activities against CVB3.These structure-activity relationship analyses indicated that theintroduction of dinitro phenyl in the R2position was critical for the highantiviral activity.Due to the introduction of dinitro phenyl in the R2position, compounds18~25exhibited good antiviral potency againstCVB3.The introduction of methyl in the R2position resulted inapproximately no biological activities, but their cytotoxicities weresignificantly decreasedIt was also found that a compound seemed to be effective against other virus if it was effective against one virus of the same family.Hopefully, these1,2,4-triazole derivatives might be effective against all theenteroviruses, even the entire picornavirus family, because of the similarinhibitory mechanism.