Design and synthesis of novel thioether analogs as promising antiviral agents. In vitro activity against enteroviruses of interest

The Enterovirus genus contains two major subgroups: rhinovirus (RV) species A-C and enterovirus (EV) ones A-D. While RV only infects the respiratory system, the EV can cause a wide variety of diseases, ranging from non-specific febrile illness to severe neurologic complications. To date, no curative treatments are commercially available. Our research team had recently developed EV-A71 inhibitors. To improve their activity and broaden their spectrum, we performed optimization of the structure following an iterative cycle of chemical modulations. As a result, we obtained two broad-spectrum inhibitors with micromolar activity against these 3 types of viruses (OM1260: EC50 (MRC-5, EV-A71) = 1.15 μM; EC50 (RD, EV-A71) = 4.38 μM; EC50 (MRC-5, E30) = 0.41 μM; EC50 (MRC-5, CVA24) = 1.15 μM; HR-568: EC50 (MRC-5, EV-A71) = 3.25 μM; EC50 (RD, EV-A71) = 1.53 μM; EC50 (MRC-5, E30) = 0.40 μM; EC50 (MRC-5, CVA24) = 1.22 μM). Docking studies shed light on structure-activity relationships, while time-of-drug addition assays confirmed their intervention during the early step of viral replication. Eventually, some pharmacokinetic modelling has been carried out to evaluate their druggability. All these results showed that OM1260 and HR-568 are promising candidates for further development.