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 EC₅₀ 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 (EC₅₀ = 1.41 μM) or boscalid (EC₅₀ = 2.01 μM) and fluxapyroxad (EC₅₀ = 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.

中文翻译：

---

R-LE001 的多维优化，用于具有增强抗真菌特性的新先导化合物


支架跳跃和结构微调是农化创新的重要策略。通过设计、合成和生物评价 53 种支架或取代基不同的新化合物，对预先验证的抗真菌先导药物 R-LE001 进行了多维优化。抗真菌构效关系（SAR）显示，许多含有 2-(2-恶唑啉基)苯胺 (NHPhOx) 或 2-(2-噻唑啉基) 苯胺 (NHPhthiOx) 的酰胺比 R-LE001 表现出更有前景的抗真菌作用和阳性对照啶酰菌胺。具体而言，化合物10（编码LEX-K01）对灰葡萄孢表现出优异的抗真菌作用，EC ₅₀ 值低于0.11μM。与 R-LE001 (EC ₅₀ = 1.41 μM) 或啶酰菌胺 (EC ₅₀ = 2.01 μM) 和 Fluxapyroxad (EC ₅₀ = 4.35 μM)。由于耐药因子低得多，LEX-K01 (10) 对两种啶酰菌胺耐药菌株 B. cinerea TZ01 和 NJBH2017 更有效。 LEX-K01 (10) 与啶酰菌胺以 1:3 的比例组合，对抗性灰霉病菌 TZ01 和 NJBH2017 表现出协同作用，SR 值分别为 3.01 和 2.55。 LEX-K01（10）在防治灰霉病方面的疗效（70.3%）比啶酰菌胺（51.2%）更显着。 LEX-K01 (10) 与 B. cinerea 的 SDH 蛋白的分子对接模拟显示，与氨基酸残基 TYR144、ARG88、TRP81 和 SER84 存在四个氢键，说明其亲和力比啶酰菌胺更强。扫描电镜（SEM）特征表明，它会导致灰霉病菌菌丝体明显崩溃。 这项工作表明 LEX-K01 (10) 作为一种新型抗真菌剂具有进一步探索的潜力。