A Review on Synthesis, Characterization, and Anticonvulsant Activity of Novel Substituted Chloroacetic Acid Derivatives

Epilepsy is one of the most prevalent neurological disorders worldwide, affecting more than 70 million individuals across all age groups. Despite the availability of numerous antiepileptic drugs (AEDs), approximately one-third of patients remain refractory to existing pharmacotherapy, underscoring a critical need for novel therapeutic agents with improved efficacy, safety profiles, and selectivity. Chloroacetic acid and its substituted derivatives have emerged as a structurally versatile scaffold in medicinal chemistry, offering broad potential for the development of anticonvulsant compounds. This review comprehensively examines the synthetic strategies employed to prepare novel substituted chloroacetic acid derivatives, the physicochemical and spectroscopic methods used in their structural characterization, and their evaluated anticonvulsant activities across in vitro and in vivo experimental models. Particular attention is directed toward structure-activity relationships (SAR), mechanistic pathways including sodium channel blockade, GABA-ergic potentiation, and NMDA receptor antagonism, as well as comparative assessments with established reference drugs such as phenytoin, valproic acid, and carbamazepine. The article also addresses toxicological considerations, metabolic stability, and future directions in the rational design of more potent and selective anticonvulsants derived from the chloroacetic acid pharmacophore.