Discovery of Novel Small Molecule Inhibitors of Dengue Viral NS2B-NS3 Protease Using Virtual Screening and Scaffold Hopping

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• 作者：Jing Deng ; Ning Li ; Hongchuan Liu ; Zhili Zuo ; Oi Wah Liew ; Weijun Xu ; Gang Chen ; Xiankun Tong ; Wei Tang ; Jin Zhu ; Jianping Zuo ; Hualiang Jiang ; Cai-Guang Yang ; Jian Li ; Weiliang Zhu
• 刊名：Journal of Medicinal Chemistry
• 出版年：2012
• 出版时间：July 26, 2012
• 年：2012
• 卷：55
• 期：14
• 页码：6278-6293
• 全文大小：797K
• 年卷期：v.55,no.14(July 26, 2012)
• ISSN：1520-4804

文摘

By virtual screening, compound 1 was found to be active against NS2B-NS3 protease (IC₅₀ = 13.12 卤 1.03 渭M). Fourteen derivatives (22) of compound 1 were synthesized, leading to the discovery of four new inhibitors with biological activity. In order to expand the chemical diversity of the inhibitors, small-molecule-based scaffold hopping was performed on the basis of the common scaffold of compounds 1 and 22. Twenty-one new compounds (23, 24) containing quinoline (new scaffold) were designed and synthesized. Protease inhibition assays revealed that 12 compounds with the new scaffold are inhibitors of NS2B-NS3 protease. Taken together, 17 new compounds were discovered as NS2B-NS3 protease inhibitors with IC₅₀ values of 7.46 卤 1.15 to 48.59 卤 3.46 渭M, and 8 compounds belonging to two different scaffolds are active to some extent against DENV based on luciferase reporter replicon-based assays. These novel chemical entities could serve as lead structures for discovering therapies against DENV.