基于C–H键直接官能化反应构建香豆素类DNA拓扑异构酶IIA抑制剂

In recent years, antibiotic resistance is a public health problem of increasing magnitude. Therefore, it's very important to discover and optimize of a new class of bacterial topoisomerase IIA inhibitors with good antibacterial activity to confront the global need of antibacterial resistance. In this research subject, a series of C3-substituted coumarins fragments were designed by using natural product of coumarins as lead, and bacterial DNA topoisomerase IIA as target. In order to achieve the practical and efficient synthesis of C3-substituted coumarins, we intend to explore and develop direct C–H bond functionalization reaction. Moreover, we would also like to prepare a library of C3-substituted coumarins base on skeleton transition strategy, isostere principle, drug stitching principle. Furthermore, the structure-activity relationship (SAR) between C3-substituted coumarins and antibacterial activities should be established.

近年来，细菌耐药性问题已成为全球关注的医学问题。因此研发具有优异活性的抗菌药物不仅具有重要的科研意义，而且有助于解决全球性的细菌耐药危机。本项目以C3-取代型香豆素天然产物为先导物、细菌DNA拓扑异构酶IIA为靶标，探索香豆素的C3–H键直接官能化反应，发展一种简洁、高效的C3-取代型香豆素的新合成策略；运用骨架跃迁、电子等排、药物拼接等原理创制一系列结构新颖、作用机制独特的C3-取代型香豆素抗菌药物分子库；开展香豆素先导物抗菌活性研究，初步建立C3-取代型香豆素先导物的构效关系模型，为后续C3-取代型香豆素抗菌药物的开发提供一定的借鉴。

近年来，细菌耐药性问题已成为全球关注的医学问题。因此研发具有优异活性的抗菌药物不仅具有重要的科研意义，而且有助于解决全球性的细菌耐药危机。该项目执行期间，发展了的香豆素的C3–H 键直接功能化反应；NHC催化对映选择性合成二氢吡喃酮；铜催化对映选择性合成光学活性烷基胺；镍催化对映选择性合成C3-取代基茚酮等反应。同时，利用创制C3-取代香豆素抗菌分子进行生物活性的测试；筛选出抗菌活性最高，选择性最好的化合物后对其进一步研究，并初步确定药物分子的构效关系。