Wu Heng, Zhao Haiqing, Lu Tong, Xie Baoxing, Niu Chao, Aisa Haji Akber
State Key Laboratory Basis of Xinjiang Indigenous Medicinal Plants Resource Utilization, Key Laboratory of Chemistry of Plant Resources in Arid Regions, Xinjiang Technical Institute of Physics and Chemistry, Chinese Academy of Sciences, Urumqi, 830011, China.
University of Chinese Academy of Sciences, Beijing, 100049, China.
Med Chem. 2023;19(7):686-703. doi: 10.2174/1573406419666230203105246.
Based on bioactive group splicing, classical bioisosterism, and the rule of alkene insertion, forty-eight aurone, and indanone derivatives were designed and synthesized. They were evaluated for inhibitory activity against C. albicans, E. coli, and S. aureus. Among them, thirty compounds exhibited moderate to excellent antibacterial activity.
The maximum circle of inhibition was 18 mm (compounds B15, B16, and E7), and the minimum values of MIC and MBC were respectively 15.625 μM (compounds A5 and D2) and 62.5 μM (compounds A6, A8, and E7).
The SAR showed that aurone and indanone derivatives could strongly inhibit the growth of Gram-positive bacteria. The introduction of electron-withdrawing groups or hydroxyl is beneficial to the activity. It was exciting that the 3-phenylallylbenzofuranone and 3-allylindanone skeletons with antimicrobial activity were first reported in this study. Compounds A5 and E7 were selected for molecular docking studies with targets MetRS (PBD: 7WPI) and PBP (PDB: 6C3K) to determine the binding interactions at the active site.
On this basis, the physicochemical and pharmacological properties of the compounds were predicted and analyzed. The influence of these properties on antimicrobial activity and their implications for subsequent work were discussed. The ADMET (Absorption, Distribution, Metabolism, Excretion, Toxicity) predictions showed that most of the compounds had good pharmacokinetic profiles and high safety profiles.
基于生物活性基团拼接、经典生物电子等排体以及烯烃插入规则，设计并合成了48种金酮和茚满酮衍生物。对它们针对白色念珠菌、大肠杆菌和金黄色葡萄球菌的抑制活性进行了评估。其中，30种化合物表现出中度至优异的抗菌活性。
最大抑菌圈为18毫米（化合物B15、B16和E7），最小MIC和MBC值分别为15.625 μM（化合物A5和D2）和62.5 μM（化合物A6、A8和E7）。
构效关系表明，金酮和茚满酮衍生物可强烈抑制革兰氏阳性菌的生长。吸电子基团或羟基的引入有利于活性。令人兴奋的是，本研究首次报道了具有抗菌活性的3-苯基烯丙基苯并呋喃酮和3-烯丙基茚满酮骨架。选择化合物A5和E7与靶标甲硫氨酸-tRNA合成酶（PBD：7WPI）和青霉素结合蛋白（PDB：6C3K）进行分子对接研究，以确定活性位点处的结合相互作用。
在此基础上，对化合物的理化性质和药理性质进行了预测和分析。讨论了这些性质对抗菌活性的影响及其对后续工作的意义。ADMET（吸收、分布、代谢、排泄、毒性）预测表明，大多数化合物具有良好的药代动力学特征和高安全性特征。
