Department of Chemical Technology of Drugs, Faculty of Pharmacy, Medical University of Gdańsk, Al. Gen. J. Hallera 107, 80-416, Gdańsk, Poland; Drug Research Program, Division of Pharmaceutical Biosciences, Faculty of Pharmacy, University of Helsinki, P.O. Box 56 (Viikinkaari 5E), FI-00014, Helsinki, Finland.
Drug Research Program, Division of Pharmaceutical Biosciences, Faculty of Pharmacy, University of Helsinki, P.O. Box 56 (Viikinkaari 5E), FI-00014, Helsinki, Finland.
Eur J Med Chem. 2023 Jun 5;254:115373. doi: 10.1016/j.ejmech.2023.115373. Epub 2023 Apr 14.
A series of quaternary ammonium fluoroquinolones was obtained by exhaustive methylation of the amine groups present at the 7-position of fluoroquinolones, including ciprofloxacin, enoxacin, gatifloxacin, lomefloxacin, and norfloxacin. The synthesized molecules were tested for their antibacterial and antibiofilm activities against Gram-positive and Gram-negative human pathogens, i.e. Staphylococcus aureus and Pseudomonas aeruginosa. The study showed that the synthesized compounds are potent antibacterial agents (MIC values at the lowest 6.25 μM) with low cytotoxicity in vitro as assessed on the BALB 3T3 mouse embryo cell line. Further experiments proved that the tested derivatives are able to bind to the DNA gyrase and topoisomerase IV active sites in a fluoroquinolone-characteristic manner. The most active quaternary ammonium fluoroquinolones, in contrast to ciprofloxacin, reduce the total biomass of P. aeruginosa ATCC 15442 biofilm in post-exposure experiments. The latter effect may be due to the dual mechanism of action of the quaternary fluoroquinolones, which also involves disruption of bacterial cell membranes. IAM-HPLC chromatographic experiments with immobilized artificial membranes (phospholipids) showed that the most active compounds were those with moderate lipophilicity and containing a cyclopropyl group at the N1 nitrogen atom in the fluoroquinolone core.
通过对氟喹诺酮类药物 7 位氨基进行彻底甲基化，得到了一系列季铵型氟喹诺酮类化合物，包括环丙沙星、依诺沙星、加替沙星、洛美沙星和诺氟沙星。合成的分子被测试了其对革兰氏阳性和革兰氏阴性人类病原体（即金黄色葡萄球菌和铜绿假单胞菌）的抗菌和抗生物膜活性。研究表明，合成的化合物具有很强的抗菌活性（最低 MIC 值为 6.25 μM），在体外对 BALB 3T3 小鼠胚胎细胞系的细胞毒性低。进一步的实验证明，测试的衍生物能够以氟喹诺酮类特有的方式结合到 DNA 拓扑异构酶 II 和拓扑异构酶 IV 的活性部位。与环丙沙星相比，最有效的季铵型氟喹诺酮类化合物能够减少暴露后铜绿假单胞菌 ATCC 15442 生物膜的总生物量。这种效应可能是由于季铵氟喹诺酮类化合物的双重作用机制，它还涉及破坏细菌细胞膜。用固定化人工膜（磷脂）进行 IAM-HPLC 色谱实验表明，最有效的化合物是那些具有中等亲脂性并在氟喹诺酮核心的 N1 氮原子上含有环丙基的化合物。
