Fang Xian-Fu, Li Di, Tangadanchu Vijai Kumar Reddy, Gopala Lavanya, Gao Wei-Wei, Zhou Cheng-He
Institute of Bioorganic & Medicinal Chemistry, Key Laboratory of Applied Chemistry of Chongqing Municipality, School of Chemistry and Chemical Engineering, Southwest University, Chongqing 400715, PR China.
Institute of Bioorganic & Medicinal Chemistry, Key Laboratory of Applied Chemistry of Chongqing Municipality, School of Chemistry and Chemical Engineering, Southwest University, Chongqing 400715, PR China.
Bioorg Med Chem Lett. 2017 Nov 15;27(22):4964-4969. doi: 10.1016/j.bmcl.2017.10.020. Epub 2017 Oct 13.
A series of novel potentially antifungal hybrids of 5-flucytosine and fluconazole were designed, synthesized and characterized by H NMR, C NMR, IR and HRMS spectra. Bioactive assay manifested that some prepared compounds showed moderate to good antifungal activities in comparison with fluconazole and 5-flucytosine. Remarkably, the 3,4-dichlorobenzyl hybrid 7h could inhibit the growth of C. albicans ATCC 90023 and clinical resistant strain C. albicans with MIC values of 0.008 and 0.02 mM, respectively. The active molecule 7h could not only rapidly kill C. albicans but also efficiently permeate membrane of C. albicans. Molecular docking study revealed that compound 7h could interact with the active site of CACYP51 through hydrogen bond. Quantum chemical studies were also performed to explain the high antifungal activity. Further preliminary mechanism research suggested that molecule 7h could intercalate into calf thymus DNA to form a steady supramolecular complex, which might block DNA replication to exert the powerful bioactivities.
设计、合成了一系列5-氟胞嘧啶和氟康唑的新型潜在抗真菌杂合物，并通过氢核磁共振谱、碳核磁共振谱、红外光谱和高分辨质谱对其进行了表征。生物活性测定表明，与氟康唑和5-氟胞嘧啶相比，一些制备的化合物表现出中等至良好的抗真菌活性。值得注意的是，3,4-二氯苄基杂合物7h能够抑制白色念珠菌ATCC 90023和临床耐药菌株白色念珠菌的生长，其最小抑菌浓度分别为0.008和0.02 mM。活性分子7h不仅能快速杀死白色念珠菌，还能有效穿透白色念珠菌的细胞膜。分子对接研究表明，化合物7h可通过氢键与白色念珠菌细胞色素P450 51（CACYP51）的活性位点相互作用。还进行了量子化学研究以解释其高抗真菌活性。进一步的初步机制研究表明，分子7h可插入小牛胸腺DNA形成稳定的超分子复合物，这可能会阻断DNA复制以发挥强大的生物活性。
