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Design, synthesis and biological evaluation of peptidomimetic benzothiazolyl ketones as 3CLpro inhibitors against SARS-CoV-2

文献类型：期刊论文

作者Yang, Hanxi2,3; You, Mengyuan4; Shu, Xiaoyang5; Zhen, Jingyao3,6; Zhu, Mengwei1,7; Fu, Tiantian1,7; Zhang, Yan3; Jiang, Xiangrui3,6; Zhang, Leike5,8; Xu, Yechun3,4
刊名EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
出版日期2023-09-05
卷号257页码:13
关键词Peptidomimetics Benzothiazolyl ketone 3CLpro inhibitor Pharmacokinetic properties SARS-CoV-2
ISSN号0223-5234
DOI10.1016/j.ejmech.2023.115512
通讯作者Zhang, Yumin(ymzhang@wh.iov.cn) ; Su, Haixia(suhaixia1@simm.ac.cn) ; Zhang, Qiumeng(qmzhang@simm.ac.cn)
英文摘要A series of peptidomimetic compounds containing benzothiazolyl ketone and [2.2.1] azabicyclic ring was designed, synthesized and evaluated in the hope of obtaining potent oral 3CLpro inhibitors with improved pharmacokinetic properties. Among the target compounds, 11b had the best enzymatic potency (IC50 = 0.110 mu M) and 11e had the best microsomal stability (t1/2 > 120 min) and good enzyme activity (IC50 = 0.868 mu M). Therefore, compounds 11b and 11e were chosen for further evaluation of pharmacokinetics in ICR mice. The results exhibited that the AUC(0-t) of 11e was 5143 h*ng/mL following single-dose oral administration of 20 mg/ kg, and the F was 67.98%. Further structural modification was made to obtain compounds 11g -11j based on 11e. Among them, 11j exhibited the best enzyme inhibition activity against SARS-CoV-2 3CLpro (IC50 = 1.646 mu M), the AUC(0-t) was 32473 h*ng/mL (20 mg/kg, po), and the F was 48.1%. In addition, 11j displayed significant anti-SARS-CoV-2 activity (EC50 = 0.18 mu M) and low cytotoxicity (CC50 > 50 mu M) in Vero E6 cells. All of the above results suggested that compound 11j was a promising lead compound in the development of oral 3CLpro in-hibitors and deserved further research.
WOS关键词DISCOVERY ; SARS
资助项目National Key Research and Devel- opment Plan of China[2021YFC2300700] ; National Key Research and Devel- opment Plan of China[2022YFC2303300] ; Strategic Priority Research Program of Chinese Academy of Sciences[SIMM010120]
WOS研究方向Pharmacology & Pharmacy
语种英语
WOS记录号WOS:001010407100001
出版者ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
源URL[http://119.78.100.183/handle/2S10ELR8/306194]  
专题新药研究国家重点实验室
通讯作者Zhang, Yumin; Su, Haixia; Zhang, Qiumeng
作者单位1.Yangtze Delta Drug Adv Res Inst, Yangtze Delta Pharmaceut Coll, Nantong 226133, Peoples R China
2.Zhengzhou Univ, Coll Chem, 100 Kexuedadao Rd, Zhengzhou 450001, Peoples R China
3.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China
4.Nanjing Univ Chinese Med, Sch Chinese Mat Med, Nanjing 210023, Peoples R China
5.Chinese Acad Sci, Wuhan Inst Virol, Ctr Biosafety Mega Sci, State Key Lab Virol, Wuhan 430071, Hubei, Peoples R China
6.Univ Chinese Acad Sci, 19A Yuquan Rd, Beijing 100049, Peoples R China
7.An Hui Univ Tradit Chinese Med, Coll Pharm, Hefei 230012, Peoples R China
8.Hubei Jiangxia Lab, Wuhan 430200, Peoples R China
推荐引用方式
GB/T 7714		 Yang, Hanxi,You, Mengyuan,Shu, Xiaoyang,et al. Design, synthesis and biological evaluation of peptidomimetic benzothiazolyl ketones as 3CLpro inhibitors against SARS-CoV-2[J]. EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,2023,257:13.
APA Yang, Hanxi.,You, Mengyuan.,Shu, Xiaoyang.,Zhen, Jingyao.,Zhu, Mengwei.,...&Shen, Jingshan.(2023).Design, synthesis and biological evaluation of peptidomimetic benzothiazolyl ketones as 3CLpro inhibitors against SARS-CoV-2.EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,257,13.
MLA Yang, Hanxi,et al."Design, synthesis and biological evaluation of peptidomimetic benzothiazolyl ketones as 3CLpro inhibitors against SARS-CoV-2".EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY 257(2023):13.

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来源：上海药物研究所

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