Sulfonamide drugs which have brought about an antibiotic revolution in medicine are associated with a wide range of biological activities. We have synthesized a series of α-tolylsulfonamide, 1–11 and their substituted N,N-diethyl-2-(phenylmethylsulfonamido) alkanamide derivatives, 12–22 in improved and excellent yields in aqueous medium at room temperature through highly economical synthetic routes. The chemical structures of the synthesized compounds 1–22 were confirmed by analytical and spectral data such as IR, 1H- and 13C-NMR, and mass spectra. The in vitro antibacterial activity of these compounds along with standard clinical reference, streptomycin, was investigated on two key targeted organisms. It was observed that 1-(benzylsulfonyl)pyrrolidine-2-carboxylic acid, 2 emerged as the most active compound against Staphylococcus aureus at MIC value of 1.8？μg/mL while 4-(3-(diethylamino)-3-oxo-2-(phenylmethylsulfonamido) propyl)phenyl phenylmethanesulfonate, 22 was the most active sulfonamide scaffold on Escherichia coli at MIC value of 12.5？μg/mL. 1. Introduction The development of sulfonamides is a fascinating and informative area in medicinal chemistry [1–3]. Its functional group has a long and rich history in organic chemistry and drug discovery [4, 5]. The p-toluenesulfonamide and benzenesulfonamides have been widely explored in synthetic chemistry [4, 5]; however, few work has been done on the α-tolylsulfonamide. For instance, synthesis of benzenesulfonamide derivative of pipecolic acid [6] and that of glycine [7] had been reported. In addition, benzenesulfonamide of alanine was achieved as a result of synthetic usage of such amino acid as a linker to 6H-1,3,4-thiadiazine scaffold [8] while naphthylsulfonamide was prepared as antagonist of chemokine receptor [9]. Domagk’s discovery of antibacterial activity for the azo dye prontosil led to the first effective chemotherapeutic agent, sulfanilamide [10]. A retrospective look at sulfonamides leaves no doubt that besides providing the first effective treatment of bacterial infections [10, 11], they also unleashed an antibiotic revolution in medicine [12–15] to rationally design new therapeutic agents [16, 17]. These compounds provided an excellent lead for structural modification and ushered in the modern era of chemotherapy and drug design. Sulfonamides inhibit the multiplication of bacteria by acting as competitive inhibitors of p-aminobenzoic acid (PABA) in the folic acid metabolism cycle [18, 19]. In fact, the discovery that sulfonamides act through folate inhibition resulted in the development
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