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 EC50 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.