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 <b>D35</b>, 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 <b>D35</b> 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 <b>D35</b> for the TMV CP than Ningnanmycin. Additionally, transmission electron microscopy (TEM) demonstrated that compound <b>D35</b> effectively disrupts the TMV particles and inhibits their spread. These collective findings strongly suggest that compound <b>D35</b> has the potential to serve as a lead compound for the development of novel antiviral agents.