Identification of 4-Hydroxybenzaldehyde Schiff Base Derivatives as Novel Fungal Chitin Deacetylase Inhibitors via Pocket-Based Design and Molecular Hybridization

Fungal chitin deacetylase (CDA) is a key virulence factor in plant pathogenic fungi, and developing CDA inhibitors represents a promising disease-control strategy. This study optimized the reported PstCDA inhibitor VS-24 by a dual-track strategy integrating pocket-based design and molecular hybridization. The optimized M-09 (K_i = 27.5 μmol/L) exhibited 4-5-fold higher activity against PstCDA than VS-24 (K_i = 124 μmol/L). Structure-activity relationship (SAR) and mechanism studies revealed the critical role of the 4-hydroxyl-phenyl group across compounds in enzymatic inhibition through interactions with Zn²⁺ and His207. Additionally, the rhodanine ring in M-09 can establish dual hydrogen bonds with Trp174 and Tyr152, enhancing the binding affinity. Moreover, M-09 can inhibit Infection by Rhizoctonia solani, Pyricularia oryzae, and Botrytis cinerea and exhibited moderate control efficacy against rice sheath blight at 100 μg/mL. With favorable fungicide-likeness, M-09 showed strong potential as a candidate for further development of novel Antifungal agents targeting CDA.

chitin deacetylase; inhibitors; plant fungal disease control; structural optimization.