Design and Synthesis of Novel Pyridazinone Derivatives as Cardiac Myosin Activator for the Systolic Heart Failure

Reduced cardiac contractility characterizes systolic heart failure. Current drugs elevate cAMP or calcium but increase myocardial oxygen consumption, cause arrhythmias, and have poor long-term outcomes. To overcome these limitations, in this study, novel compounds were designed using a diazineone ring core and a fragment growth strategy. Based on molecular dockin exhibiting high docking scores, multiple hydrogen bonds, and strong residue interactions were chosen for synthesis, with five compounds as the primary candidates. Compounds 4 and 2 showed docking scores with myosin (PDB: 4PA0) of -8.8 and -7.4 kcal/mol, respectively, and exhibited favorable solubility and high plasma protein binding. Biological assays confirmed that all five compounds improved cardiomyocyte survival. Compound 2 exhibited a greater enhancement of ATPase activity than other compounds, demonstrating promising anti-heart failure potential.