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This work focuses on the design, synthesis, and evaluation of novel quinazolinone\u2010based compounds and predicts their potential to interact with mycobacterial penicillin\u2010binding proteins (PBPs). Relying on established structure\u2013activity relationships of antibacterial quinazolinones, a total of 53 compounds belonging to three different structural types are synthesized and biologically evaluated for antimycobacterial, antibacterial, and antifungal activities. Biological evaluations reveal selective efficacy against <jats:italic>Mycobacterium tuberculosis<\/jats:italic> with minimum inhibitory concentrations (MICs) as low as 6.25 \u03bcg\u2009mL<jats:sup>\u22121<\/jats:sup> for some derivatives, and this activity is preserved against drug\u2010resistant strains. Molecular docking studies suggest a potential allosteric binding site in mycobacterial PBP 1A (PonA1, UniProt ID: P71707), and subsequential molecular dynamics confirm stable binding with key stabilizing interaction between the carbonyl oxygen of the quinazolinone and either ARG399 or ASP474. These findings suggest quinazolinone derivatives as viable candidates for further development as non\u2010\u03b2\u2010lactam PBP inhibitors, addressing the urgent need for new antitubercular therapies.<\/jats:p>","DOI":"10.1002\/cmdc.202500147","type":"journal-article","created":{"date-parts":[[2025,4,16]],"date-time":"2025-04-16T06:22:47Z","timestamp":1744784567000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Novel Quinazolinones Active against Multidrug\u2010Resistant <i>Mycobacterium Tuberculosis:<\/i> Synthesis, Antimicrobial Evaluation, and in Silico Exploration of Penicillin\u2010Binding Protein 1A as a Potential Target"],"prefix":"10.1002","volume":"20","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5850-5381","authenticated-orcid":false,"given":"Marek","family":"Kerda","sequence":"first","affiliation":[{"name":"Faculty of Pharmacy in Hradec Kr\u00e1lov\u00e9 Charles University  500 05 Hradec 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