Rational Design of Chitin Deacetylase Inhibitors for Sustainable Agricultural Use Based on Molecular Topology.

Fungicide resistance is a major concern in modern agriculture; therefore, there is a pressing demand to develop new, greener chemicals. Chitin is a major component of the fungal cell wall and a well-known elicitor of plant immunity. To overcome chitin recognition, fungal pathogens developed different strategies, with chitin deacetylase (CDA) activity being the most conserved. This enzyme is responsible for hydrolyzing the N -acetamido group in N -acetylglucosamine units of chitin to convert it to chitosan, a compound that can no longer be recognized by the plant. In previous works, we observed that treatments with CDA inhibitors, such as carboxylic acids, reduced the symptoms of cucurbit powdery mildew and induced rapid activation of chitin-triggered immunity, indicating that CDA could be an interesting target for fungicide development. In this work, we developed an in silico strategy based on QSAR (quantitative structure-activity relationship) and molecular topology (MT) to discover new, specific, and potent CAD inhibitors. Starting with the chemical structures of few carboxylic acids, with and without disease control activity, three predictive equations based on the MT paradigm were developed to identify a group of potential molecules. Their fungicidal activity was experimentally tested, and their specificity as CDA inhibitors was studied for the three best candidates by molecular docking simulations. To our knowledge, this is the first time that MT has been used for the identification of potential CDA inhibitors to be used against resistant powdery mildew strains. In this sense, we consider of special interest the discovery of molecules capable of stimulating the immune system of plants by triggering a defensive response against fungal species that are highly resistant to fungicides such as powdery mildew.