Zibo Hospital of Traditional Chinese Medicine, Zibo 255000, China.
School of Biological Science and Technology, University of Jinan, Jinan 250022, China.
Bioorg Med Chem Lett. 2024 Sep 1;109:129822. doi: 10.1016/j.bmcl.2024.129822. Epub 2024 May 31.
The quest for novel antibacterial agents is imperative in the face of escalating antibiotic resistance. Naturally occurring tetrahydro-β-carboline (THβC) alkaloids have been highlighted due to their significant biological derivatives. However, these structures have been little explored for antibacterial drugs development. In this study, a series of 1,2,3,4-THβC derivatives were synthesized and assessed for their antibacterial prowess against both gram-positive and gram-negative bacteria. The compounds exhibited moderate to good antibacterial activity, with some compounds showing superior efficacy against gram-positive bacteria, especially methicillin-resistant Staphylococcus aureus (MRSA), to that of Gentamicin. Among these analogs, compound 3k emerged as a hit compound, demonstrating rapid bactericidal action and a significant post-antibacterial effect, with significant cytotoxicity towards human LO2 and HepG2 cells. In addition, compound 3k (10 mg/kg) showed comparable anti-MRSA efficacy to Ciprofloxacin (2 mg/kg) in a mouse model of abdominal infection. Overall, the present findings suggested that THβC derivatives based on the title compounds hold promising applications in the development of antibacterial drugs.
面对日益严重的抗生素耐药性，寻找新型抗菌剂势在必行。天然存在的四氢-β-咔啉（THβC）生物碱因其具有重要的生物衍生性而备受关注。然而，这些结构在抗菌药物开发方面的研究还很少。在这项研究中，合成了一系列 1,2,3,4-THβC 衍生物，并评估了它们对革兰氏阳性菌和革兰氏阴性菌的抗菌能力。这些化合物表现出中等至良好的抗菌活性，一些化合物对革兰氏阳性菌（尤其是耐甲氧西林金黄色葡萄球菌（MRSA））的疗效优于庆大霉素。在这些类似物中，化合物 3k 表现出良好的抗菌效果，具有快速杀菌作用和显著的抗菌后效应，对人 LO2 和 HepG2 细胞的细胞毒性较小。此外，化合物 3k（10mg/kg）在 MRSA 感染的小鼠模型中显示出与环丙沙星（2mg/kg）相当的抗 MRSA 疗效。总的来说，这些发现表明基于标题化合物的 THβC 衍生物在抗菌药物的开发中有很大的应用潜力。
