Dipeptide Sulfonamides: Synthesis and Pharmacological Activities

Currently, the synthesis of dipeptide sulfonamides has become an area of significant interest in organic chemistry due to their structural diversity and wide range of pharmacological activities. About two decades after the first synthesis (tail approach) of carbonic anhydrase-inhibiting dipeptide sulfonamides in 1999, facile synthetic strategies that enhance structural diversity and pharmacological potential have emerged. These synthetic strategies employ methodologies that enable regioselective sulfonamide bond formation and peptide coupling. They are primarily eco-friendly solution-phase reaction methods. The incorporation of the sulfonamide functional group into dipeptide frameworks creates synergy, accounting for the wide range of pharmacological activity and improved drug-like properties of sulfonamide dipeptide conjugates. The structural and functional diversity of dipeptide sulfonamides enhances the anticancer, antioxidant, antimicrobial, anti-inflammatory, antidiabetic, anti-ulcer, and antimalarial properties of these hybrid molecules, thereby making them attractive candidates for drug development. Dipeptide sulfonamide analogues bearing an aromatic sulfonamide scaffold exhibit better radical-scavenging activity than those with an aliphatic scaffold. However, dipeptide sulfonamide synthesis, being a complex multi-step process, sometimes produces low yields or undesirable byproducts. To minimize by-products and increase yields, mild, chemoselective sulfonylating reagents should be used. The current review provides a historical and contemporary overview of dipeptide sulfonamides, their pharmacological profiles, Structure-Activity Relationships (SARs), therapeutic potential, current challenges, and future perspectives. Recent dipeptide sulfonamide analogues synthesized from 2018 to 2025 were reviewed. Being multifunctional therapeutic agents, dipeptide sulfonamides remain valuable scaffolds for drug development.