Broad‐spectrum antifungal activity of aniline‐modified tavaborole derivatives: insights from molecular docking and bioassays

Phytopathogenic fungi pose a severe threat to global agriculture, and the emergence of drug-resistant strains underscores the urgent need for novel fungicides. Tavaborole (AN2690), a clinically approved benzoxaborole antifungal, suppresses fungal growth by selectively targeting leucyl-tRNA synthetase (LeuRS) through covalent binding-a unique mode of action. In this study, we designed and synthesized a series of novel tavaborole derivatives featuring substituted aniline moieties. Our rational design strategy aimed to preserve the boron-dependent LeuRS inhibition while optimizing binding affinity and broadening the antifungal spectrum through strategic aniline modifications. A series of aniline-modified tavaborole derivatives were synthesized and evaluated against six kinds of common agricultural pathogens such as Botrytis cinerea and Gibberella zeae. A series of designed compounds demonstrated remarkably potent antifungal activity, and this is highlighted by compound 5e, surpassing Osthole and Flutriafol in bioassays in vitro. In vivo, 5e reduced rice sheath blight by 62.3%. Molecular docking studies further confirmed strong binding affinity between the active derivatives and LeuRS, validating the design strategy. This study establishes substituted aniline-tavaborole hybrids as highly promising candidates for next-generation agricultural fungicides. The unique LeuRS inhibition mechanism of the designed molecules presents an innovative and effective strategy to counter fungal pathogens, demonstrating substantial potential for crop protection.