Multidimensional Optimization of R -LE001 for New Leads with Enhanced Antifungal Profiles.

Scaffold hopping and structural fine-tuning are important strategies for agrochemical innovation. Multidimensional optimization of the prevalidated antifungal lead R -LE001 was conducted via the design, synthesis, and bioevaluation of 53 new compounds differing in either scaffold or substituent. The antifungal structure-activity relationship (SAR) revealed that a number of amides containing 2-(2-oxazolinyl) aniline (NHPhOx) or 2-(2-thiazolinyl) aniline (NHPhthiOx) demonstrated a more promising antifungal effect than both R -LE001 and the positive control boscalid. Specifically, compound 10 (encoded LEX-K01 ) shows an excellent antifungal effect against Botrytis cinerea with an EC 50 value lower than 0.11 μM. This small change leads to a significant improvement (over 1 order of magnitude) in bioactivity compared to that of either R -LE001 (EC 50 = 1.41 μM) or boscalid (EC 50 = 2.01 μM) and fluxapyroxad (EC 50 = 4.35 μM). With much lower resistance factors, LEX-K01 ( 10 ) was more efficacious against the two boscalid-resistant strains of B. cinerea TZ01 and NJBH2017. A combination of LEX-K01 ( 10 ) and boscalid in a ratio of 1:3 showed synergistic effects against resistant B. cinerea TZ01 and NJBH2017, with SR values of 3.01 and 2.55, respectively. LEX-K01 ( 10 ) has a curative efficacy (70.3%) more prominent than that of boscalid (51.2%) in controlling disease caused by B. cinerea . The molecular docking simulation of LEX-K01 ( 10 ) with the SDH protein of B. cinerea displayed four hydrogen bonds with amino acid residues TYR144, ARG88, TRP81, and SER84, rationalizing a stronger affinity than boscalid. The scanning electron microscopy (SEM) characteristic revealed that it could cause an obvious collapse of B. cinerea mycelium. This work indicates that LEX-K01 ( 10 ) has the potential to be further explored as a new antifungal agent.