Synthesis, biological activity and structure–activity relationship of 4,5-dimethoxybenzene derivatives inhibitor of rhinovirus 14 infection

• Description of new and potent derivatives with HRV 14 activity.
• Presentation of Structure Activity Relationships with topological approach.
• The derivatives presented EC50 around 2 μM and promising selectivity index from 6 to 92.
• The synthesis is straightforward and mainly achieved by using TDAE.

Human rhinoviruses are a common cause of respiratory infections, and thus constitute an important target for medicinal chemistry. Still, no drug has been approved for clinical use. We report herein the discovery of dibenzenic derivatives with potent and specific in vitro anti-rhinoviral 14 activity. A total of 99 structural analogues were synthesized by an original synthesis method, i.e. through one organic agent Tetrakis(DimethylAmino)Ethylene (TDAE) and a structure–activity relationship was established. It was shown that 4,5-dimethoxy scaffold and the presence of a C-4 substituted aromatic moiety were necessary to the in vitro activity of these original agents. However, modifications on liker were not convincing. The benzonitrile derivative 23 was identified as the most potent and selective inhibitor of rhinovirus replication in these series (EC50 of 2 ± 0.5 μM, CC50 of 184 μM, selectivity index of 92).

Figure optionsDownload as PowerPoint slide