Abstract：
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.
摘要：
面对不断升级的抗生素耐药性，寻求新型抗菌剂势在必行。天然存在的四氢-β-咔啉（THβC）生物碱由于其重要的生物衍生物而受到关注。然而,这些结构很少被用于抗菌药物的开发。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。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表现出优异的功效，尤其是耐甲氧西林金黄色葡萄球菌（MRSA），庆大霉素。在这些类似物中，化合物3k作为一种热门化合物出现，表现出快速的杀菌作用和显着的后抗菌效果，对人LO2和HepG2细胞具有显著的细胞毒性。此外,在腹腔感染的小鼠模型中,化合物3k(10mg/kg)显示与环丙沙星(2mg/kg)相当的抗MRSA功效。总的来说,目前的发现表明，基于标题化合物的THβC衍生物在抗菌药物的开发中具有广阔的应用前景。
