Development of Phenoxyacetic Acid Hybrids With COX‐2 Inhibitory Activity as Potential Anti‐Neuroinflammatory Agents

Abstract

This research employs a molecular hybridization strategy to repurpose the pyrazoline scaffold 6a, 6c, 7a-c, 11a, and 12b, transforming it into a high-efficiency conjugate designed to tackle the multifaceted pathology of neuroinflammation and epilepsy. By integrating a selective phenoxyacetic acid moiety. Our findings identified compound 7c as a potential lead candidate for the development of novel anticonvulsant agents. In vivo trials demonstrated that 7c offers a superior therapeutic window compared to valproic acid, yielding 90% seizure protection in PTZ models and a remarkable 212.27% delay in seizure onset within the pilocarpine model, alongside 100% survival. Beyond mere symptomatic suppression, 7c re-engineers the hippocampal environment by slashing glutamate-driven excitotoxicity by 64.23% and silencing the cytokine-glial activation axis (TNF-alpha, IL-6, GFAP, and Iba-1). Supported by ADME profile confirming optimal BBB permeability and molecular docking indicating a robust binding affinity of -10.3 kcal/mol, this study positions 7c as a versatile, non-toxic, and repurposed-ready hybrid candidate for advanced neuroprotective intervention.