Scaffold Hopping of Florylpicoxamid for Structurally and Biologically Distinct Antifungal Leads

Abstract

Simplification of the complex macrolide UK-2A delivers florylpicoxamid, while optimization of its synthetically challenging pyridinyl acid remained underdeveloped. Scaffold hopping with 14 structurally distinctive heterocyclic acids in the molecular evolution of florylpicoxamid led to thiazole amide as a novel antifungal chemotype. The concomitant antifungal optimization achieved a structurally unique candidate, LEX-K02 (9al, EC50 = 0.140 μM), exhibiting 49-fold higher activity against Gaeumannomyces graminis than florylpicoxamid (EC50 = 7.06 μM). It was demonstrated to possess a unique mechanism in view of both antifungal phenotypes and molecular docking simulation. This antifungal candidate can disrupt the cell membrane. Transcriptomics and metabolomics analysis suggested that compound LEX-K02 may affect the synthesis of N-glycans by targeting the map00510 pathway, and is safe for wheat. Pyridinyl acid optimization of UK-2A-related molecules was validated as a viable fungicide discovery strategy.