期刊
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
卷 27, 期 22, 页码 4964-4969出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmcl.2017.10.020
关键词
5-Flucytosine; Fluconazole; Antifungal; Molecular modeling; Quantum chemical studies; DNA
资金
- National Natural Science Foundation of China (NSFC) [21672173, 21372186]
- NSFC [81650110529]
- Chongqing Special Foundation [Xm2016039, Xm2017185]
- State Administration of Foreign Experts Affairs, China [WQ2017XNDX047]
A series of novel potentially antifungal hybrids of 5-flucytosine and fluconazole were designed, synthesized and characterized by H-1 NMR, C-13 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. (C) 2017 Elsevier Ltd. All rights reserved.
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