Discovery of Dithioacetal Derivatives Containing Sulfonamide Moiety of Novel Antiviral Agents by TMV Coat Protein as a Potential Target

[Image: see text] Tobacco mosaic virus coat protein (TMV CP) plays an important role in viral replication, translation, and intracellular and intercellular movements. Thus, TMV CP could be regarded as a potential target for antiviral agents. In this study, in order to find out whether dithioacetal derivatives act on the CP target, a series of dithioacetal derivatives containing sulfonamide moiety was first designed and synthesized. Bioassay results demonstrated that Y14, Y18, and Y21 exhibited excellent activities against TMV, with half-maximal effective concentrations (EC(50)) of the curative, protective, and inactivate activities being 183.0 ± 3.2, 252.3 ± 2.6, and 63.8 ± 1.2 μg/mL, 270.6 ± 3.7, 249.7 ± 3.5, and 57.7 ± 1.4 μg/mL, and 329.5 ± 1.5, 269.2 ± 3.7, and 48.1 ± 2.0 μg/mL for Y14, Y18, and Y21, respectively, which were higher than those for the control agents ningnanmycin (331.0 ± 2.8, 271.0 ± 2.8, and 77.4 ± 1.3 μg/mL, respectively) and d2 (471.5 ± 1.4, 447.2 ± 2.1, and 91.7 ± 1.8 μg/mL, respectively). Transmission electron microscopy showed that the particle morphology of TMV was destroyed by Y21, and microscale thermophoresis (MST) showed that Y21 bonded to CP with a dissociation constant (K(d)) of 9.7 ± 1.7 μM. Then, molecular docking and MST further illustrated that Y21 had a weak binding affinity with the TMV mutant protein (K(d) = 561.3 ± 83.2 μM). Thus, we deduced that the dithioacetal derivative Y21 may inhibit TMV activity by binding TMV CP. This work provides some new insights for the design and optimization of novel anti-TMV agents.