Abstract：
In order to make novel breakthroughs in molecular salt studies of BCS class-IV antifungal medication bifonazole (BIF), a salification-driven strategy towards ameliorating attributes and aiding augment efficiency is raised. This strategy fully harnesses structural characters together attributes and benefits of caffeic acid (CAF) to concurrently enhance dissolvability and permeability of BIF by introducing the two ingredients into the identical molecular salt lattice through the salification reaction, which, coupled with the aroused potential activity of CAF significantly amplifies the antifungal efficacy of BIF. Guided by this route, the first BIF-organic molecular salt, BIF-CAF, is directionally designed and synthesized with satisfactorily structural characterizations and integrated theoretical and experimental explorations on the pharmaceutical properties. Single-crystal X-ray diffraction resolving confirms that there is a lipid-water amphiphilic sandwich structure constructed by robust charge-assistant hydrogen bonds in the salt crystal, endowing the molecular salt with the potential to enhance both dissolvability and permeability relative to the parent drug, which is validated by experimental evaluations. Remarkably, the comprehensive DFT-based theoretical investigations covering frontier molecular orbital, molecular electrostatic potential, Hirshfeld surface analysis, reduced density gradient, topology, sphericity and planarity analysis strongly support these observations, thereby allowing some positive relationships between macroscopic properties and microstructures of the molecular salt can be made. Intriguingly, the optimal properties, together with the stimulated activity of CAF markedly augment in vitro antifungal ability of the molecular salt, with magnifying inhibition zones and reducing minimum inhibitory concentrations. These findings fill in the gaps on researches of BIF-organic molecular salt, and adequately exemplify the feasibility and validity by integrating theoretical and experimental approaches to resolve BIF\'s problems via the salification-driven tactic.
摘要：
为了在BCSIV类抗真菌药物联苯苄唑（BIF）的分子盐研究中取得新的突破，提出了一种盐化驱动的改善属性和辅助增强效率的策略。该策略充分利用咖啡酸（CAF）的结构特征，通过成盐反应将两种成分引入相同的分子盐晶格中，同时增强BIF的溶解性和渗透性。which,再加上CAF的潜在活性，BIF的抗真菌功效显着增强。在这条路线的指引下，第一个BIF-有机分子盐，BIF-CAF,定向设计和合成，具有令人满意的结构表征以及对药物特性的综合理论和实验探索。单晶X射线衍射解析证实，在盐晶体中存在由稳健的电荷辅助氢键构建的脂质-水两亲三明治结构，赋予分子盐相对于母体药物具有增强溶解性和渗透性的潜力，这是通过实验评估验证的。值得注意的是,涵盖前沿分子轨道的基于DFT的综合理论研究，分子静电势，Hirshfeld曲面分析,降低密度梯度，拓扑,球形度和平面性分析强烈支持这些观察，从而允许在分子盐的宏观性质和微观结构之间形成一些正的关系。有趣的是，最优属性，与CAF的刺激活性一起显着增强分子盐的体外抗真菌能力，放大抑制区和降低最小抑制浓度。这些发现填补了BIF-有机分子盐研究的空白,通过整合理论和实验方法，通过盐化驱动策略解决BIF问题，充分例证了其可行性和有效性。
