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 EC(90) value of approximately 0.5 μM in vitro. Attempts to develop ring constrained analogs did not lead to active HBV inhibitors.