Piperazine Derivatives Containing the α-Ketoamide Moiety Discovered as Potential Anti-Tomato Spotted Wilt Virus Agents

A total of 35 piperazine derivatives were designed and synthesized, and their activities against tomato spotted wilt virus (TSWV) were evaluated systematically. Compounds 34 and 35 with significant anti-TSWV activity were obtained. Their EC₅₀ values were 62.4 and 59.9 μg/mL, prominently better than the control agents ningnanmycin (113.7 μg/mL) and ribavirin (591.1 μg/mL). To explore the mechanism of the interaction between these compounds and the virus, we demonstrated by agrobacterium-mediated, molecular docking, and microscale thermophoresis (MST) experimental methods that compounds 34 and 35 could inhibit the infection of TSWV by binding with the N protein to prevent the assembly of the virus core structure ribonucleoprotein (RNP), and it also meant that the arginine at 94 of the N protein was the key site of interaction between the compounds and the TSWV N target. Therefore, this study demonstrated the potential for forming antiviral agents from piperazine derivatives containing α-ketoamide moieties.