European Journal of Medicinal Chemistry ( IF 6.7 ) Pub Date : 2022-06-11 , DOI: 10.1016/j.ejmech.2022.114526 Fei-Fei Yang 1 , Jin-Zhu Zhou 1 , Xue-Li Xu 1 , Ting Hu 1 , Jian-Quan Liu 1 , Ya-Xi Wu 1 , Bo Wei 1 , Li-Ying Ma 2
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.
中文翻译:
发现含有双酰胺部分的 1,3,4-恶二唑衍生物作为一类新的潜在心脏保护剂
心肌损伤是心血管疾病和癌症治疗中不可忽视的问题。含氮杂环化合物在心血管领域的功能特性近年来备受关注。在此,我们通过广泛筛选含有氮杂环的抗癌衍生物发现了一种含有 1,3,4-恶二唑的先导化合物12a ,该化合物对心肌细胞的氧化应激表现出潜在的保护活性。后续的构效关系 (SAR) 研究还强调了取代位点和双酰胺部分在增强抗氧化应激保护活性中的作用。具体来说,化合物12d在高浓度下表现出低细胞毒性,并在 H9c2 细胞中表现出对氧化应激的有效心肌保护作用。初步机制研究表明,化合物12d可降低心肌肥大和氧化应激相关蛋白/基因的表达,减少线粒体介导的细胞凋亡,从而增强受损心肌细胞的细胞活力。在本研究中,1,3,4-恶二唑可能代表了一种具有潜在心肌保护作用的新型药效团,为未来心血管药物的优化提供了更多选择,特别是用于治疗肿瘤心脏病学。