The reactivity of 2-bromo-N-(phenylsulfonyl)acetamide derivatives 3a-c towards some nitrogen-based nucleophiles was studied in this investigation and gave the corresponding aminothiazole 6a-c, amino-oxazole 7a-c, quinazoline-2-yl 10a-c; respectively. Furthermore, the reaction of acetamide derivatives 3a-c with aminopyridine gave pyridine-4-ylamino 12a-c. Reaction of acetamide derivatives 3a-c with benzo-2-thiol derivatives afforded benzo [d] thiazol-2-ylthio 14a-c and 1H-benzo[d]imidazol-2-yl)thio derivatives 16a-c; respectively. The synthesized compounds displayed good antimicrobial activity. Additionally, compounds 12a and 14a exhibited high activity towards most of the strains. The computational calculations for 12a and 14a were carried out via HF/6-31G(d) and DFT B3LYP/6-31G(d) basis sets and the corresponding results of HOMO–LUMO energy gap and Mulliken atomic charges were tabulated. This correlation between experimental and theoretical calculations provided a good confirmation for anticipated new compounds.