Design and synthesis of 4-azaindoles derivatives: targeting the cardiac troponin I-interacting kinase (TNNI3K).

Cardiac troponin I-interacting kinase (TNNI3K) is a cardiac-specific protein kinase, whose overexpression is closely linked to heart failure and ventricular remodeling. TNNI3K inhibitors regulate the phosphorylation of serine residues in downstream cardiac troponin I (cTnI) and affect the p38 pathway to prevent ventricular remodeling and myocardial cell damage. This study designed 120 compounds based on the reported quantitative structure-activity relationships (QSAR) of TNNI3K inhibitors. Following virtual screening, 4-azaindole was identified as the optimal scaffold. Subsequent synthesis of derivatives SK1-SK5 demonstrated their protective effects on damaged cardiomyocytes. Importantly, molecular dynamics (MD) simulations confirmed that compound SK5 forms a stable complex with TNNI3K and elucidated key binding residues and their interaction modes. These findings collectively validate the rational design of TNNI3K-targeted compounds and support SK5's potential as an anti-heart failure lead candidate.