The conformational restriction switch concept has been adopted as a major tool for structural optimization of pharmaceuticals in order to expand the chemical structure scope and improve therapeutic activity against specific proteins. Several of the 1-aminocyclobutanecarboxylic acid derivatives produced in this way exhibited satisfactory antifungal activity in vitro compared with positive control boscalid. In vitro antifungal tests revealed that compound A21 had comparable, even higher antifungal activity against Rhizoctonia solani (R.s., EC₅₀ = 0.03 mg/L) and Botrytis cinerea (B.c., EC₅₀ = 0.04 mg/L) than fluxapyroxad (R.s., EC₅₀ = 0.02 mg/L; B.c., EC₅₀ = 0.20 mg/L) and boscalid (R.s., EC₅₀ = 0.29 mg/L; B.c., EC₅₀ = 0.42 mg/L). Furthermore, compound A20 was successfully screened and exhibited good inhibitory activity against porcine SDH, its IC₅₀ value was 3.73 μM, which has considerable potency compared with fluxapyroxad (IC₅₀ = 3.76 μM). The mode of action was determined using SEM and membrane potential research. The effects of the substituent steric hindrance, electrostatic property, hydrophobicity, and hydrogen-bond fields on structure–activity relationships were elaborated by the reliable models of comparative molecular field analysis and comparative molecular similarity index analysis. Furthermore, density functional theory simulations, molecule electrostatic potential, and molecular docking were also used to study the probable binding mode of target compounds with flexible fragments. The results showed that the scaffold of 1-aminocyclobutanecarboxylic acid derivatives could be used as lead for discovering new succinate dehydrogenase inhibitors.

中文翻译：

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作为琥珀酸脱氢酶抑制剂的新型氨基环丁烷甲酸衍生物的发现

构象限制开关概念已被采用作为药物结构优化的主要工具，以扩大化学结构范围并提高针对特定蛋白质的治疗活性。与阳性对照啶酰菌胺相比，以此方式生产的几种1-氨基环丁烷甲酸衍生物在体外表现出令人满意的抗真菌活性。体外抗真菌试验表明，化合物A21对立枯丝核菌( R.s.，EC ₅₀ = 0.03 mg/L)和灰葡萄孢( B.c.，EC ₅₀ = 0.04 mg/L)具有相当甚至更高的抗真菌活性。Fluxapyroxad（R.s.，EC ₅₀ = 0.02 mg/L；B.c.，EC ₅₀ = 0.20 mg/L）和啶酰菌胺（R.s. ， EC 50 = 0.29 mg/ _L；B.c.，EC ）₅₀ = 0.42 毫克/升）。此外，成功筛选到的化合物A20对猪SDH具有良好的抑制活性，其IC ₅₀值为3.73 μM，与fluxapyroxad（IC ₅₀ = 3.76 μM）相比具有相当的药效。使用 SEM 和膜电位研究确定作用方式。通过比较分子场分析和比较分子相似性指数分析的可靠模型，详细阐述了取代基空间位阻、静电性质、疏水性和氢键场对构效关系的影响。此外，还利用密度泛函理论模拟、分子静电势和分子对接来研究目标化合物与柔性片段的可能结合模式。结果表明，1-氨基环丁烷甲酸衍生物的支架可以作为发现新的琥珀酸脱氢酶抑制剂的先导。