Scaffold Hopping from Dehydrozingerone: Design, Synthesis, and Antifungal Activity of Phenoxyltrifluoromethylpyridines

TL;DR

Researchers designed and tested new antifungal compounds based on dehydrozingerone, finding some with strong activity against plant pathogens.

Contribution

A novel scaffold hopping strategy was used to create and evaluate antifungal trifluoromethylpyridine derivatives.

Findings

Compound 17 showed the highest antifungal efficacy with EC50 values between 2.88 and 9.09 μg/mL.

Phenoxytrifluoromethylpyridines outperformed benzyloxy derivatives in antifungal activity.

Compound 23 interacts with succinate dehydrogenase, as shown by molecular docking studies.

Abstract

In response to the urgent need for innovative fungicides to ensure food security and safety, a series of twenty-three novel trifluoromethylpyridine compounds were designed and synthesized using a scaffold hopping strategy derived from dehydrozingerone. This approach involved converting the α, β-unsaturated ketone moiety into a pyridine ring. Bioassay results indicated that the majority of these compounds exhibited promising in vitro antifungal activity, particularly against Rhizoctonia solani and Colletotrichum musae. Notably, compound 17 showed the highest efficacy and broad-spectrum activity, with median effective concentrations (EC50) ranging from 2.88 to 9.09 μg/mL. Phenoxytrifluoromethylpyridine derivatives, including compound 17, exhibited superior antifungal activity compared to benzyloxytrifluoromethylpyridine derivatives. In vivo tests revealed that both compounds 17 and 23 exhibited moderate control effects against C. musae. The degradation half-lives of compounds 17 and 23 in bananas were determined to be 176.9 h and 94.8 h, respectively, indicating the stability of their structures in the environment. Molecular docking studies indicated that compound 23 interacts with succinate dehydrogenase, offering valuable insights for the structural optimization of compound 23.

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