文献类型：期刊文献

英文题名：Drug Repurposing of Quisinostat to Discover Novel Plasmodium falciparum HDAC1 Inhibitors with Enhanced Triple-Stage Antimalarial Activity and Improved Safety

作者：Wang, Manjiong[1];Tang, Tongke[2,3];Li, Ruoxi[1];Huang, Zhenghui[2];Ling, Dazheng[1];Zheng, Lulu[1];Ding, Yan[4];Liu, Taiping[4];Xu, Wenyue[4];Zhu, Feng[5];Min, Hui[5];Boonhok, Rachasak[5];Mao, Fei[1];Zhu, Jin[1];Li, Xiaokang[1];Jiang, Lubin[2,3];Li, Jian[1,6]

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]Univ Chinese Acad Sci, Chinese Acad Sci, Inst Pasteur Shanghai, Key Lab Mol Virol & Immunol, Shanghai 200031, Peoples R China;[3]ShanghaiTech Univ, Sch Life Sci & Technol, Shanghai 201210, Peoples R China;[4]Army Med Univ, Dept Pathogen Biol, Chongqing 400038, Peoples R China;[5]Univ S Florida, Morsani Coll Med, Dept Internal Med, Div Infect Dis & Int Med, Tampa, FL 33612 USA;[6]East China Univ Sci & Technol, Frontiers Sci Ctr Materiobiol & Dynam Chem, Shanghai 200237, Peoples R China

年份：2022

卷号：65

期号：5

起止页码：4156

外文期刊名：JOURNAL OF MEDICINAL CHEMISTRY

收录：;WOS:【SCI-EXPANDED(收录号:WOS:000772205900026)】；

基金：We thank Dr. Didier Menard for providing the ART-resistant field isolates. This work was supported by the National Natural Science Foundation of China (82173689, 22037002, 81872747, and 81903457), the National Key R&D Program of China (2017YFB0202600), the National Science and Technology Major Project (2018ZX10101004003001), the Key Collaborative Research Program of the Alliance of International Science Organizations (ANSO-CR-KP-202006), the Shanghai Frontiers Science Center of Optogenetic Techniques for Cell Metabolism (2021 Sci & Tech 03-28), the Innovative Research Team of High-Level Local Universities in Shanghai, the Chinese Special Fund for State Key Laboratory of Bioreactor Engineering (2060204), the Pu'er Municipal Expert Workstation of L.J., the Shanghai Sailing Program (19YF1412600), and the Shanghai Morning Light Program (18CG33).

语种：英文

摘要：Our previous work found that the clinical histone deacetylase (HDAC) inhibitor quisinostat exhibited a significant antimalarial effect but with severe toxicity. In this work, 35 novel derivatives were designed and synthesized based on quisinostat as the lead compound, and their in vitro antimalarial activities and cytotoxicities were systematically evaluated. Among them, JX35 showed potent inhibition against both wild-type and multidrug-resistant parasite strains and displayed a significant in vivo killing effect against all life cycles of parasites, including the blood stage, liver stage, and gametocyte stage, indicating its potential for the simultaneous treatment, chemoprevention, and blockage of malaria transmission. Compared with quisinostat, JX35 exhibited stronger antimalarial efficacy, more adequate safety, and good pharmacokinetic properties. Additionally, mechanistic studies via molecular docking studies, induced Pf HDAC1/2 knockdown assays, and PfHDAC1 enzyme inhibition assays jointly indicated that the antimalarial target of JX35 was Pf HDAC1. In summary, we discovered the promising candidate PfHDAC1 inhibitor JX35, which showed stronger triple-stage antimalarial effects and lower toxicity than quisinostat.