Design and Discovery of α-Oximido-arylacetamides as Novel Antifungal Leads.

The discovery of novel and easily accessible antifungal compounds is an imperative issue in agrochemical innovation. Our continuing research with the o -aminophenyloxazoline ( NHPhOx ) scaffold demonstrated the viability of introducing phenylacetamides for identifying novel antifungal leads. An antifungal function-oriented molecular evaluation was conducted for the previously identified lead R -LE008 . Fine-tuning of the α-position and scaffold hopping of acid segment and NHPhOx enables α-oximido-arylacetamide as a novel antifungal model. The concomitant function-oriented diversification produces a panel of antifungal leads CN19 , CN21b, CN28 , and CN31 against Sclerotinia sclerotiorum and Botrytis cinerea . The crucial and multidimensional effect of the configuration of the acquired amides on the antifungal performance is demonstrated specifically by the separable CN21 isomers. The Z -isomer ( CN21b ), with an EC 50 value of 0.97 μM against B. cinerea , is significantly more potent than its E -isomer ( CN21a ) and the positive control boscalid. More importantly, compound CN21b can efficiently inhibit resistant B. cinerea strains. CN21b demonstrates a better in vivo preventative effect (82.1%) than those of CN21a (48.1%) and boscalid (55.1%) at 100 μM. CN21b showed a distinct binding model from those of the boscalid and CN21a in the molecular docking simulation. A further morphological investigation by scanning electron microscopy revealed the different mycelia shrinkage of B. cinerea treated by CN21 isomers. The easy accessibility and cost-effectiveness demonstrated the practical potential of α-oximido-phenylacetamide containing NHPhOx as a new model for agrochemical innovation.