Design, synthesis and biological evaluation of novel pyxinol derivatives with anti-heart failure activity

• Published in: Biomedicine & pharmacotherapy Vol. 133; p. 111050
• Main Authors: Liu, Junli, Liu, Yunhe, Yu, Hui, Zhang, Ying, Hsu, Alan Chen-Yu, Zhang, Mingming, Gou, Yawei, Sun, Wei, Wang, Fang, Li, Pingya, Liu, Jinping
• Format: Journal Article
• Language: English
• Published: France Elsevier Masson SAS 01.01.2021; Elsevier
• Subjects: ACE inhibition; Angiotensin-Converting Enzyme Inhibitors - chemical synthesis; Angiotensin-Converting Enzyme Inhibitors - pharmacology; Angiotensin-Converting Enzyme Inhibitors - toxicity; Animals; Cell Line; Disease Models, Animal; Drug Design; Energy Metabolism - drug effects; Fatty acid esters; Heart failure; Heart Failure - chemically induced; Heart Failure - drug therapy; Heart Failure - metabolism; Heart Failure - physiopathology; Metabolomics; Molecular docking; Molecular Docking Simulation; Molecular Structure; Myocardial Contraction - drug effects; Myocytes, Cardiac - drug effects; Myocytes, Cardiac - metabolism; Myocytes, Cardiac - pathology; Pyxinol; Rats; Structure-Activity Relationship; Ventricular Function - drug effects; Verapamil; Zebrafish; Heart failure; Pyxinol; Metabolomics; ACE inhibition; Fatty acid esters; Molecular docking
• ISSN: 0753-3322; 1950-6007
• DOI: 10.1016/j.biopha.2020.111050

[Display omitted] •A total of 32 novel fatty acid ester derivatives of pyxinol were synthesized.•Compounds 2e and 3b displayed excellent ACE inhibitory activity in vitro.•Compounds 2e and 3b exhibited good activity in zebrafish heart failure model.•The preliminary mechanism of compound 2e on heart failure was studied by using untargeted metabolomics Heart failure (HF) is an important and leading cause of substantial morbidity and mortality globally. The angiotensin-converting enzymatic (ACE) is the causative source for congestive heart failure. Natural products and its derivatives play a vital role in drug discovery and development owing to their efficacy and low toxicity. Pyxinol is a potent natural agent for cardiovascular disease. Thus we investigated the effect on ACE and HF of pyxinol derivatives. We designed and synthesized 32 novel fatty acid ester derivatives of pyxinol via esterification. Among them, compounds 2e (IC50=105 nM) and 3b (IC50=114 nM) displayed excellent ACE inhibitory activity in vitro, and exhibited non-toxic to H9c2 cells. The interactions between ACE and compounds were predicted by molecular docking respectively. In verapamil-induced zebrafish HF model, the activity assay showed that these two derivatives could improve cardiovascular physiological indexes including heart beats, venous congestion, heart dilation, cardiac output, ejection fraction and fractional shortening in a dose-dependent manner. A UPLC-QTOF-MS-based serum metabolomics approach was applied to explore the latent mechanism. A total of 25 differentiated metabolites and 8 perturbed metabolic pathways were identified. These results indicated that pyxinol fatty acid ester derivatives 2e and 3b might be considered as potent drug candidates against heart failure and deserved further research and development.