College of Chemistry & Pharmacy, Northwest A&F University, 22 Xinong Road, Yangling, 712100, Shaanxi, China.
College of Chemistry & Pharmacy, Northwest A&F University, 22 Xinong Road, Yangling, 712100, Shaanxi, China.
Eur J Med Chem. 2018 Dec 5;160:23-36. doi: 10.1016/j.ejmech.2018.10.012. Epub 2018 Oct 6.
Thirty-three new quaternization harman analogues were synthesized and their antibacterial activity against four Gram-positive and two Gram-negative bacteria were evaluated. The structure-activity relationships were summarized and compounds 4f, 4i, 4l, 4u, 4w, 4x and 5c showed excellent antibacterial activity, low cytotoxicity, good thermal stability and "drug-like" properties. In particular, compound 4x exhibited better bactericidal effect (4-fold superiority against methicillin-resistant Staphylococcus aureus) than standard drugs fosfomycin sodium and ampicillin sodium (minimum inhibitory concentration = 50 nmol/mL). Scanning electron microscopy revealed morphological changes of the bacterial cell surface and the docking evaluation provided a good total score (6.4952) for 4x which is close to the score of ciprofloxacin (6.9723). The results indicated that the quaternization harman analogues might exert their bactericidal effect by damaging bacterial cell membrane and wall, and disrupting the function of type II topoisomerase. In addition, the in vivo antibacterial assay with a protective efficacy of 81.3% further demonstrated the potential of these derivatives as new bactericides and antibiotics.
合成了 33 种新型季铵化哈尔满类似物，并评价了它们对 4 种革兰氏阳性菌和 2 种革兰氏阴性菌的抗菌活性。总结了构效关系，化合物 4f、4i、4l、4u、4w、4x 和 5c 表现出优异的抗菌活性、低细胞毒性、良好的热稳定性和“类药性”。特别是化合物 4x 对耐甲氧西林金黄色葡萄球菌的杀菌效果（比标准药物磷霉素钠和氨苄西林钠强 4 倍，最小抑菌浓度=50nmol/mL）优于标准药物。扫描电子显微镜显示了细菌细胞表面的形态变化，对接评价为 4x 提供了一个很好的总评分（6.4952），接近环丙沙星（6.9723）的评分。结果表明，季铵化哈尔满类似物可能通过破坏细菌细胞膜和细胞壁以及干扰 II 型拓扑异构酶的功能来发挥杀菌作用。此外，体内抗菌试验的保护效力为 81.3%，进一步证明了这些衍生物作为新型杀菌剂和抗生素的潜力。
