Sulfonamides in Drug Discovery: A Review of Synthetic Approaches and Biological Activities

Sulfonamides represent one of the most versatile scaffolds in medicinal chemistry. Since their introduction as the first synthetic antibacterial agents in the 1930s, the sulfonamide functional group (–SO₂NR₂) has enabled extensive structural diversification, leading to compounds with broad therapeutic applications. In recent years, sulfonamide derivatives have gained renewed attention in drug discovery due to their roles in antimicrobial, anticancer, antimalarial, antiviral, antiinflammatory, antidiabetic, and antioxidant therapies. This review provides a comprehensive and structured overview of modern synthetic strategies for sulfonamide construction, including classical sulfonyl chloride–amine coupling, metal-catalyzed synthesis of sulfonamides, microwave-assisted synthesis, and other advanced methodologies that enable efficient access to structurally diverse derivatives. In parallel, recent advances in the biological evaluation of sulfonamide analogues are discussed, with emphasis on emerging pharmacological targets and mechanistic insights, such as enzyme inhibition, metabolic interference, and receptor modulation. By correlating synthetic approaches with observed biological activities, this review highlights the structure–activity relationships that guide rational drug design. Current challenges, research gaps, and future perspectives for sulfonamide-based therapeutics are also outlined. Collectively, the adaptability of the sulfonamide scaffold, combined with continued advances in synthetic chemistry and biological screening, underscores its sustained importance in the development of next-generation therapeutic agents.