结构多样性酰胺类化合物库的构建与新型SDH抑制剂的发现

Succinate dehydrogenase (SDH)-inhibiting fungicides, classified as one of the most important agricultural fungicides, contain an amide bond as the key functional group. Since discovery of new pesticides is more and more difficult, providing structurally diverse libraries of compounds with a variety of functionalities is a valuable way to increase the possibility of discovering novel and highly active lead compounds. Therefore, finding out fast and highly efficient strategies for construction of a structurally diverse library of amides is highly important for development of new SDH inhibitors. A reported ruthenium-catalyzed strategy and diversity-oriented synthesis (DOS) could serve as effective solutions for realizing this goal. Herein, this proposal aims to design and synthesize novel and highly active SDH inhibitors directed by the interaction between the inhibitor and the enzyme (SDH). Generally, an SDH inhibitor includes an amide bond, an acid side, and an amine side. By retaining the amide bond and fixing one side (either the acid side or the amine side) with active substructures from commercial SDH-inhibiting fungicides, we intend to construct the other side with a structurally diverse library of amide fragments based on the above-mentioned ruthenium-catalyzed strategy and diversity-oriented synthesis (DOS). Moreover, we will focus on optimization of the ruthenium-catalyzed strategy, and then establish a structurally diverse library of amides in a fast, efficient and atom-economic manner. Finally, two or three novel and highly active SDH inhibitors are expected via extensive screening of biological activities from the obtained library of amides.

以琥珀酸脱氢酶(SDH)为靶标的杀菌剂是当前最重要的杀菌剂品种之一。从结构特点上看，这类杀菌剂均为酰胺类化合物。由于新农药的发现日趋困难，提供化学空间覆盖较广的结构多样性化合物库是提高发现新颖、高活性先导化合物概率的重要途径。因此，如何快速、高效构建结构多样性的酰胺类化合物库是开发新型SDH杀菌剂的关键，而文献报道的一种钌催化的策略及多样性导向的有机合成（DOS）策略正是实现这一目标的有效策略。为此，本项目拟以酰胺类抑制剂与SDH的作用机制为指导，设计与合成新型SDH抑制剂。我们拟在保留酰胺桥的基础上固定其一端为商品化SDH抑制剂的活性片段，而在其另一端利用上述提及的钌催化策略与DOS策略构建结构多样性的组分库。然后，我们通过进一步优化这种钌催化策略从而以快速、高效、和高原子经济性的方式构建结构多样性的酰胺类化合物库。最后，我们将通过生物活性筛选获得2-3个高活性、结构新颖的SDH抑制剂。

酰胺化合物广泛存在于各种生物活性分子中，尤其是存在于琥珀酸脱氢酶（SDH）及细胞色素bc1复合物抑制剂中。为了发现基于上述两个靶标的新颖、高活性先导化合物，本项目计划快速、高效构建具有结构多样性的酰胺化合物库，而文献报道的一种钌（Ru）催化的策略及多样性导向的有机合成（DOS）策略正是实现这一目标的有效策略。为此，本项目利用上述提及的钌催化及DOS策略设计并构建了酰胺化合物所需的组分库。然后，为了以快速、高效、及高原子经济性的方式合成具有结构多样性的酰胺化合物库，我们对上述钌催化策略进行了优化。于是，我们通过构建一个具有结构多样性的氮杂环卡宾（NHC）前体库来调控钌的催化活性，并从中发现了一些高活性的氮杂环卡宾-钌（NHC-Ru）催化体系。最后，我们基于这种优化后的钌催化策略构建了具有结构多样性的酰胺类化合物库，并通过生物活性筛选从中获得几个高活性、结构新颖的SDH和/或细胞色素bc1复合物抑制剂。本项目已获得的高活性催化体系及化合物均具有潜在的应用前景，为后续开发出具有实际应用价值的催化剂及先导化合物奠定了良好的基础。