Antimicrobial Potential of Novel Quinazolin‐2,4‐dione Derivatives Bearing One and/or Two Amide Moieties: In Vitro Evaluation, Molecular Docking, and Semiempirical Calculations

The increase in microbial infections worldwide suggests that new drug candidates for combating infectious diseases caused by microbial pathogens are urgently needed. Quinazolin‐2,4‐diones are well‐known for their potential activities as antibacterial and antifungal agents, making them crucial in pharmaceutical chemistry. The synthesis of quinazolin‐2,4‐diones incorporating bridgehead amide moiety has garnered significant interest due to their wide‐ranging applications in different biological and pharmaceutical fields. Herein, the present study focuses on the synthesis and evaluation of novel quinazolin‐2,4‐dione derivatives linked to one and/or two amide moieties through methylene linkage 2a–d–4a–d , for their antimicrobial potential against pathogen strains, Gram‐negative bacteria ( Escherichia coli ATCC 25955 and Pseudomonas aeruginosa ATCC 10145), two Gram‐positive bacteria ( Bacillus subtilis ATCC 6633 and Staphylococcus aureus NRRL B‐767) and unicellular fungi ( Candida albicans ATCC 10231). The biological evaluation revealed that compounds 2b , 2c , and 4c exhibited the most potent antimicrobial activity. Subsequently, the newly synthesized compounds were characterized by IR, 1 H and 13 C NMR, and mass spectral analysis. In addition, molecular docking studies indicated that the potent compounds 2b , 2c , and 4c have the lowest binding energies (better than reference drugs) and favorable intermolecular interactions with the active site residues of the target enzymes S. aureus gyrase B and Human 14α‐demethylase. The semiempirical computations were performed to evaluate the structural confirmation and chemical reactivity behavior of the quinazolin‐2,4‐dione skeleton. The obtained results suggest that compounds 2b , 2c , and 4c are promising lead compounds for further development of new potent antimicrobial inhibitors.