Sulfonamides: a decade of development in synthetic methods and biological activity studies

Sulfonamides are privileged structural motifs widely found in bioactive molecules and pharmaceuticals, and their derivatives exhibit excellent structural diversity, a feature proven useful for discovering novel therapeutic agents. The development of novel sulfonamide-containing compounds with reduced toxicity, low production costs, and high potency constitutes a research focus in medicinal chemistry. Recent advances in sulfur dioxide insertion, reactions of sulfinate salts, transformation of thiols/disulfides, and sulfonyl precursor coupling have enabled efficient, green, and functional-group-tolerant synthesis of diverse sulfonamides. Moreover, the biological applications and structure-activity relationships of sulfonamides are comprehensively reviewed, including anti-diabetic, antimicrobial, anti-inflammatory, carbonic anhydrase inhibitory, anticancer, and anti-Alzheimer's disease activities, highlighting their critical roles in medicinal chemistry and drug development. In addition, FDA-approved drugs bearing the sulfonamide moiety over the past 50 years are also summarized. It is anticipated that this review will provide medicinal chemists with clear insights for the structural design and development of low-toxicity, high-potency sulfonamide-based drugs targeting numerous life-threatening diseases.