Ahrens Hartmut, Barber David M, Bojack Guido, Bollenbach-Wahl Birgit, Churchman Luke, Getachew Rahel, Helmke Hendrik, Hohmann Sabine, Laber Bernd, Lange Gudrun, Rees Shaun, Reingruber Anna M, Schmutzler Dirk, Frackenpohl Jens
Research and Development, Weed Control, Division Crop Science, Bayer AG, Industriepark Höchst, Frankfurt am Main, Germany.
Pest Manag Sci. 2025 May;81(5):2635-2651. doi: 10.1002/ps.8357. Epub 2024 Aug 6.
Weed control is a significant challenge for farmers around the globe. Of the various methods available for combatting weeds, small molecules remain the most effective and versatile technology to date. In the search for novel chemical entities with new modes of action toward herbicide-resistant weeds, we have investigated hexahydrofuro[3,4-b]furan-based acyl-acyl carrier protein (ACP) thioesterase inhibitors inspired by X-ray co-crystal structure-based modeling studies.
By exploiting scaffold hopping concepts and molecular modeling studies we were able to identify new hexahydrofuro[3,4-b]furan-based lead structures showing promising activity in vivo against commercially important grass weeds in line with strong target affinity.
The present work covers a series of novel herbicidal lead structures that possess a hexahydrofuro[3,4-b]furan scaffold as a structural key feature, carrying ortho-substituted aryloxy side chains. Based on an optimized synthetic approach a broad structure-activity relationship (SAR) study was carried out. The new compounds emerging from our modeling-inspired structural variations show good acyl-ACP thioesterase inhibition in line with promising initial herbicidal activity. Glasshouse trials showed that the hexahydrofuro[3,4-b]furans outlined herein display good control of cold and warm season grass-weed species in pre-emergence application. Remarkably, some of the novel acyl-ACP thioesterase-inhibitors also showed promising efficacy against warm season weeds that are difficult to control. © 2024 The Author(s). Pest Management Science published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry.
杂草控制对全球农民来说是一项重大挑战。在各种可用的杂草防治方法中，小分子至今仍是最有效且用途广泛的技术。在寻找对抗除草剂杂草具有新作用模式的新型化学实体的过程中，我们基于X射线共晶体结构建模研究，对六氢呋喃并[3,4 - b]呋喃基酰基 - 酰基载体蛋白（ACP）硫酯酶抑制剂进行了研究。
通过利用骨架跃迁概念和分子建模研究，我们能够确定新的基于六氢呋喃并[3,4 - b]呋喃的先导结构，这些结构在体内对具有商业重要性的禾本科杂草显示出有前景的活性，且具有较强的靶标亲和力。
本研究涵盖了一系列新型除草先导结构，其具有六氢呋喃并[3,4 - b]呋喃骨架作为结构关键特征，并带有邻位取代的芳氧基侧链。基于优化的合成方法，开展了广泛的构效关系（SAR）研究。从我们受建模启发的结构变化中产生的新化合物显示出良好的酰基 - ACP硫酯酶抑制作用，同时具有有前景的初始除草活性。温室试验表明，本文所述的六氢呋喃并[3,4 - b]呋喃在芽前施用时对冷季和暖季禾本科杂草具有良好的防除效果。值得注意的是，一些新型酰基 - ACP硫酯酶抑制剂对难以控制的暖季杂草也显示出有前景的防治效果。© 2024作者。由John Wiley & Sons Ltd代表化学工业协会出版的《害虫管理科学》。
