Synthesis of Indol-3-yl\nMorpholino Derivatives Containing\na Hydrazone Moiety as Potential Antiplant Virus Agents

A series of indol-3-yl morpholino\nderivatives containing a hydrazone moiety were designed and synthesized\nusing indole-3-carboxylic acid as the starting material. The antiviral\nactivities of the synthesized compounds were systematically evaluated.\nCompound <b>D35</b>, optimized using the comparative molecular\nfield analysis (CoMFA) model, exhibited the most potent inhibitory\nactivity against Tobacco mosaic virus (TMV) in vivo with a 50% effective\nconcentration (EC<sub>50</sub>) value of 69.9 mg/L and exceeded that\nof Ningnanmycin (142.4 mg/L). Molecular docking and molecular dynamics\nsimulations revealed that compound <b>D35</b> could form stable\ninteractions with the TMV coat protein (CP), exhibiting a lower binding\nenergy of −9.37 kcal/mol compared to that of Ningnanmycin (−8.55\nkcal/mol). Microscale thermophoresis (MST) experiments further confirmed\nthe stronger binding affinity of compound <b>D35</b> for the\nTMV CP than Ningnanmycin. Additionally, transmission electron microscopy\n(TEM) demonstrated that compound <b>D35</b> effectively disrupts\nthe TMV particles and inhibits their spread. These collective findings\nstrongly suggest that compound <b>D35</b> has the potential\nto serve as a lead compound for the development of novel antiviral\nagents.