Antifungal Function Oriented Scaffold Hopping for the Discovery of Oxazolyl-oxazoline as a Novel Model against Fusarium graminearum.

Discovery of novel structural models is extremely important in agrochemical innovation. Scaffold hopping was conducted, and 16 kinds of novel models were synthesized and biologically evaluated. Oxazolyl-oxazoline 25 showed a promising in vitro potential against Fusarium graminearum with EC50 value of 18.25 µM, which was 2.4 times more potent than that of carbendazim (EC50 = 43.06 µM). The antifungal structure-activity relationship (SAR) revealed that compound 25am had the most promising antifungal activity against F. graminearum, with an EC50 value of 13.46 µM, which was 3.2 more potent than that of carbendazim. Different from carbendazim, the candidate 25am could form five hydrogen bonds with the amino acid residues in ß-tubulin in the molecular docking and could effectively inhibit the carbendazim-resistant F. graminearum strain. Scanning electron microscopy (SEM) revealed that compound 25am induced the mycelia of F. graminearum slight collapse. This work suggests that compound 25am should be prioritized for further evaluation for new antifungal agents.

Asymmetric Synthesis of Sakuranetin-Relevant Flavanones for the Identification of New Chiral Antifungal Leads.

Discovery and efficient synthesis of new promising leads have a central role in agrochemical science. Reported herein is the sakuranetin-directed synergistic exploration of an asymmetric synthesis and an antifungal evaluation of chiral flavanones. A new palladium catalytic system with CarOx-type ligands was successfully identified for the highly enantioselective addition of arylboronic acids to chromones. This enabled the facile and programmable construction of a constellation of chiral flavanones (up to 98% yield and 97% ee), in which (R)-pinostrobin was efficiently constructed without laborious protecting/deprotecting operations. Its good performance in asymmetric induction and functional tolerance expanded the chemical space of pharmaceutically important flavanones. The chiral differentiation of flavanones based on antifungal activity and a concise structure-activity relationship model was disclosed and summarized. This synergistic project culminated with acquisition of the naturally unprecedented flavanones with better antifungal potentials than sakuranetin, in which the R-enantiomer of flavanone 54 (EC50 = 0.8 µM) demonstrated better performance than boscalid against Rhizoctonia solani. The novel scaffold and predicted new target compared with the commercial fungicides in the FRAC reinforce the value of further exploration.

Palladium Catalyzed Enantioselective Hayashi-Miyaura Reaction for Pharmaceutically Important 4-Aryl-3,4-dihydrocoumarins.

The first palladium-catalyzed asymmetric addition of arylboronic acids to coumarins was successfully established, providing a straightforward asymmetric approach to achieving pharmaceutically important 4-aryl-3,4-dihydrocoumarins. This methodology features easily accessible and bench-stable ligands, a wide substrate scope, mild conditions, and accommodation of electron-withdrawing arylboronic acids.

Multifunctional isoquinoline-oxazoline ligands of chemical and biological importance.

Multifunctional isoquinoline-oxazolines (MIQOXs) were conceived and synthesized from commercially available chiral amino acids. The multifunctional role of MIQOXs was demonstrated by Pd-catalyzed highly enantioselective addition of arylboronic acids to nitrostyrenes, and by the discovery of novel antifungal candidates.