Dehydroacetic acid (DHA) is a significant heterocyclic mol. whose derivatives are highly prevalent.Thus, a new series of heterocyclic derivatives starting from dehydroacetic acid were synthesized and investigated for their antimicrobial and antioxidant activities.The antimicrobial activity of the twenty-one new compounds was determined against S. aureus ATCC 6538-P, E. coli ATCC 25922, C. albicans ATCC 10231, and A. niger NRRL A-326.Out of twenty one compounds, 7a, 8a, 9, 10d and 14 showed promising in vitro antimicrobial activity.Compounds 7a, 8a, and 10d were equipotent to ciprofloxacin reference drug against S. aureus, while compounds 9 and 14 were 4-fold and 2-fold higher than ciprofloxacin, resp.For E. coli, compounds 9 and 10d were equipotent to ciprofloxacin whereas compounds 7a, 8a, and 14 were 4-fold, 8-fold, and 2-fold higher than ciprofloxacin, resp.Regarding C. albicans,7a showed moderate activity with 2-fold lower than nystatin (reference drug).To further analyze the antimicrobial potential of the compounds (7a, 8a, 9, 10d, and 14), their in vitro inhibitory activity against E. coli DNA gyrase was evaluated.The results revealed that compound 8a showed the lowest IC50 required for DNA gyrase inhibition almost similar IC50 to ciprofloxacin.A mol. docking study was established to assess the binding mode of 8a, the most active derivative, with the crystal structure of DNA gyrase B (PDB: 5MMN). 8a demonstrated a good binding mode inside the active pocket of the DNA gyrase B with good binding energy value.Addnl., 8a displayed the highest antioxidant activity compared with ascorbic acid.Collectively, the compound 8a is a highly promising antimicrobial candidate for further studies.