文献类型：期刊文献

英文题名：Design, Synthesis and Therapeutic Evaluation of Novel Antimalarial Derivatives Based on the Clinical Antitumor Candidate Drug Quisinostat

作者：Li, Jian[1,3,4]; Song, Jiamei[1]; Li, Ruoxi[1]; Huang, Zhenghui[2,5]; Qian, Yunan[2]; Wang, Xicheng[1]; Shao, Qiqi[1]; Mao, Fei[1]; Wang, Manjiong[1]; Jiang, Lubin[2,5]; Li, Xiaokang[1]

机构：[1] State Key Laboratory of Bioreactor Engineering, Shanghai Frontiers Science Center of Optogenetic Techniques for Cell Metabolism, Frontiers Science Center for Materiobiology and Dynamic Chemistry, Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai, 200237, China; [2] Key Laboratory of Molecular Virology and Immunology, Shanghai Institute of Immunity and Infection, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, 200031, China; [3] Key Laboratory of Xinjiang Phytomedicine Resource and Utilization, Ministry of Education, School of Pharmacy, Shihezi University, Shihezi, 832003, China; [4] Key Laboratory of Tropical Biological Resources of Ministry of Education, College of Pharmacy, Hainan University, Haikou, 570228, China; [5] Nanjing Advanced Academy of Life and Health, Nanjing, 211135, China

年份：2024

外文期刊名：SSRN

收录：EI(收录号：20240323311)

语种：英文

外文关键词：Acetylation - Diseases - Electrophoresis - Structural optimization

摘要：In previous studies, we identified the clinical antitumor drug candidate Quisinostat is a potent Plasmodium falciparum histone deacetylase (PfHDAC) inhibitor with significant activity against drug-resistant malaria but with severe toxicity. To delve deeper into its antimalarial potential, herein we designed and synthesized 36 novel analogues of Quisinostat and systematically evaluated their antimalarial activities and cytotoxicity. Among them, compounds 33 and 37 could effectively eliminate both wild-type and multidrug resistant P. falciparum parasites along with significantly attenuated cytotoxicity, and their metabolic properties were also notably improved. Western blot analysis showed that 33 and 37 upregulated Plasmodium histone acetylation, suggesting that they exerted antimalarial effects through inhibition of PfHDAC like Quisinostat. Furthermore, compounds 33 and 37 also displayed significant antimalarial therapeutic effect and improved animal safety in rodent malaria model. Collectively, 33 and 37 were structurally novel PfHDAC inhibitor and promising antimalarial lead compounds for the next generation of antimalarial drug research. ? 2024, The Authors. All rights reserved.