Phenylpropenamide derivatives: Anti-hepatitis B virus activity of the Z isomer, SAR and the search for novel analogs

Phenylpropenamides have been reported to be a class of non-nucleoside inhibitors of the hepatitis B virus (HBV). This class of compounds was explored with the objective of developing potent anti-HBV agents, with a novel mechanism of action, that could be combined with nucleos(t)ide analogs currently used to treat HBV infection. To accomplish this objective a series of substituted arylpropenamide derivatives were prepared and the E and Z geometrical isomers were separated. The structural identity of each of the E and Z isomers was determined by single crystal X-ray crystallography. Contrary to previous reports, the activity of this class of molecules resides in the Z isomer. Further structure–activity relationship studies around the active Z isomer identified compounds that displayed potent antiviral activity against HBV with EC90 value of approximately 0.5 μM in vitro. Attempts to develop ring constrained analogs did not lead to active HBV inhibitors.

Graphical abstractA series of substituted phenylpropenamide derivatives were prepared and the SAR against HBV was studied. The activity of this class of molecules resides in the Z isomer. The active compounds displayed potent antiviral activity with EC90 value of approximately 0.5 μM in vitro.Figure optionsDownload full-size imageDownload as PowerPoint slideHighlights► Phenylpropenamides are non-nucleoside inhibitors of the hepatitis B virus (HBV). ► The Z isomer of phenylpropenamides was shown to be the active isomer by X-ray analysis. ► SAR studies resulted in identification of Z-phenylpropenamides with submicromolar activity against HBV. ► Attempts to mimic the conformation of the phenylpropenamides by preparation of cyclic analogs did not result in active agents.