New Thiosemicarbazones derived from 1-indanones with Antiviral Activity against Bovine Viral Diarrhea Virus

M. FABIANI; E.F. CASTRO; M.C. SORAIRES SANTACRUZ; L. M. FINKIELSZTEIN; L. V. CAVALLARO

Conferencia; International Conference on Antiviral Research ICAR 2015; 2015

Bovine viral diarrhea virus (BVDV) is the prototype Pestivirus. BVDV infection isdistributed worldwide and causes serious problems for the livestock industry. Thethiosemicarbazone (TSC) of 5,6­dimethoxy­1­indanone (lead compound) is a potent non­nucleoside polymerase inhibitor of BVDV.In order to find compounds with an improved anti­BVDV activity, a series of thirteen novel TSCs was synthesized. The aim of this work was to evaluate their antiviral activity in vitro against BVDV and to preliminarily analyze their structure­activity relationship. The most active compounds were also evaluated against BVDV mutants resistant to the lead compound (BVDV­TSCr).From the N4 ­substituted TSCs with phenyl groups (1­9), only derivatives 4­9 were active,suggesting that the 5,6­dimethoxy substitution would improve the anti­BVDV activity. It should be noted that the nature of the substituent at the R3 position has an important effect:compounds with electron­withdrawing substituents (7 and 8) were the most active.Derivative 8 (R3=NO2) resulted to be almost six times more active than the lead compound(EC50= 0.7±0.3 and 3.8±0.4 µM, respectively). Among the TSCs 10­13, only compound 11 exerted an activity similar to that of the lead compound, suggesting that the NO2 group at the R3 position would enhance the antiviral activity in the absence of the 5,6­dimethoxy substitution. Finally, BVDV­TSCr were also resistant to compound 8 but, interestingly, they were slightly inhibited by compound 11. Further experiments and docking studies of thesecompounds should be held to determine the molecular interactions with the viralpolymerase.