Novel quinazolinones active against multidrug‐resistant Mycobacterium tuberculosis: synthesis, antimicrobial evaluation and in silico exploration of PonA1 as a potential target

Quinazolinone derivatives have emerged as promising scaffolds in antimicrobial drug discovery. This work focuses on the design, synthesis, and evaluation of novel quinazolinone-based compounds and predicts their potential to interact with mycobacterial penicillin-binding proteins (PBPs). Relying on established structure-activity relationships of antibacterial quinazolinones, a total of 53 compounds belonging to three different structural types were synthesized and biologically evaluated for antimycobacterial, antibacterial, and antifungal activities. Biological evaluations revealed selective efficacy against Mycobacterium tuberculosis with minimum inhibitory concentrations (MICs) as low as 6.25 µg/mL for some derivatives, and this activity was preserved against drug-resistant strains. Molecular docking studies suggested a potential allosteric binding site in mycobacterial Penicillin-binding protein 1A (PonA1, UniProt ID: P71707), and subsequential molecular dynamics confirmed 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-β-lactam PBP inhibitors, addressing the urgent need for new antitubercular therapies.