Design, enantioselective synthesis, and antiviral activities against potato virus Y of axially chiral thiazine derivatives

A series of novel thiazine derivatives featuring axial chirality in both (R) and (S) configurations were successfully synthesized by N-heterocyclic carbene (NHC)-catalyzed enantioselective [3 + 3] annulations, and their potential as anti-plant virus agents against potato virus Y (PVY) was evaluated. Biological activity results demonstrated that most of these chiral thiazine derivatives exhibited significant activities against PVY. Notably, compound (S)-3g displayed a remarkable 58% inactivation effect against PVY at a concentration of 500 μg/mL, slightly surpassing the effectiveness of Ningnanmycin (NNM) at 57%. Additionally, (S)-3g exhibited curative activity of 57%, which is superior to NNM (53%). Molecular docking studies revealed preliminary insights into the distinct biological properties of the two different enantiomers, (R) or (S)-3g against PVY, wherein single enantiomer (S)-3g formed a more stable interaction with PVY-CP, as indicated by its lower binding free energy (−41.18 kcal/mol) compared to (R)-3g (−36.9 kcal/mol). The findings in this study with a new class of axially chiral thiazine derivatives shall inspire further development of chiral heterocycles as potential drug candidates for the protection of plant virus infections.