文献类型：期刊文献

英文题名：Discovery of Novel Plasmodium falciparum HDAC1 Inhibitors with Dual-Stage Antimalarial Potency and Improved Safety Based on the Clinical Anticancer Drug Candidate Quisinostat

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

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]Dali Univ, Coll Pharm & Chem, Dali 671000, Peoples R China;[6]East China Univ Sci & Technol, Frontiers Sci Ctr Materiobiol & Dynam Chem, Shanghai 200237, Peoples R China

年份：2021

卷号：64

期号：4

起止页码：2254

外文期刊名：JOURNAL OF MEDICINAL CHEMISTRY

收录：;WOS:【SCI-EXPANDED(收录号:WOS:000624369300028)】；

基金：We thank Dr. Didier Menard for providing the artemisininresistant field isolates. This work was supported by the National Key R&D Program of China (2017YFB0202600, 2018YFA0507300), the National Natural Science Foundation of China (81872747, 81903457), the National Science and Technology Major Project (2018ZX10101004003001), 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 Chinese Postdoctoral Science Foundation (2018M641946), the Shanghai Sailing Program (19YF1412600), and the Shanghai Morning Light Program (18CG33).

语种：英文

摘要：Previously, we identified the clinical anticancer drug candidate quisinostat as a novel and potent antimalarial lead compound. To further enhance the antimalarial effect and improve safety, 31 novel spirocyclic hydroxamic acid derivatives were synthesized based on the structure of quisinostat, and their antimalarial activities and cytotoxicity were evaluated. Among them, compound 11 displayed broad potency in vitro against several multiresistant malarial parasites, especially two artemisinin-resistant clinical isolates. Moreover, 11 could eliminate both liver and erythrocytic parasites in vivo, kill all morphological erythrocytic parasites with specific potency against schizonts, and show acceptable metabolic stability and pharmacokinetic properties. Western blot analysis, PfHDAC gene knockdown, and enzymatic inhibition experiments collectively confirmed that PfHDAC1 was the target of 11. In summary, 11 is a structurally novel PfHDAC1 inhibitor with the potential to prevent and cure malaria, overcome multidrug resistance, and provide a prospective prototype for antimalarial drug research.