Bioisosteric replacement serves as a fundamental approach in modern synthetic and medicinal chemistry, plays a pivotal role in the design of mimetics. This approach has garnered widespread recognition in the scientific community due to the extensive practical application in the development of next-generation pharmaceuticals. Numerous studies show that the incorporation of bioisosteric moieties leads to enhanced selectivity, pharmacokinetic properties, as well as affinity and efficacy of drug candidates. The ubiquitous presence of the amide group within important natural and synthetic molecules has made it one of the most prevalent structural motifs among FDA-approved drugs. This fact advocates the reasonable exploration of isosters of amides in classical and modern drug design. Among these analogs, the S(VI)-containing sulfonamide moiety emerges as the most commonly utilized isostere of the amide bond, as supported by various physicochemical parameters (Figure ). The discovery of sulfanilamide 1 in 1908 and subsequent research on prontosil 2 in 1932, both containing the SO2NH2 group, marked a seminal milestone in drug development. Sulfonamides have since emerged as essential compounds in the pursuit of novel therapeutics, with approximately a hundred FDA-approved drugs currently available on the pharmaceutical market (Figure ). The aformentioned derivatives made a class of sulfonamide antibiotics (known as "sulfa drugs"), which was then expanded by derivatives extensively used for several decades, e.g. sulfamethoxazole 3, acetazolamide 4, and celecoxib 5.