Abstract: Reaction of p-toluenesulfonyl chloride with amino acids gave sulfonamides p-T1a-k which upon amidation afforded p-T2a-k. Similarly, treatment involving α-toluenesulfonyl chloride and amino acids afforded the sulfonamides α-T1a-k. These two classes of sulfonamides were synthetically modified at their COOH end position to achieve N,N-diethylamido substituted p-toluenesulfonamides p-T2a-k and α-toluenesulfonamides α-T2a-k, respectively. The chemical structures of the compounds were validated with IR, Mass spectra, NMR as well as elemental analytical data. Both classes of compounds were screened against Escherichia coli and Staphylococcus aureus and their activity were compared. It was remarkable to note that the α-toluene sulfonamides α-T2a-k were more active than their p-toluenesulfonamide counterparts p-T2a-k. Compound 1-(benzylsulfonyl)-N,N-diethylpyrrolidine-2-carboxamide α-T2a was the most potent antibacterial compound on S. aureus with MIC value of 3.12 μg mL-1 while N,N-Diethyl-3-phenyl-2-(phenylmethylsulfonamide) propanamide α-T2j emerged as the best antibacterial motif against E. coli with MIC value of 12.5 μg mL-1. Hence, these compounds especially the α-toluenesulfonamide core structural templates are good candidates for further study for future drug discovery.