文献类型：期刊文献

英文题名：Design and synthesis of small molecular dual inhibitor of falcipain-2 and dihydrofolate reductase as antimalarial agent

作者：Huang, Huang[1];Lu, Weiqiang[1];Li, Xi[1];Cong, Xiaoli[2];Ma, Hongmei[1];Liu, Xiaofeng[1];Zhang, Yu[1];Che, Peng[1];Ma, Ruoqun[1];Li, Honglin[1];Shen, Xu[1,2,3];Jiang, Hualiang[1,2,3];Huang, Jin[1];Zhu, Jin[1]

机构：[1]E China Univ Sci & Technol, Sch Pharm, Shanghai 200237, Peoples R China;[2]Minsheng Pharma, Binjiang Branch, Hangzhou 310051, Zhejiang, Peoples R China;[3]Chinese Acad Sci, Drug Discovery & Design Ctr, Shanghai Inst Mat Med, Shanghai 201203, Peoples R China

年份：2012

卷号：22

期号：2

起止页码：958

外文期刊名：BIOORGANIC & MEDICINAL CHEMISTRY LETTERS

收录：;WOS:【SCI-EXPANDED(收录号:WOS:000299653500037)】；

基金：We gratefully acknowledge the financial supports from the National Natural Science Foundation of China (Grant 21002028), National S&T Major Project, China (Grant 2011ZX09102-005-02), the 111 Project(Grant B07023), and the Fundamental Research Funds for the Central Universities(Grant 0911009). A synthetic Plasmodium falciparum DHFR sequence with the Escherichia coli codon bias in pET-17b vector was kindly provided by Professor Carol Hopkins Sibley (Department of Genome Sciences, University of Washington).

语种：英文

外文关键词：Falcipain-2; Dihydrofolate reductase; Dual inhibitor; Antimalarial drug; SAR; Molecular docking

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.