A series of novel tetrazole derivatives was synthetized using N-alkylation or Michael-type addition reactions, and screened for their fungistatic potential against Candida albicans (the lack of endpoint = 100%). Among them, the selected compounds 2d, 4b, and 6a differing in substituents at the tetrazole ring were non-toxic to Galleria mellonella larvae in vivo and exerted slight toxicity against Caco-2 in vitro (CC₅₀ at 256 μg/mL). An antagonistic effect of tetrazole derivatives 2d, 4b, and 6a respectively in combination with Fluconazole was shown using the checker board and colorimetric methods (fractional inhibitory concentration indexes FICIs >1). The most active 2d and 6a displayed an inverse relation between MICs in the presence of exogenous ergosterol, the effect was opposite to Itraconazole and Amphotericin B. The differences between 6a's and 2d's action mode were noted. Combining both flow cytometry and fluorescence image analyses respectively showed the complexity of planktonic and biofilm cell demise mode under the tetrazole derivatives tested. The following evidences for 6a's interaction with fungal membrane were noted: necrosis-like programmed cell death (97.03 ± 0.88), DNA denaturation (no laddering), mitochondrial damage (XTT assay), reduced adhesion to human epithelium (>50% at 0.0313 μg/mL, p ≤ .05), irregular deposit of chitin, and attenuated morphogenesis in mature biofilm. The treatment with 6a reduced pathogenicity of C. albicans during infection in G. mellonella. Contrariwise, 2d enhancing fungal adhesion displayed mechanism targeted to the cell wall (due to the presence of 3-chloropropyl clubbed with aryltetrazole) in the presence of osmotic protector. Under 2d, the accidental cell death (88.60% ± 4.81) was observed.

In conclusion, all tetrazole derivatives were obtained in satisfactory yields (60–95%) using efficient, simple and not expensive methods. Fungistatic and slightly anticancer tetrazole derivatives with the novel action mode can circumvent an appearance of antifungal-resistant strains. These results indicate that they are worthy of further studies.

使用N-烷基化或Michael型加成反应合成了一系列新颖的四唑衍生物，并筛选了它们对白色念珠菌的抑菌潜力（终点= 100％）。其中，所选化合物在四唑环上具有不同取代基的化合物2d，4b和6a在体内对梅花蝇幼虫无毒，并且在体外对Caco-2产生轻微毒性（CC ₅₀在256μg/ mL）。四唑衍生物2d，4b和6a的拮抗作用使用检查板和比色法分别显示了氟康唑与氟康唑的组合（分数抑制浓度指数FICIs> 1）。在存在外源麦角固醇的情况下，最活跃的2d和6a显示MIC之间呈反比关系，其作用与伊曲康唑和两性霉素B相反。注意到6a和2d的作用方式之间的差异。结合流式细胞仪和荧光图像分析分别显示了在测试的四唑衍生物下浮游生物和生物膜细胞死亡模式的复杂性。以下是6a的证据注意到与真菌膜的相互作用：坏死样程序性细胞死亡（97.03±0.88），DNA变性（无梯形），线粒体损伤（XTT分析），与人上皮的粘附力降低（在0.0313μg/ mL时> 50％， p≤.05），几丁质的不规则沉积以及成熟生物膜中的形态发生减弱。与处理6A降低的致病性白色念珠菌感染的过程中蜡螟。相反，在存在渗透保护剂的情况下，第2d增强真菌粘附显示了针对细胞壁的机制（由于存在3-氯丙基与芳基四唑组成的球状分子）。在第2天，观察到细胞意外死亡（88.60％±4.81）。

总之，使用有效，简单且不昂贵的方法，可以令人满意的产率（60-95％）获得所有四唑衍生物。具有新颖作用方式的抑真菌和略微具有抗癌作用的四唑衍生物可以避开抗真菌耐药菌株的出现。这些结果表明它们值得进一步研究。