Bioactivity of Indole Derivatives Containing 1,3,4-Thiadiazole against the Tobacco Mosaic Virus

Introduction: Based on 24 previously synthesized indole derivatives bearing 1,3,4- thiadiazole moieties, further evaluation of their antiviral potential against tobacco mosaic virus (TMV) was conducted. The anti-TMV potential of compound Z23 was assessed via multimodal analysis and compared with that of ningnanmycin (NNM). Methods: The anti-TMV activity of the synthesized derivatives was evaluated via in vivo curative and protective assays. Target engagement was analyzed using microscale thermophoresis (MST) and molecular docking with tobacco mosaic virus coat protein (TMV-CP). Additionally, their physiological impacts were assessed through the quantification of malondialdehyde (MDA) and chlorophyll content. Results: Z23 demonstrated stronger in vivo antiviral activity than NNM, with curative and protective EC50 values of 96.7 and 71.9 μg/mL, respectively (NNM: 194.5 and 159.2 μg/mL). MST analysis indicated higher TMV-CP binding for Z23 (Kd = 0.03202 μmol/L) versus NNM (Kd = 1.86660 μmol/L). Molecular docking confirmed stable Z23 TMV-CP interactions through hydrogen bonds and hydrophobic forces. The determination of MDA and chlorophyll content showed that Z23 could improve the disease resistance of tobacco. Discussion: These findings demonstrate the superior antiviral efficacy of Z23 compared to the reference NNM, likely mediated by potent TMV-CP binding and the induction of host defense responses. This positions Z23 as a highly promising lead compound. However, further in-plant validation and field studies are warranted. Conclusion: 1,3,4-Thiadiazole-modified indole derivatives have laid the foundation for the development of new antiviral agricultural chemicals.