Current development in sulfonamide derivatives to enable CNS-drug discovery.

The encouraging therapeutic potential of sulfonamide-based derivatives has been unraveled by breakthrough discovery of Paul Ehrlich, who pointed out the possibility of fighting microbes with chemicals. Over the decades, the utility of sulfonamides has expanded beyond antimicrobial agents, revealing their usefulness in many areas of pharmacotherapy, including the treatment of central nervous system (CNS) diseases. Through a detailed analysis of preclinical and clinical data, we identify key sulfonamide-based compounds that have demonstrated significant CNS activity. We also discuss the challenges in the development of sulfonamide derivatives as enzyme/ion channel inhibitors or receptor ligands for CNS applications, describing their mode of action and therapeutic significance. This is followed by the characteristics of pharmacological targets, structure-activity relationships, ADMET properties, efficacy in experimental animal models, and outcomes from clinical trials. Overall, the versatile nature of arylsulfonamides makes them a valuable motif in drug discovery, offering diverse opportunities for the development of novel agents for treating CNS disorders.