文献类型：期刊文献

英文题名：Repurposing of antitumor drug candidate Quisinostat lead to novel spirocyclic antimalarial agents

作者：Li, Ruoxi[1];Ling, Dazheng[1];Tang, Tongke[2,5];Huang, Zhenghui[2];Wang, Manjiong[1];Mao, Fei[1];Zhu, Jin[1];Jiang, Lubin[2,5];Li, Jian[1,3,4];Li, Xiaokang[1]

机构：[1]East China Univ Sci & Technol, Sch Pharm, State Key Lab Bioreactor Engn, Shanghai Key Lab New Drug Design, Shanghai 200237, Peoples R China;[2]Chinese Acad Sci, Univ Chinese Acad Sci, Inst Pasteur Shanghai, Key Lab Mol Virol & Immunol, Shanghai 200031, Peoples R China;[3]Dali Univ, Coll Pharm & Chem, Dali 671000, Peoples R China;[4]East China Univ Sci & Technol, Frontiers Sci Ctr Materiobiol & Dynam Chem, Shanghai 200237, Peoples R China;[5]ShanghaiTech Univ, Sch Life Sci & Technol, Shanghai 201210, Peoples R China

年份：2021

卷号：32

期号：5

起止页码：1660

外文期刊名：CHINESE CHEMICAL LETTERS

收录：;WOS:【SCI-EXPANDED(收录号:WOS:000647702900011)】；

基金：This work was supported by the National Key R&D Program of China (Nos. 2017YFB0202600, 2018YFA0507300), the National Mega-project for Innovative Drugs of China (No. 2019ZX09721001004-003), the National Natural Science Foundation of China (Nos. 81872747, 81903457, 31972169), the National Science and Technology Major Project (No. 2018ZX10101004003001), the Innovative Research Team of High-level Local Universities in Shanghai, the National Special Fund for State Key Laboratory of Bioreactor Engineering (No. 2060204), the Shanghai Sailing Program (No. 19YF1412600) and the Shanghai Morning Light Program (No. 18CG33).

语种：英文

外文关键词：Malaria; PfHDAC inhibitor; Drug repurposing; Epigenetic modulator; Erythrocytic therapy

摘要：Antimalarial chemotherapies endowed with effectiveness against drug-resistant parasites and good safety are urgently required in clinical. Our previous research revealed that clinical phase II antitumor drug Quisinostat was a promising antimalarial prototype by inhibiting the activity of Plasmodium falciparum (P. falciparum) histone deacetylase (PfHDAC). Herein, 30 novel spirocyclic linker derivatives were designed and synthesized based on Quisinostat as lead compound, and then their antimalarial activities and cytotoxicity were systematically evaluated. Among them, compounds 8 and 27 could effectively eliminate wild-type and multi-drug resistant P. falciparum parasites, and display weakened cytotoxicity and good metabolic stability. Western blot assay demonstrated that they could inhibit PfHDAC activity like Quisinostat. In addition, both 8 and 27 showed certain antimalarial efficacy in rodent malaria model, and the animal toxicity of 8 was significantly improved compared with Quisinostat. Overall, 8 and 27 were structurally novel PfHDAC inhibitors and provided prospective prototype for further antimalarial drug research. (c) 2021 Chinese Chemical Society and Institute of Materia Medica, Chinese Academy of Medical Sciences. Published by Elsevier B.V. All rights reserved.