Abstract：
Recognizing that metal ions play an important role in modifying the pharmacological properties of known organic-based drugs, the present manuscript addresses the complexation of the antifungal agent voriconazole (vcz) with the biologically relevant silver(I) ion as a strategy for the development of new antimycotics. The synthesized silver(I) complexes with vcz were characterized by mass spectrometry, IR, UV-Vis and NMR spectroscopy and single-crystal X-ray diffraction analysis. The crystallographic results showed that complexes {[Ag(vcz)(H2O)]CH3SO3}n (1), {[Ag(vcz)2]BF4}n (2) and {[Ag(vcz)2]PF6}n (3) have polymeric structures in the solid state, in which silver(I) ions have a distorted tetrahedral geometry. On the other hand, DFT calculations revealed that the investigated silver(I) complexes 1-3 in DMSO exist as linear [Ag(vcz-N2)(vcz-N19)]+ (1a), [Ag(vcz-N2)(vcz-N4)]+ (2a) and [Ag(vcz-N4)2]+ (3a) species, respectively. The evaluated complexes showed an enhanced anti-Candida activity compared to the parent drug with minimal inhibitory concentration (MIC) values in the range of 0.02-1.05 μM. In comparison with vcz, the corresponding silver(I) complexes showed better activity in prevention hyphae and biofilm formation of C. albicans, indicating that they could be considered as promising agents against Candida that significantly inhibit its virulence. Also, these complexes are much better inhibitors of ergosterol synthesis in the cell membrane of C. albicans at the concentration of 0.5 × MIC. This is also confirmed by a molecular docking, which revealed that complexes 1a - 3a showed better inhibitory activity than vcz against the sterol 14α-demethylase enzyme cytochrome P450 (CYP51B), which plays a crucial role in the formation of ergosterol.
摘要：
认识到金属离子在改变已知有机药物的药理特性方面发挥着重要作用，本手稿解决了抗真菌剂伏立康唑（vcz）与生物学相关的银（I）离子的络合，作为开发新的抗真菌剂的策略。合成的银（I）配合物与vcz通过质谱进行了表征，IR,UV-Vis和NMR光谱以及单晶X射线衍射分析。晶体学结果表明,配合物{[Ag(vcz)(H2O)]CH3SO3}n(1),{[Ag(vcz)2]BF4}n(2)和{[Ag(vcz)2]PF6}n(3)具有固态聚合物结构，其中银(I)离子具有扭曲的四面体几何形状。另一方面,DFT计算表明，DMSO中研究的银（I）络合物1-3以线性[Ag（vcz-N2）（vcz-N19）]（1a）的形式存在，[Ag(vcz-N2)(vcz-N4)]+(2a)和[Ag(vcz-N4)2]+(3a)种，分别。与母体药物相比，评估的复合物显示出增强的抗念珠菌活性，最小抑制浓度（MIC）值在0.02-1.05μM范围内。与vcz相比，相应的银（I）络合物在预防白色念珠菌菌丝和生物膜形成方面表现出更好的活性，表明它们可以被认为是针对念珠菌的有希望的药物，可以显着抑制其毒力。此外，在0.5×MIC的浓度下，这些复合物是白色念珠菌细胞膜中麦角甾醇合成的更好的抑制剂。分子对接也证实了这一点，这表明复合物1a-3a对固醇14α-脱甲基酶细胞色素P450(CYP51B)表现出比vcz更好的抑制活性，在麦角甾醇的形成中起着至关重要的作用。
