Synthesis of Indol-3-yl Morpholino Derivatives Containing a Hydrazone Moiety as Potential Antiplant Virus Agents

A series of indol-3-yl morpholino derivatives containing a hydrazone moiety were designed and synthesized using indole-3-carboxylic acid as the starting material. The antiviral activities of the synthesized compounds were systematically evaluated. Compound D35, optimized using the comparative molecular field analysis (CoMFA) model, exhibited the most potent inhibitory activity against Tobacco mosaic virus (TMV) in vivo with a 50% effective concentration (EC50) value of 69.9 mg/L and exceeded that of Ningnanmycin (142.4 mg/L). Molecular docking and molecular dynamics simulations revealed that compound D35 could form stable interactions with the TMV coat protein (CP), exhibiting a lower binding energy of −9.37 kcal/mol compared to that of Ningnanmycin (−8.55 kcal/mol). Microscale thermophoresis (MST) experiments further confirmed the stronger binding affinity of compound D35 for the TMV CP than Ningnanmycin. Additionally, transmission electron microscopy (TEM) demonstrated that compound D35 effectively disrupts the TMV particles and inhibits their spread. These collective findings strongly suggest that compound D35 has the potential to serve as a lead compound for the development of novel antiviral agents.