Structural Simplification of Marine Natural Products: Discovery of Hamacanthin Derivatives Containing Indole and Piperazinone as Novel Antiviral and Anti-phytopathogenic-fungus Agents

With
the increasing severity of plant diseases and the emergence
of pathogen resistance, there is an urgent need for the development
of new efficient and environment-friendly pesticides. Marine natural
product (MNP) resources are rich and diverse. Structural simplification
based on MNPs is an important strategy to find novel pesticide candidates.
In this work, the marine natural product 6″-debromohamacanthin
A (1a) was efficiently prepared and selected as the parent
structure. A series of hamacanthin derivatives were designed, synthesized,
and studied on the antiviral and antifungal activities. Most of these
compounds displayed higher antiviral activities than ribavirin. The
antiviral activities of compounds 1a and 13e–13h are similar to or higher than that of ningnanmycin
(perhaps the most efficient anti-plant-virus agent). Compound 13h was selected for further antiviral mechanism research
via transmission electron microscopy, molecular docking, and fluorescence
titration. The results showed that compound 13h could
bind to TMV CP and interfere with the assembly process of TMV CP and
RNA. In addition, these hamacanthin derivatives also exhibited broad-spectrum
inhibitory effects against eight common agricultural pathogens. Compounds 1a, 12b, and 12f with excellent
fungicidal activities can be considered as new fungicidal candidates
for further research. These results provide a basis for the application
of hamacanthin alkaloids in crop protection.