A novel molecular design based on a quinazolinone scaffold was developed via the attachment of aryl alkanesulfonates to the quinazolinone core through a thioacetohydrazide azomethine linker, leading to a new series of quinazolinone-alkanesulfonates 5a-r. The antimicrobial properties of the newly synthesized quinazolinone derivatives 5a-r were investigated to examine their bactericidal and fungicidal activities against bacterial pathogens like Bacillus subtilis, Staphylococcus aureus (Gram-positive), Pseudomonas aeruginosa, Klebsiella pneumonia, Sallmonella Typhimurium (Gram-negative), in addition to Candida albicans (unicellular fungal). The tested compounds demonstrated reasonable bactericidal activities compared to standard drugs. Notably, derivatives 5g and 5k exhibited the greatest MIC values against Candida albicans, while 5g was the best against Staphylococcus aureus with MIC of 11.3 ± 2.38 μg mL-1, two-fold efficacy more than that was recorded with sulfadiazine. Furthermore, 5k significantly prevented biofilm formation for all bacterial pathogens, with a percentage ratio reaching 63.9%, surpassing the standard drug Ciprofloxacin. Additionally, 5k caused elevated lipid peroxidation (LPO) when added to the tested microbial pathogens. Confocal Laser Scanning Microscopy (CLSM) visualization revealed fewer live cells after treatment. Molecular docking studies showed that the quinazolinone derivatives bind strongly to the DNA gyrase enzyme, with the acid hydrazide core interacting effectively with key residues GLU50, ASN46, GLY77, and ASP136, consistent with their antimicrobial activity. Additionally, these compounds exhibited promising physicochemical properties, paving the way for discovering new antimicrobial drugs.
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