Design, synthesis and evaluation of anti-heart failure activity of O-glucoside derivatives

Yu Liu; Heng Liu; Xutong Wang; Bing Wang; Xiaodong Fang; Qiming Li; Meng Sun; Kejing Ma; Zeyu Gao; Yong Zhang; Weina Han

doi:10.1016/j.ejmech.2025.117802

Design, synthesis and evaluation of anti-heart failure activity of O-glucoside derivatives

Eur J Med Chem. 2025 Jun 10:296:117802. doi: 10.1016/j.ejmech.2025.117802. Online ahead of print.

Authors

Yu Liu¹, Heng Liu², Xutong Wang¹, Bing Wang¹, Xiaodong Fang¹, Qiming Li¹, Meng Sun¹, Kejing Ma¹, Zeyu Gao¹, Yong Zhang³, Weina Han⁴

Affiliations

¹ Department of Medicinal Chemistry and Natural Medicine Chemistry, College of Pharmacy, HarBin Medical University, Harbin, 150081, China.
² State Key Laboratory of Frigid Zone Cardiovascular Diseases (SKLFZCD), Department of Pharmacology, College of Pharmacy, and Department of Cardiology, the Second Affiliated Hospital, Harbin Medical University, Harbin 150081, China.
³ State Key Laboratory of Frigid Zone Cardiovascular Diseases (SKLFZCD), Department of Pharmacology, College of Pharmacy, and Department of Cardiology, the Second Affiliated Hospital, Harbin Medical University, Harbin 150081, China; State Key Laboratory -Province Key Laboratories of Biomedicine-Pharmaceutics of China, and Key Laboratory of Cardiovascular Research, Ministry of Education, College of Pharmacy, Harbin 150081, China; Research Unit of Noninfectious Chronic Diseases in Frigid Zone (2019RU070), Chinese Academy of Medical Sciences, Harbin, 150081, China. Electronic address: zy@ems.hrbmu.edu.cn.
⁴ Department of Medicinal Chemistry and Natural Medicine Chemistry, College of Pharmacy, HarBin Medical University, Harbin, 150081, China. Electronic address: hanweina@hrbmu.edu.cn.

PMID: 40578252
DOI: 10.1016/j.ejmech.2025.117802

Abstract

Heart failure (HF) is a progressive disease characterized by persistent or episodic worsening of symptoms, leading to functional deterioration. Clinically, guidelines recommend the use of SGLT2 inhibitors for the treatment of heart failure. However, the SGLT2 inhibitors exist potential risks including weight loss and euglycemic diabetic ketoacidosis. We designed and synthesized a series of O-glucoside derivatives by introducing nitrogen-containing heterocyclic fragments. Among them, compound E9 showed the most protective effect on the glucose-free DMEM-induced injured cardiomyocytes, and the structure-activity relationships (SAR) of these compounds were preliminarily evaluated in cardiomyocyte injury model. Furthermore, compound E9 significantly enhanced the inhibition of SGLT2, NHE1, and SOD enzyme activity, increased ATP levels in damaged cardiomyocytes, and suppressed Ang II-induced myocardial fibrosis, the autophagy receptor protein P62 and the expression of cell injury markers. Additionally, compound E9 significantly improved cardiac function in TAC-induced HF mice, inhibited cardiomyocyte hypertrophy and collagen deposition, ameliorated myocardial tissue damage, enhanced mitochondrial autophagy in injured cardiomyocytes, and ultimately increased survival rates in HF mice. In conclusion, this study reveals that the novel O-glucoside derivative E9 was a promising compound for the treatment of heart failure.