Facile Synthesis of Ciprofloxacin Prodrug Analogues to Improve its Water Solubility and Antibacterial Activity
Facile Synthesis of Ciprofloxacin Prodrug Analogues to Improve its Water Solubility and Antibacterial Activity
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DOI：
10.1002/slct.201600091
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发表时间：
2016-05-01
期刊：
影响因子：
2.1
通讯作者：
Zaid, Abdel Naser
中科院分区：
文献类型：
--
作者：
Assali, Mohyeddin;Joulani, Maysa;Zaid, Abdel Naser
环丙沙星是一种广谱氟喹诺酮类抗生素，通过抑制细菌拓扑异构酶II型（DNA促旋酶）发挥作用，并对革兰氏阳性和阴性细菌具有强效活性。然而，由于其刚性和固态结构，其具有有限的水溶性。通过前药策略合成环丙沙星的乙二醇衍生物，在不降低其抗菌活性的前提下，改善其药代动力学特性，特别是水溶性，是本工作的关注点。采用摇瓶法测定了其在磷酸盐缓冲液中的溶解度。环丙沙星类似物在酸性和生理pH值下足够稳定。合成的衍生物进行酯酶介导的水解反应，从其前药形式释放药物，25分钟后显示总水解。还对金黄色葡萄球菌和大肠杆菌的抗菌活性进行了研究。与环丙沙星相比，三种衍生物的溶解度均有所增加，抑菌活性提高了40%。
Ciprofloxacin is a broad spectrum fluoroquinolone antibiotic that acts by the inhibition of bacterial topoisomerase type II (DNA gyrase) and have a potent activity against Gram positive and negative bacteria. However, due to its rigid and solid-state structure it suffers from limited water solubility. Improving its pharmacokinetic properties especially its water solubility is the concern of this work through the synthesis of various derivatives of ciprofloxacin with ethylene glycols through prodrug strategy without reducing its antibacterial activity. Shake-flask method was used to measure the aqueous solubility in phos-phate buffer. The ciprofloxacin analogues were adequately stable at acidic and physiological pH. Synthesized derivatives were subjected to esterase-mediated hydrolysis reaction for the release of the drug from its prodrug form and showed a total hydrolysis after 25 min. Also antibacterial activity was studied against Staphylococcus aureus and Escherichia coli. Compared to ciprofloxacin, the solubility was increased for the three derivatives, and the antimicrobial activity was enhanced up to 40%.