Synthesis of 1,2,4‐Oxadiazole‐sulfonamide Conjugates and Their Synergistic Effect with Ampicillin as Antimicrobial Agents

In this investigation, we synthesized substituted 1,2,4‐oxadiazole‐sulfonamide conjugates (8 a–8 l) through a multistep synthetic approach. These compounds were then evaluated against six bacterial strains, consisting of three Gram‐positive and three Gram‐negative strains. Among them, compound 8 d displayed notable inhibitory activity, with minimum inhibitory concentration (MIC) values of 64 μg/mL observed against the Gram‐positive bacteria Staphylococcus aureus and Enterococcus faecalis. Notably, in the disk diffusion assay, compound 8 d exhibited the most substantial zone of inhibition (ZOI) against Escherichia coli and S. aureus, with respective ZOI measurements of 14 mm and 15 mm, both at a concentration of 2MIC. Additionally, supplementary investigations, including the Fractional Inhibitory Concentration Index (FICI) provided further support for the inhibitory potential of 8 d against the standard bacterial strains. When combined with Ampicillin (Amp), it demonstrated a synergistic effect, significantly augmenting its antibacterial activity against Klebsiella pneumoniae, Pseudomonas aeruginosa, and Enterococcus faecalis. Importantly, it exhibited no toxicity toward human red blood cells (hRBC). Furthermore, The Absorption, Distribution, Metabolism, and Excretion (ADME) profile of 8 d indicated its favorable drug‐like characteristics. A series of novel I,2,4‐oxadiazole sulfonamides were synthesized, characterized, and tested for antimicrobial activity. Compound 8 d emerged as the most potent one on which further antimicrobial studies were performed. Notably this compound demonstrated good antimicrobial activity against both the tested gram positive and negative bacterial strains.