Structure-activity and structure-property relationships of novel Nrf2 activators with a 1,2,4-oxadiazole core and their therapeutic effects on acetaminophen (APAP)-induced acute liver injury

Li-Li Xu; Yu-Feng Wu; Lei Wang; Cui-Cui Li; Li Li; Bin Di; Qi-Dong You; Zheng-Yu Jiang

doi:10.1016/j.ejmech.2018.08.071

Structure-activity and structure-property relationships of novel Nrf2 activators with a 1,2,4-oxadiazole core and their therapeutic effects on acetaminophen (APAP)-induced acute liver injury

Eur J Med Chem. 2018 Sep 5:157:1376-1394. doi: 10.1016/j.ejmech.2018.08.071. Epub 2018 Aug 28.

Authors

Li-Li Xu¹, Yu-Feng Wu², Lei Wang³, Cui-Cui Li², Li Li³, Bin Di⁴, Qi-Dong You⁵, Zheng-Yu Jiang⁶

Affiliations

¹ State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing, 210009, China; Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, 210009, China; Key Laboratory on Protein Chemistry and Structural Biology, Key Laboratory of Drug Quality Control and Pharmacovigilance, Ministry of Education, China Pharmaceutical University, Nanjing, 210009, China.
² Key Laboratory on Protein Chemistry and Structural Biology, Key Laboratory of Drug Quality Control and Pharmacovigilance, Ministry of Education, China Pharmaceutical University, Nanjing, 210009, China.
³ State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing, 210009, China; Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, 210009, China.
⁴ Key Laboratory on Protein Chemistry and Structural Biology, Key Laboratory of Drug Quality Control and Pharmacovigilance, Ministry of Education, China Pharmaceutical University, Nanjing, 210009, China. Electronic address: dibin@cpu.edu.cn.
⁵ State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing, 210009, China; Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, 210009, China. Electronic address: youqd@163.com.
⁶ State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing, 210009, China; Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, 210009, China. Electronic address: jiangzhengyucpu@163.com.

PMID: 30196061
DOI: 10.1016/j.ejmech.2018.08.071

Abstract

The antioxidant function induced by Nrf2 protects the liver from damage. We found a novel Nrf2 activator named compound 25 via structural modification of compound 1 we previously reported. In vitro, compound 25 induced Nrf2 transport into the nucleus and protected hepatocyte L02 cells from APAP-induced cytotoxicity via activating the Nrf2-ARE signaling pathway. In vivo, 25 exhibited therapeutic effects in a mouse model of acute liver injury induced by acetaminophen (APAP) by up-regulating Nrf2-dependent antioxidases and down-regulating liver injury markers in serum. Together, these results indicated that 25 is a potent Nrf2/ARE activator both in vitro and in vivo. The drug-like properties of compound 25 further revealed its potential for development as a therapeutic drug against acute liver injury.

Keywords: Acute liver injury; Antioxidant function; Nrf2 activators; Oxadiazole core; Structure-activity relationship.

MeSH terms

Acetaminophen
Cell Line
Chemical and Drug Induced Liver Injury / drug therapy*
Dose-Response Relationship, Drug
Humans
Molecular Structure
NF-E2-Related Factor 2 / metabolism*
Oxadiazoles / chemical synthesis
Oxadiazoles / chemistry
Oxadiazoles / pharmacology*
Structure-Activity Relationship

Substances

NF-E2-Related Factor 2
Oxadiazoles
Acetaminophen