Center for Molecular Diversity in Drug Design, Discovery, and Delivery, Department of Chemistry, University of South Florida, Tampa, FL 33620, USA.
Bioorg Med Chem Lett. 2012 Oct 15;22(20):6513-20. doi: 10.1016/j.bmcl.2012.05.026. Epub 2012 Jul 1.
Fluoroquinolone antibiotics have been a mainstay in the treatment of bacterial diseases. The most notable representative, ciprofloxacin, possesses potent antimicrobial activity; however, a rise in resistance to this agent necessitates development of novel derivatives to prolong the clinical lifespan of these antibiotics. Herein we have synthesized and analyzed the antimicrobial properties of a library of N-acylated ciprofloxacin analogues. We find that these compounds are broadly effective against Gram-positive and Gram-negative bacteria, with many proving more effective than the parental drug, and several possessing MICs ≤1.0 μg/ml against methicillin-resistant Staphylococcus aureus and Bartonella species. An analysis of spontaneous mutation frequencies reveals very low potential for resistance in MRSA compared to existing fluoroquinolones. Mode of action profiling reveals that modification of the piperazinyl nitrogen by acylation does not alter the effect of these molecules towards their bacterial target. We also present evidence that these N-acylated compounds are highly effective at killing intracellular bacteria, suggesting the suitability of these antibiotics for therapeutic treatment.
氟喹诺酮类抗生素一直是治疗细菌疾病的主要药物。其中最著名的代表是环丙沙星，具有很强的抗菌活性；然而，由于该药物的耐药性上升，需要开发新的衍生物来延长这些抗生素的临床寿命。在这里，我们合成并分析了一系列 N-酰化环丙沙星类似物的抗菌特性。我们发现这些化合物对革兰氏阳性菌和革兰氏阴性菌均有广泛的有效性，其中许多比原药更有效，并且有几种对耐甲氧西林金黄色葡萄球菌和巴尔通体属的 MIC 值≤1.0μg/ml。自发突变频率的分析表明，与现有的氟喹诺酮类药物相比，MRSA 的耐药潜力非常低。作用模式分析表明，酰化修饰哌嗪氮不会改变这些分子对其细菌靶标的作用。我们还提供了证据表明，这些 N-酰化化合物在杀死细胞内细菌方面非常有效，这表明这些抗生素非常适合治疗。
