乌克兰Enamine公司Mykhailiuk, Pavel K.团队报道了2-氧杂二环[2.1.1]己烷作为邻位取代苯环的饱和生物同位体。相关研究成果于2023年6月5日发表在《自然—化学》。

邻位取代苯环是化学中的一种基本结构元素。它存在于三百多种药物和农用化学品中。在过去的十年里，科学家们试图用饱和的生物异构体取代生物活性化合物中的苯环，以获得新的可申请专利的结构。然而，该领域的大多数研究都致力于对位取代苯环的取代。

该文中，研究人员开发了具有更好物理化学性能的邻位取代苯环的饱和生物同位体：2-氧杂双环[2.1.1]己烷。晶体学分析表明，这些结构和邻位取代的苯环确实具有相似的几何性质。用2-氧杂双环[2.1.1]己烷取代市售农用化学品fluxapyroxad（BASF）和boscalid（BASV）中的苯环，显著提高了它们的水溶性，降低了亲脂性，最重要的是保留了生物活性。

该项工作为化学家提供了一个在药物化学和农业化学中，用饱和生物同位体取代生物活性化合物中的邻位取代苯环的机会。邻位取代苯环是化学中的一种基本结构元素。现在，2-氧杂双环[2.1.1]己烷已被开发为邻位取代苯环的饱和生物异山梨醇，具有更好物理化学性能。在市场上销售的农用化学品fluxapyroxad和boscalid中，用2-氧杂双环[2.1.1]己烷取代苯环提高了水溶性，降低了亲脂性，并保留了生物活性。

附：英文原文

Title: 2-Oxabicyclo[2.1.1]hexanes as saturated bioisosteres of the ortho-substituted phenyl ring

Author: Denisenko, Aleksandr, Garbuz, Pavel, Voloshchuk, Nataliya M., Holota, Yuliia, Al-Maali, Galeb, Borysko, Petro, Mykhailiuk, Pavel K.

Issue&Volume: 2023-06-05

Abstract: The ortho-substituted phenyl ring is a basic structural element in chemistry. It is found in more than three hundred drugs and agrochemicals. During the past decade, scientists have tried to replace the phenyl ring in bioactive compounds with saturated bioisosteres to obtain novel patentable structures. However, most of the research in this area has been devoted to the replacement of the para-substituted phenyl ring. Here we have developed saturated bioisosteres of the ortho-substituted phenyl ring with improved physicochemical properties: 2-oxabicyclo[2.1.1]hexanes. Crystallographic analysis revealed that these structures and the ortho-substituted phenyl ring indeed have similar geometric properties. Replacement of the phenyl ring in marketed agrochemicals fluxapyroxad (BASF) and boscalid (BASF) with 2-oxabicyclo[2.1.1]hexanes dramatically improved their water solubility, reduced lipophilicity and most importantly retained bioactivity. This work suggests an opportunity for chemists to replace the ortho-substituted phenyl ring in bioactive compounds with saturated bioisosteres in medicinal chemistry and agrochemistry. The ortho-substituted phenyl ring is a basic structural element in chemistry. Now, 2-oxabicyclo[2.1.1]hexanes have been developed as saturated bioisosteres of the ortho-substituted phenyl ring with improved physicochemical properties. Replacement of the phenyl ring with 2-oxabicyclo[2.1.1]hexanes in marketed agrochemicals fluxapyroxad and boscalid improved water solubility, reduced lipophilicity and retained bioactivity.

DOI: 10.1038/s41557-023-01222-0

Source: https://www.nature.com/articles/s41557-023-01222-0