Antibacterial Spiropyrimidinetriones with N‑Linked Azole Substituents on a Benzisoxazole Scaffold Targeting DNA Gyrase

Herein,
we report spiropyrimidinetriones (SPTs) incorporating N-linked
azole substituents on a benzisoxazole scaffold with improved Gram-positive
antibacterial activity relative to previously described analogues.
SPTs have an unusual spirocyclic architecture and represent a new
antibacterial class of bacterial DNA gyrase and topoisomerase IV inhibitors.
They are not cross-resistant to fluoroquinolones and other DNA gyrase/topoisomerase
IV inhibitors used clinically. The activity of the SPTs was assessed
for DNA gyrase inhibition, and the antibacterial activity across Gram-positive
and Gram-negative pathogens with N-linked 1,2,4-triazoles substituted
on the 5-position provides the most worthwhile profile. Directed nucleophilic
and electrophilic chemistry was developed to vary this 5-position
with carbon, nitrogen, or oxygen substituents and explore structure–activity
relationships including those around a target binding model. Compounds
with favorable pharmacokinetic parameters were identified, and two
compounds demonstrated cidality in a mouse model of Staphylococcus aureus infection.

本文中，我们报道了一类在苯并异恶唑（benzisoxazole）骨架上引入N-连接唑类取代基的螺嘧啶三酮类（spiropyrimidinetriones，SPTs）化合物，其相较于此前报道的类似物，抗革兰氏阳性（Gram-positive）菌活性更为优异。
SPTs具有独特的螺环骨架，代表了一类靶向细菌DNA促旋酶（DNA gyrase）与拓扑异构酶IV（topoisomerase IV）的新型抗菌抑制剂类别。
该类化合物与临床使用的氟喹诺酮类（fluoroquinolones）及其他DNA促旋酶/拓扑异构酶IV抑制剂无交叉耐药性。
我们评估了SPTs的DNA促旋酶抑制活性，并测试了其对革兰氏阳性及革兰氏阴性（Gram-negative）病原菌的抗菌活性；其中，5位带有N-连接1,2,4-三唑取代基的化合物展现出最具开发价值的活性谱。
我们开发了定向亲核与亲电化学方法，通过碳、氮或氧取代基对该5位位点进行修饰，并探究了包括靶标结合模型在内的构效关系。
最终筛选得到了具备优良药代动力学参数的化合物，其中两种化合物在金黄色葡萄球菌（Staphylococcus aureus）感染小鼠模型中展现出杀菌活性。