Repurposing of antitumor drug candidate Quisinostat lead to novel spirocyclic antimalarial agents  

作　　者：Ruoxi Li Dazheng Ling Tongke Tang Zhenghui Huang Manjiong Wang Fei Mao Jin Zhu Lubin Jiang Jian Li Xiaokang Li 

机构地区：[1]State Key Laboratory of Bioreactor Engineering,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,Institut Pasteur of Shanghai,University of Chinese Academy of Sciences,Chinese Academy of Sciences,Shanghai 200031,China [3]College of Pharmacy and Chemistry,Dali University,Dali 671000,China [4]Frontiers Science Center for Materiobiology and Dynamic Chemistry,East China University of Science and Technology,Shanghai 200237,China [5]School of Life Science and Technology,ShanghaiTech University,Shanghai 201210,China

出　　处：《Chinese Chemical Letters》2021年第5期1660-1664,共5页中国化学快报（英文版）

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.2019ZX09721001-004-003);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);the Shanghai Morning Light Program(No.18CG33).

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 phaseⅡantitumor 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.

关 键 词：MALARIA PfHDAC inhibitor Drug repurposing Epigenetic modulator Erythrocytic therapy 

分 类 号：TQ460.1[化学工程—制药化工]