Institute of Bioorganic & Medicinal Chemistry, Key Laboratory of Applied Chemistry of Chongqing Municipality, School of Chemistry and Chemical Engineering, Southwest University, Chongqing, 400715, China.
Institute of Bioorganic & Medicinal Chemistry, Key Laboratory of Applied Chemistry of Chongqing Municipality, School of Chemistry and Chemical Engineering, Southwest University, Chongqing, 400715, China.
Eur J Med Chem. 2018 Jul 15;155:579-589. doi: 10.1016/j.ejmech.2018.06.022. Epub 2018 Jun 15.
A series of carbazole-triazole conjugates were designed, synthesized and characterized by IR, NMR, and HRMS spectra. Biological assay showed that most of the synthesized compounds exhibited moderate and even strong antifungal activities, especially 3,6-dibromocarbazolyl triazole 5d displayed excellent inhibitory efficacy against most of the tested fungal strains (MIC = 2-32 μg/mL) and effectively fungicidal ability towards C. albicans, C. tropicals and C. parapsilosis ATCC 22019 (MFC = 4-8 μg/mL). Its combination use with fluconazole could enhance the antifungal efficacy, and compound 5d also did not obviously trigger the development of resistance in C. albicans even after 10 passages. Preliminary mechanism study revealed that the active molecule 5d could depolarize fungal membrane potential and intercalate into DNA to possibly block DNA replication, thus possibly exhibiting its powerful antifungal abilities. Conjugate 5d could interact with HSA, which was constructive for the further design, modification and screening of drug molecules. Docking investigation demonstrated a non-covalent binding of 5d with CYP51 through hydrogen bond and hydrophobicity. These results strongly suggested that compound 5d could act as a potential template for the development of promising antifungal drugs.
一系列咔唑-三唑缀合物被设计、合成并通过红外光谱、核磁共振谱和高分辨质谱进行了表征。生物测定表明，大多数合成化合物表现出中等甚至强的抗真菌活性，特别是 3,6-二溴咔唑基三唑 5d 对大多数测试的真菌菌株表现出优异的抑制效果（MIC=2-32μg/mL），并且对白色念珠菌、热带念珠菌和近平滑念珠菌 ATCC 22019 具有有效的杀菌能力（MFC=4-8μg/mL）。它与氟康唑联合使用可以增强抗真菌功效，并且即使在经过 10 次传代后，化合物 5d 也不会明显引发白色念珠菌的耐药性发展。初步的机制研究表明，活性分子 5d 可以使真菌膜电位去极化并嵌入 DNA 中，从而可能阻止 DNA 复制，从而可能表现出其强大的抗真菌能力。缀合物 5d 可以与 HSA 相互作用，这有助于进一步设计、修饰和筛选药物分子。对接研究表明，5d 通过氢键和疏水性与 CYP51 发生非共价结合。这些结果强烈表明，化合物 5d 可以作为开发有前途的抗真菌药物的潜在模板。
