Evaluation of the influence of fluoroquinolone chemical structure on stability: forced degradation and in silico studies

ABSTRACT Fluoroquinolones are a known antibacterial class commonly used around the world. These compounds present relative stability and they may show some adverse effects according their distinct chemical structures. The chemical hydrolysis of five fluoroquinolones was studied using alkaline and photolytic degradation aiming to observe the differences in molecular reactivity. DFT/B3LYP-6.31G* was used to assist with understanding the chemical structure degradation. Gemifloxacin underwent degradation in alkaline medium. Gemifloxacin and danofloxacin showed more degradation perceptual indices in comparison with ciprofloxacin, enrofloxacin and norfloxacin in photolytic conditions. Some structural features were observed which may influence degradation, such as the presence of five member rings attached to the quinolone ring and the electrostatic positive charges, showed in maps of potential electrostatic charges. These measurements may be used in the design of effective and more stable fluoroquinolones as well as the investigation of degradation products from stress stability assays.

摘要：氟喹诺酮类（fluoroquinolones）是全球范围内广泛使用的经典抗菌药物类别。该类化合物具备相对稳定性，但依据其各异的化学结构，可能呈现不同程度的不良反应。本研究采用碱性降解与光降解两种方式，对5种氟喹诺酮类化合物的化学水解过程进行探究，以考察其分子反应活性的差异。研究借助DFT/B3LYP-6.31G*方法辅助解析化学结构的降解机制。实验结果表明，吉米沙星（gemifloxacin）可在碱性介质中发生降解；在光降解条件下，吉米沙星与达氟沙星（danofloxacin）的降解可观测指标显著高于环丙沙星（ciprofloxacin）、恩诺沙星（enrofloxacin）及诺氟沙星（norfloxacin）。本研究观察到若干可能影响降解过程的结构特征，例如连接于喹诺酮环的五元环以及静电势能图中所显示的正静电电荷。上述研究成果可用于设计高效且稳定性更优的氟喹诺酮类化合物，同时也可为强制稳定性试验中的降解产物研究提供参考。