Design, synthesis and lipid-lowering activities of penipyridone derivatives

Liping Li; Zhongwei Duan; Donghui Bai; Fang Lu; Jiejie Hao; Tianjiao Zhu; Deihai Li

doi:10.1016/j.bmc.2021.116192

Design, synthesis and lipid-lowering activities of penipyridone derivatives

Bioorg Med Chem. 2021 Jun 15:40:116192. doi: 10.1016/j.bmc.2021.116192. Epub 2021 May 1.

Authors

Liping Li¹, Zhongwei Duan¹, Donghui Bai¹, Fang Lu¹, Jiejie Hao¹, Tianjiao Zhu², Deihai Li³

Affiliations

¹ Key Laboratory of Marine Drugs, Chinese Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao 266003, People's Republic of China.
² Key Laboratory of Marine Drugs, Chinese Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao 266003, People's Republic of China. Electronic address: zhutj@ouc.edu.cn.
³ Key Laboratory of Marine Drugs, Chinese Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao 266003, People's Republic of China; Laboratory for Marine Drugs and Bioproducts of Qingdao Pilot National Laboratory for Marine Science and Technology, Qingdao 266237, People's Republic of China; Open Studio for Druggability Research of Marine Natural Products, Pilot National Laboratory for Marine Science and Technology, Qingdao 266237, People's Republic of China. Electronic address: dehaili@ouc.edu.cn.

PMID: 33965838
DOI: 10.1016/j.bmc.2021.116192

Abstract

On the basis of our earlier discovered natural product penipyridone G with potential lipid-lowering utility, 35 penipyridone derivatives were designed, synthesized and characterized. Based on the oleic acid-induced HepG2 cell lipid accumulation model, compounds 12c, 14, 15f, 15k, 15o, 15p and 16f showed potent lipid-lowering activities among the synthetic compounds at 10 μM. In particular, compounds 4, 15k, 15o showed significant activities on inhibiting lipid accumulation in insulin resistant HepG2 cells, and these three compounds were safe and non-toxic within the concentration range of 400 μM. In comparison, 15o possessed the best lipid-lowering activity. Compared with the vehicle group, the triglyceride inhibition rate of 15o was about 30.2%, and the total cholesterol inhibition rate was about 14.8% at 20 μM, which was equipotent to Simvastatin. Our research indicates that 15o may serve as a promising lead compound for the development of hypolipidemic drugs.

Keywords: Lipid-lowering activity; Molecular docking; No cytotoxicity; Penipyridone derivatives; Synthesis.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Dose-Response Relationship, Drug
Drug Design*
Humans
Hypolipidemic Agents / chemical synthesis
Hypolipidemic Agents / chemistry
Hypolipidemic Agents / pharmacology*
Lipids / antagonists & inhibitors*
Molecular Structure
Pyridones / chemical synthesis
Pyridones / chemistry
Pyridones / pharmacology*
Structure-Activity Relationship

Substances

Hypolipidemic Agents
Lipids
Pyridones
penipyridone A