2-(3,4-Dihydro-4-Oxothieno[2,3-d]pyrimidin-2-ylthio) Acetamides as a New Class of Falcipain-2 Inhibitors. 3. Design, Synthesis and Biological Evaluation

Molecules

Jin Zhu¹  Tong Chen¹  Jie Liu¹  Ruoqun Ma¹  Weiqiang Lu¹  Jin Huang¹  Honglin Li¹  Jian Li¹ 

[1] School of Pharmacy, East China University of Science and Technology, 130 Mei Long Road, Shanghai 200237, P.R. China

关键词: 2-(3;    4-Dihydro-4-oxothieno[2;    3-d]pyrimidin-2-ylthio)acetamide derivatives;    Falcipain-2 inhibitor;    Malaria;    SAR;   

DOI  :  10.3390/molecules14020785

来源: mdpi

【 摘 要 】

The cysteine protease falcipain-2 (FP-2) of Plasmodium falciparum is a principal cysteine protease and an essential hemoglobinase of erythrocytic P. falciparum trophozoites, making it become an attractive target enzyme for developing anti-malarial drugs. In this study, a series of novel small molecule FP-2 inhibitors have been designed and synthesized based on compound 1, which was identified by using structure-based virtual screening in conjunction with an enzyme inhibition assay. All compounds showed high inhibitory effect against FP-2 with IC₅₀s of 1.46-11.38 μM, and the inhibitory activity of compound 2a was ~2 times greater than that of prototype compound 1. The preliminary SARs are summarized and should be helpful for future inhibitor design, and the novel scaffold presented here, with its potent inhibitory activity against FP-2, also has potential application in discovery of new anti-malarial drugs.

【 授权许可】

CC BY   
© 2009 by the authors; licensee Molecular Diversity Preservation International, Basel, Switzerland.