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

Area of Science:

• Cardiovascular Research
• Medicinal Chemistry
• Pharmacology

Background:

• Heart failure (HF) is a progressive condition with significant morbidity and mortality.
• Current treatments, including SGLT2 inhibitors, have limitations and potential risks.
• Novel therapeutic strategies are needed to effectively manage HF.

Purpose of the Study:

• To design and synthesize novel O-glucoside derivatives as potential HF treatments.
• To evaluate the efficacy of these compounds in preclinical models of HF.
• To identify structure-activity relationships (SAR) for optimized therapeutic effects.

Main Methods:

• Synthesis of O-glucoside derivatives with nitrogen-containing heterocyclic fragments.
• In vitro assessment using glucose-free DMEM-induced injured cardiomyocytes.
• In vivo evaluation in Transverse Aortic Constriction (TAC)-induced HF mouse models.

Main Results:

• Compound E9 demonstrated significant protective effects on injured cardiomyocytes.
• E9 enhanced SGLT2, NHE1, and SOD enzyme inhibition, increased ATP, and suppressed fibrosis and cell injury markers.
• E9 improved cardiac function, reduced hypertrophy and collagen deposition, and increased survival rates in HF mice.

Conclusions:

• Novel O-glucoside derivative E9 exhibits significant cardioprotective and therapeutic potential for heart failure.
• E9 effectively ameliorates HF pathologies in both cellular and animal models.
• This compound represents a promising candidate for future HF drug development.