Synthesis and antiviral evaluation of cytisine derivatives against dengue virus types 1 and 2.

Autor: Tsypysheva IP; Ufa Institute of Chemistry, Ufa Federal Research Centre of the Russian Academy of Sciences, 71 prosp. Oktyabrya, 450054 Ufa, Russian Federation. Electronic address: tsypysheva.ip@gmail.com., Lai HC; Division of Hepato-Gastroenterology, Department of Internal Medicine, China Medical University Hospital, Taichung 40447, Taiwan, ROC., Kiu YT; Department of Medical Laboratory Science and Biotechnology, China Medical University, 91, Hsueh-Shih Rd., Taichung 40402, Taiwan, ROC., Koval'skaya AV; Ufa Institute of Chemistry, Ufa Federal Research Centre of the Russian Academy of Sciences, 71 prosp. Oktyabrya, 450054 Ufa, Russian Federation., Tsypyshev DO; Ufa Institute of Chemistry, Ufa Federal Research Centre of the Russian Academy of Sciences, 71 prosp. Oktyabrya, 450054 Ufa, Russian Federation., Huang SH; Department of Biotechnology, Asia University, 500, Lioufeng Rd., Wufeng, Taichung 41354, Taiwan, ROC., Lin CW; Department of Medical Laboratory Science and Biotechnology, China Medical University, 91, Hsueh-Shih Rd., Taichung 40402, Taiwan, ROC; Department of Biotechnology, Asia University, 500, Lioufeng Rd., Wufeng, Taichung 41354, Taiwan, ROC. Electronic address: cwlin@mail.cmu.edu.tw.
Jazyk: angličtina
Zdroj: Bioorganic & medicinal chemistry letters [Bioorg Med Chem Lett] 2021 Dec 15; Vol. 54, pp. 128437. Date of Electronic Publication: 2021 Nov 02.
DOI: 10.1016/j.bmcl.2021.128437
Abstrakt: Dengue virus (DENV) causes about 50-100 million cases per year worldwide. However, there is still a big challenge in developing antiviral drugs against DENV infection. Some derivatives of alkaloid (-)-cytisine, like other alkaloid analogs, have been proposed for their antiviral potential. This study investigated antiviral activity and mechanisms of the cytisine derivatives, and discovered the structure-activity relationship against DENV. The antiviral assays were performed using one strain of DENV1 and DENV2, and two cell lines Vero E6 and A549. The structure-activity relationship of the effective compounds was also evaluated using combination of time-of-addition/removal assay and molecular docking. Compounds 3, 4, 12 (N-allylcytisine-3-thiocarbamide), 16, and 20 exhibited the high antiviral activity with IC 50 values of lower than 3 μM against DENV1 and DENV2. Of them, the derivative 12 showed the highest antiviral activities against DENV1 (IC 50  = 0.14 μM) and DENV-2 (IC 50  = <0.1 μM), exhibiting the potent inhibition on virus attachment and entry stages. Meanwhile, the compounds 4 and 20 had a strong inhibition at the post-entry stage (IC 50  = <0.1 μM). A correlation between the experimental pIC 50 values and predicted pKi calculated by docking of compounds into DENV E protein was significant, correlating with the impact of compound 12 on the attachment stage, but compounds 4, and 20 on post-entry stage. The results provided the insight into the directions of synthetic modifications of starting (-)-cytisine as the inhibitors of DENV E protein at attachment and entry stages of DENV life cycle.
(Copyright © 2021 Elsevier Ltd. All rights reserved.)
Databáze: MEDLINE
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