Design, synthesis and biological evaluation of salicylanilides as novel allosteric inhibitors of human pancreatic lipase
文献类型：期刊论文
| 作者 | Zhao, Yitian1,2; Zhang, Min1; Hou, Xudong1; Han, Jiaxin2; Qin, Xiaoya1; Yang, Yun1,2; Song, Yunqing1; Liu, Zhikai1,2; Zhang, Yong2,3; Xu, Zhijian2,3
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| 刊名 | BIOORGANIC & MEDICINAL CHEMISTRY
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| 出版日期 | 2023-08-15 |
| 卷号 | 91页码:11 |
| 关键词 | Salicylanilide hPL inhibitor Structure -activity relationship Anti -obesity |
| ISSN号 | 0968-0896 |
| DOI | 10.1016/j.bmc.2023.117413 |
| 通讯作者 | Li, Bo(boli@simm.ac.cn) ; Zhu, Weiliang(wlzhu@simm.ac.cn) ; Ge, Guangbo(geguangbo@dicp.ac.cn) |
| 英文摘要 | Obesity is a growing global health problem and is associated with increased prevalence of many metabolic disorders, including diabetes, hypertension and cardiovascular disease. Pancreatic lipase (PL) has been validated as a key target for developing anti-obesity agents, owing to its crucial role in lipid digestion and absorption. In the past few decades, porcine PL (pPL) is always used as the enzyme source for screening PL inhibitors, which generate numerous pPL inhibitors but the potent inhibitors against human PL (hPL) are rarely reported. Herein, a series of salicylanilide derivatives were designed and synthesized, while their anti-hPL effects were assayed by a fluorescence-based biochemical approach. To investigate the structure-activity relationships of salicylanilide derivatives as hPL inhibitors in detail, structural modifications on three rings (A, B and C) of the salicylanilide skeleton were performed. Among all tested compounds, 2t and 2u were found possessing the most potent anti-PL activity, showing IC50 values of 1.86 & mu;M and 1.63 & mu;M, respectively. Inhibition kinetic analyses suggested that both 2t and 2u could effectively inhibit hPL in a non-competitive manner, with the ki value of 1.67 & mu;M and 1.70 & mu;M, respectively. Fluorescence quenching assays suggested that two inhibitors could quench the fluorescence of hPL via a static quenching procedure. Molecular docking simulations suggested that 2t and 2u could tightly bind on an allosteric site of hPL. Collectively, the structure-activity relationships of salicylanilide derivatives as hPL inhibitors were carefully investigated, while two newly identified reversible hPL inhibitors (2t and 2u) could be used as promising lead compounds to develop novel anti-obesity drugs. |
| WOS关键词 | OBESITY ; CONSTITUENTS ; FAT |
| 资助项目 | Natural Science Foundation of China[81922070] ; Natural Science Foundation of China[81973286] ; Natural Science Foundation of China[22277129] ; Natural Science Foundation of China[82273897] ; Chinese Pharmaceutical Association-Yiling Biopharmaceutical Innovation Project[CPAYLJ201908] ; Shanghai Sailing Program[22YF1441500] ; Shanghai Science and Technology Innovation Action Plans[21S21900600] ; Shanghai Science and Technology Innovation Action Plans[20S21901500] ; Shanghai Science and Technology Innovation Action Plans[20S21900900] |
| WOS研究方向 | Biochemistry & Molecular Biology ; Pharmacology & Pharmacy ; Chemistry |
| 语种 | 英语 |
| WOS记录号 | WOS:001048021700001 |
| 出版者 | PERGAMON-ELSEVIER SCIENCE LTD |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/307001]  |
| 专题 | 新药研究国家重点实验室 |
| 通讯作者 | Li, Bo; Zhu, Weiliang; Ge, Guangbo |
| 作者单位 | 1.Shanghai Univ Tradit Chinese Med, Shanghai 201203, Peoples R China 2.Chinese Acad Sci, Shanghai Inst Mat Med, Drug Discovery & Design Ctr, State Key Lab Drug Res, Shanghai 201203, Peoples R China 3.Univ Chinese Acad Sci, Sch Pharm, Beijing 100049, Peoples R China |
| 推荐引用方式 GB/T 7714 | Zhao, Yitian,Zhang, Min,Hou, Xudong,et al. Design, synthesis and biological evaluation of salicylanilides as novel allosteric inhibitors of human pancreatic lipase[J]. BIOORGANIC & MEDICINAL CHEMISTRY,2023,91:11. |
| APA | Zhao, Yitian.,Zhang, Min.,Hou, Xudong.,Han, Jiaxin.,Qin, Xiaoya.,...&Ge, Guangbo.(2023).Design, synthesis and biological evaluation of salicylanilides as novel allosteric inhibitors of human pancreatic lipase.BIOORGANIC & MEDICINAL CHEMISTRY,91,11. |
| MLA | Zhao, Yitian,et al."Design, synthesis and biological evaluation of salicylanilides as novel allosteric inhibitors of human pancreatic lipase".BIOORGANIC & MEDICINAL CHEMISTRY 91(2023):11. |
入库方式： OAI收割
来源：上海药物研究所
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