Synthesis of Four Optical Isomers of Antiviral Agent NK0209 and Determination of Their Configurations and Activities against a Plant Virus

Previously, we reported for the first time that harmala alkaloids harmine and tetrahydroharmine exhibit activity against plant viruses, and we developed an analogue, designated NK0209, that efficiently prevents and controls plant virus diseases. Here, to investigate the influence of the spatial configuration of NK0209 on its antiviral activities, we synthesized its four optical isomers, determined their configurations, and evaluated their activities against tobacco mosaic virus. All four isomers were significantly more active than ningnanmycin, which is one of the most successful commercial antiviral agents, with in vivo inactivation, cure, and protection rates of 57.3 ± 1.9, 54.2 ± 3.3, and 55.0 ± 4.1% at 500 μg/mL. Furthermore, analysis of structure–activity relationships demonstrated for the first time that the spatial conformation of NK0209 is an important determinant of its antiviral activity, and our results provide information about the possible optimum configuration for interaction of this molecule with its target protein.