Abstract
Neuroinflammation is an integral part of epilepsy pathogenesis and other convulsive conditions, and non-steroidal anti-inflammatory drugs (NSAIDs) present a potent tool for the contemporary search and design of novel anticonvulsants. In the present paper, evaluation of the anticonvulsant activity of the potential NSAID dual COX-2/5-LOX inhibitor darbufelone methanesulfonate using an scPTZ model in mice in dose 100 mg/kg is reported. Darbufelone possesses anticonvulsant properties in the scPTZ model and presents interest for in-depth studies as a possible anticonvulsant multi-target agent with anti-inflammatory activity. The series of 4-thiazolidinone derivatives have been synthesized following the analogue-based drug design and hybrid-pharmacophore approach using a darbufelone matrix. The synthesized derivatives showed a significant protection level for animals in the scPTZ model and are promising compounds for the design of potential anticonvulsants with satisfactory drug-like parameters.
Highlights
More than 70 million people suffer from epilepsy and seizure conditions, constituting nearly 1% of the global population [1]
Considerable attention in search of possible targets for the correction of epilepsy and related conditions has been focused on the neuroinflammation process which occurs due to many reasons, such as neuroinfection, strokes, and head injuries, and can initiate an inflammatory cascade in the central nervous system [6,7]
Neuroinflammation is a predictor of increased convulsive readiness [8] and key trigger for epilepsy pathogenic mechanisms such as the activation of microglia and microglial inflammatory mediators [9], the expression of circulating immune cells [10], cytokine and chemokine upregulation [11], free radical formation [12], and cyclooxygenases-1 and 2 (COX-1/2)
Summary
More than 70 million people suffer from epilepsy and seizure conditions, constituting nearly 1% of the global population [1]. Considerable attention in search of possible targets for the correction of epilepsy and related conditions has been focused on the neuroinflammation process which occurs due to many reasons, such as neuroinfection, strokes, and head injuries, and can initiate an inflammatory cascade in the central nervous system [6,7]. Neuroinflammation is a predictor of increased convulsive readiness [8] and key trigger for epilepsy pathogenic mechanisms such as the activation of microglia and microglial inflammatory mediators [9], the expression of circulating immune cells [10], cytokine and chemokine upregulation [11], free radical formation [12], and cyclooxygenases-1 and 2 (COX-1/2).
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