Development of Phenoxyacetic Acid Hybrids With COX‐2 Inhibitory Activity as Potential Anti‐Neuroinflammatory Agents
Mohammad H. Alqarni, Mahmoud Abdelrahman Alkabbani, Aya Mohamed Ahmed Ibrahim, Ahmed I. Foudah, Tariq M. Aljarba, Aftab Alam, Hatem A. Abdel‐Aziz, Mohamed K. ElgoharyABSTRACT
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.