Ultrasound‐Assisted Synthesis of Pyrazoline Derivatives as Potential Antagonists of RAGE‐Mediated Pathologies: Insights from SAR Studies and Biological Evaluations

In the context of age-related disorders, the receptor of advanced glycation end products (RAGE), plays a pivotal role in the pathogenesis of these conditions by triggering downstream signaling pathways associated with chronic inflammation and oxidative stress. Targeting this inflammaging phenomenon with RAGE antagonists holds promise for interventions with broad implications in healthy aging and the management of age-related conditions. This study explores the structure-activity relationship (SAR) of pyrazoline-based RAGE antagonists synthesized using an ultrasound-assisted green one-pot two-steps methodology. Our investigation identifies phenylurenyl-pyrazoline 2 g as a promising candidate, demonstrating superior efficiency compared to the reference antagonist Azeliragon (IC₅₀=13 μM). Compound 2 g exhibits potent inhibition of the AGE2-BSA/sRAGE interaction (IC₅₀=22 μM) and favorable affinity in Microscale Thermophoresis (MST) assays (K_d=17.1 μM), along with a favorable safety profile, with no apparent cytotoxicity observed in vitro in the MTS assay. These findings underscore the potential of pyrazoline-derived RAGE antagonists as therapeutic agents for addressing age-related disorders.