The Pyrazolone Scaffold: A Privileged Motif for Molecular Hybridization in Drug Discovery.

Abstract

Pyrazolone and its keto-enol tautomers constitute a privileged class of scaffolds in contemporary medicinal chemistry, characterized by remarkable structural plasticity. This review comprehensively summarizes recent advancements in the structural optimization of pyrazolone-based compounds, highlighting how molecular hybridization drives polypharmacology against complex conditions, including neurodegenerative disorders, inflammation, metabolic syndromes, cancer, and infectious diseases. By detailing structure-activity relationships, the review elucidates how the strategic pharmacophore merging at the N-1, C-3, and C-4 positions transforms the pyrazolone core into highly potent therapeutics. Mechanistically, these hybrid molecules exhibit diverse capabilities, such as inhibiting key survival kinases, blocking pathogenic protein aggregation, antagonizing immune checkpoints, and restoring cellular redox homeostasis via robust reactive oxygen species scavenging. Ultimately, this review underscores the critical role of molecular hybridization in overcoming drug resistance, minimizing systemic toxicity, and driving the future discovery of pyrazolone-based precision therapeutics.