Design and synthesis of small molecular dual inhibitor of falcipain-2 and dihydrofolate reductase as antimalarial agent
文献类型：期刊论文
| 作者 | Huang, Huang1; Lu, Weiqiang1; Li, Xi1; Cong, Xiaoli3; Ma, Hongmei1; Liu, Xiaofeng1; Zhang, Yu1; Che, Peng1; Ma, Ruoqun1; Li, Honglin1 |
| 刊名 | BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
 |
| 出版日期 | 2012-01-15 |
| 卷号 | 22期号:2页码:958-962 |
| 关键词 | Falcipain-2 Dihydrofolate reductase Dual inhibitor Antimalarial drug SAR Molecular docking |
| ISSN号 | 0960-894X |
| DOI | 10.1016/j.bmcl.2011.12.011 |
| 文献子类 | Article |
| 英文摘要 | Resistance of malaria parasites has quickly developed to almost all used antimalarial drugs. Accordingly, the discovery of new effective drugs to counter the spread of malaria parasites that are resistant to existing agents, especially acting on multi-targets, is an urgent need. The cysteine protease falcipain-2 (FP-2) and dihydrofolate reductase (DHFR) play crucial roles in the Plasmodium life cycle. In this study, a series of first-gereration small molecular dual inhibitor of FP-2 and DHFR have been designed and synthesized based on the lead compound 1, which was randomly identified by screening FP-2 inhibitors in our laboratory. Six compounds (2f-g, 2j, and 2m-o) showed improved dual inhibitory activities against FP-2 (IC50 = 2.7-13.2 mu M) and DHFR (IC50 = 1.8-19.8 mu M), and the inhibitory capability of compound 2o against FP-2 and DHFR were increased similar to 8 and similar to 6 times than that of compound 1, respectively. Moreover, compound 20 exhibited moderate in vivo antimalarial activity in a dose dependent fashion, its safety and survival rate were slightly better than that of positive drug. The preliminary SAR was obtained, meanwhile, molecular modeling result provided the key structural information to maintain the dual inhibitory activity, and was helpful for future dual inhibitors design. (C) 2011 Elsevier Ltd. All rights reserved. |
| WOS关键词 | CYSTEINE PROTEASE INHIBITORS ; PLASMODIUM-FALCIPARUM ; ARTEMISININ RESISTANCE ; MALARIA ; IDENTIFICATION ; PROTEINASE ; GENE |
| 资助项目 | National Natural Science Foundation of China[21002028] ; National S&T Major Project, China[2011ZX09102-005-02] ; 111 Project[B07023] ; Fundamental Research Funds for the Central Universities[0911009] |
| WOS研究方向 | Pharmacology & Pharmacy ; Chemistry |
| 语种 | 英语 |
| WOS记录号 | WOS:000299653500037 |
| 出版者 | PERGAMON-ELSEVIER SCIENCE LTD |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/278218]  |
| 专题 | 药物发现与设计中心 |
| 通讯作者 | Liu, Xiaofeng |
| 作者单位 | 1.E China Univ Sci & Technol, Sch Pharm, Shanghai 200237, Peoples R China; 2.Chinese Acad Sci, Drug Discovery & Design Ctr, Shanghai Inst Mat Med, Shanghai 201203, Peoples R China 3.Minsheng Pharma, Binjiang Branch, Hangzhou 310051, Zhejiang, Peoples R China; |
| 推荐引用方式 GB/T 7714 | Huang, Huang,Lu, Weiqiang,Li, Xi,et al. Design and synthesis of small molecular dual inhibitor of falcipain-2 and dihydrofolate reductase as antimalarial agent[J]. BIOORGANIC & MEDICINAL CHEMISTRY LETTERS,2012,22(2):958-962. |
| APA | Huang, Huang.,Lu, Weiqiang.,Li, Xi.,Cong, Xiaoli.,Ma, Hongmei.,...&Zhu, Jin.(2012).Design and synthesis of small molecular dual inhibitor of falcipain-2 and dihydrofolate reductase as antimalarial agent.BIOORGANIC & MEDICINAL CHEMISTRY LETTERS,22(2),958-962. |
| MLA | Huang, Huang,et al."Design and synthesis of small molecular dual inhibitor of falcipain-2 and dihydrofolate reductase as antimalarial agent".BIOORGANIC & MEDICINAL CHEMISTRY LETTERS 22.2(2012):958-962. |
入库方式： OAI收割
来源：上海药物研究所
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