Design, synthesis and characterization of novel 1,2-benzisothiazol-3(2H)-one and 1,3,4-oxadiazole hybrid derivatives: potent inhibitors of Dengue and West Nile virus NS2B/NS3 proteases.
Design, synthesis and characterization of novel 1,2-benzisothiazol-3(2H)-one and 1,3,4-oxadiazole hybrid derivatives: potent inhibitors of Dengue and West Nile virus NS2B/NS3 proteases.
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DOI：
10.1016/j.bmc.2012.10.058
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发表时间：
2013-01-01
影响因子：
3.5
通讯作者：
Groutas WC
中科院分区：
文献类型：
--
作者：
Lai H;Dou D;Aravapalli S;Teramoto T;Lushington GH;Mwania TM;Alliston KR;Eichhorn DM;Padmanabhan R;Groutas WC
1，2-苯并异噻唑-3（2 H）-酮和1，3，4-恶二唑最近在药物发现中引起了相当大的兴趣，包括作为抗细菌剂和抗真菌剂。在这项研究中，一系列功能化的1，2-苯并异噻唑-3（2 H）-酮-1，3，4-恶二唑杂合衍生物的合成，并随后筛选对登革热和西尼罗病毒蛋白酶。24种化合物中的10种显示出对DENV 2和WNV蛋白酶的大于50%的抑制（[I] = 10 μM）。发现化合物7 n对DENV 2和WNV NS 2B/NS 3的IC 50值分别为3.75 ± 0.06和4.22 ± 0.07 μM。动力学数据支持化合物7 n的竞争性抑制模式。进行分子模拟研究以描绘这一系列化合物的推定结合模式。这项研究表明，从两个支架的连接所产生的混合系列提供了一个合适的平台，通过迭代的结构-活性关系研究，体外筛选和X-射线晶体学进行命中到铅优化运动。
1,2-Benzisothiazol-3(2H)-ones and 1,3,4-oxadiazoles individually have recently attracted considerable interest in drug discovery, including as antibacterial and antifungal agents. In this study, a series of functionalized 1,2-benzisothiazol-3(2H)-one - 1,3,4-oxadiazole hybrid derivatives were synthesized and subsequently screened against Dengue and West Nile virus proteases. Ten out of twenty-four compounds showed greater than 50% inhibition against DENV2 and WNV proteases ([I] = 10 μM). The IC50 values of compound 7n against DENV2 and WNV NS2B/NS3 were found to be 3.75 ± 0.06 and 4.22 ± 0.07 μM, respectively. The kinetics data support a competitive mode of inhibition by compound 7n. Molecular modeling studies were performed to delineate the putative binding mode of this series of compounds. This study reveals that the hybrid series arising from the linking of the two scaffolds provides a suitable platform for conducting a hit-to-lead optimization campaign via iterative structure-activity relationship studies, in vitro screening and X-ray crystallography.
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影响因子：
--
作者：
Dou, Dengfeng;Viwanathan, Prasanth;Li, Yi;He, Guijia;Alliston, Kevin R.;Lushington, Gerald H.;Brown-Clay, Joshua D.;Padmanabhan, R.;Groutas, William C.
通讯作者：
Groutas, William C.
影响因子：
16.8
作者：
Erbel, P;Schiering, N;Hommel, U
通讯作者：
Hommel, U
DOI：
10.1038/nrd1853
发表时间：
2005-10
期刊：
Nature reviews. Drug discovery
影响因子：
--
作者：
Kwong AD;Rao BG;Jeang KT
通讯作者：
Jeang KT
影响因子：
--
作者：
Julander, Justin G.;Perry, Stuart T.;Shresta, Sujan
通讯作者：
Shresta, Sujan
影响因子：
6.7
作者：
Morini, G;Poli, E;Pozzoli, C
通讯作者：
Pozzoli, C