Journal
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
Volume 239, Issue -, Pages -Publisher
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2022.114526
Keywords
1,3,4-Oxadiazole; Myocardial injury; Cardioprotective agents; Onco-cardiology
Categories
Funding
- National Natural Science Foundation of China [81703328, U1904154]
- Natural Science Foundation of Henan Province [222102310030, 212300410392]
- China Postdoctoral Science Foundation [2020 M672249]
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This study discovered a compound containing 1,3,4-oxadiazole that showed potential protective activity against oxidative stress in cardiomyocytes. The study also highlighted the importance of substitution sites and bisamide moiety in enhancing the protective activity. This finding provides new choices for the optimization of cardiovascular drugs.
Myocardial injury is a nonnegligible problem in cardiovascular diseases and cancer therapy. The functional feature of N-containing heterocycles in the cardiovascular field has attracted much attention in recent years. Herein, we discovered a lead compound 12a containing 1,3,4-oxadiazole by extensive screening of anticancer derivatives containing nitrogen-heterocycle, which exhibited potential protective activity against oxidative stress in cardiomyocytes. Follow-up structure-activity relationship (SAR) studies also highlighted the role of substitution sites and bisamide moiety in enhancing the protective activity against oxidative stress. Specifically, compound 12d exhibited low cytotoxicity under high concentration and potent myocardial protection against oxidative stress in H9c2 cells. Preliminary mechanistic studies showed compound 12d could decrease the expression of cardiac hypertrophy and oxidative stress-related proteins/genes and reduce mitochondria-mediated cell apoptosis, thereby enhancing the cell vitality of injured cardiomyocytes. In this study, 1,3,4-oxadiazole may represent a novel pharmacophore that possesses potential myocardial protection and provides more choices for future optimization of cardiovascular drugs, especially for the treatment of onco-cardiology.
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