As part of our endeavor to synthesize a new series of biologically effective heterocyclic hybrids, we present various methods for one-pot three-component synthesis. The thiazolidin-4-ones (4a-i) with sulfonamide bioactive moieties were synthesized in reasonable yields by reacting sulfadiazine (1) with various substituted benzaldehydes (2a-i) and mercaptoacetic acid (3). The spectral data all agreed on all titled compounds. Assessment of their in vitro antimicrobial activity was employed by a microdilution technique, the newly synthesized compounds screened significant growth suppression against resistant strains. All compounds exhibited acceptable DPPH Radical Scavenging Activity. To investigate possible binding mechanisms for the Staphylococcus aureus MurB protein (ID Code: 1HSK), in silico molecular docking was carried out. Furthermore, The Lipinski rule of five was observed in synthesized compounds with good ADME predictions. Lastly, the DFT/B3LYP principle and the 6-31 G (d, p) base set were used to compute HUMO, LUMO, MEP analysis, and quantum parameters.