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 are synthesized and biologically evaluated for antimycobacterial, antibacterial, and antifungal activities. Biological evaluations reveal selective efficacy against Mycobacterium tuberculosis with minimum inhibitory concentrations (MICs) as low as 6.25 μg mL-1 for some derivatives, and this activity is preserved against drug-resistant 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-β-lactam PBP inhibitors, addressing the urgent need for new antitubercular therapies.

Department of Clinical Microbiology University Hospital Hradec Králové 500 05 Hradec Králové Czech Republic

Department of Pharmaceutical Sciences Università degli Studi di Milano 20133 Milano Italy

Faculty of Pharmacy in Hradec Králové Charles University 500 05 Hradec Králové Czech Republic

Zobrazit více v PubMed

Kumar Tiwary B., Pradhan K., Kumar Nanda A., Chakraborty R., in J. Chem. Biol. Ther. 2016, 1, 104.

Musiol R., Expert Opin. Drug Discovery 2017, 12, 583. PubMed

Malarz K., Mularski J., Pacholczyk M., Musiol R., J. Enzyme Inhib. Med. Chem. 2023, 38, 2201410. PubMed PMC

Gatadi S., Lakshmi T. V., Nanduri S., Eur. J. Med. Chem. 2019, 170, 157. PubMed

Babu R. R., Naresh K., Ravi A., Madhava Reddy B., Harinadha Babu V., Med. Chem. Res. 2014, 23, 4414.

Lu W., Baig I. A., Sun H.‐J., Cui C.‐J., Guo R., Jung I.‐P., Wang D., Dong M., Yoon M.‐Y., Wang J.‐G., Eur. J. Med. Chem. 2015, 94, 298. PubMed

Laleu B., Akao Y., Ochida A., Duffy S., Lucantoni L., Shackleford D. M., Chen G., Katneni K., Chiu F. C. K., White K. L., Chen X., Sturm A., Dechering K. J., Crespo B., Sanz L. M., Wang B., Wittlin S., Charman S. A., Avery V. M., Cho N., Kamaura M., J. Med. Chem. 2021, 64, 12582. PubMed

Zhu S., Wang J., Chandrashekar G., Smith E., Liu X., Zhang Y., Eur. J. Medicinal Chem. 2010, 45, 3864. PubMed PMC

Zayed M. F., J. Taibah Univ. Med. Sci. 2014, 9, 104.

Zhang H.‐J., Wang S.‐B., Quan Z.‐S., Mol Divers 2015, 19, 817. PubMed

Nowar R. M., Osman E. E. A, Abou‐Seri S. M., El Moghazy S. M., Abou El Ella D. A., Future Med. Chem. 2018, 10, 1191. PubMed

Azab M., El‐Hashash M., Morsy J., Mahmoud N., Heterocycles 2016, 92, 316.

Hassan R. M., Yehia H., El‐Behairy M. F., El‐Azzouny A. A.‐S., Aboul‐Enein M. N., Mol. DiversITY 2024, 29, 21. 10.1007/s11030-024-10830-y. PubMed DOI PMC

Gatadi S., Gour J., Kaul G., Shukla M., Dasgupta A., Akunuri R., Tripathi R., Madhavi Y. V., Chopra S., Nanduri S., Bioorg. Chem. 2018, 81, 175. PubMed

Gatadi S., Gour J., Shukla M., Kaul G., Das S., Dasgupta A., Malasala S., Borra R. S., Madhavi Y. V., Chopra S., Nanduri S., Eur. J. Med. Chem. 2018, 157, 1056. PubMed

Wang X., Yin J., Shi L., Zhang G., Song B., Eur. J. Med. Chem. 2014, 77, 65. PubMed

Tuberculosis (TB) , https://www.who.int/news‐room/fact‐sheets/detail/tuberculosis, (accessed: February 2025).

Kumar Pandey S., Yadava U., Upadhyay A., Sharma M. L., Bioorg. Chem. 2021, 108, 104611. PubMed

Al‐Deeb A. O., Alafeefy A. M., World Appl. Sci. J. 2008, 5, 94.

Pandit U., Dodiya A., Med. Chem. Res. 2013, 22, 3364.

Samotrueva M. A., Starikova A. A., Bashkina O. A., Tsibizova A. A., Borisov A. V., Merezhkina D. V., Tyurenkov I. N., Ozerov A. A., Dokl Chem 2023, 510, 107.

Sauvage E., Kerff F., Terrak M., Ayala J. A., Charlier P., FEMS Microbiol. Rev. 2008, 32, 234. PubMed

Bouley R., Ding D., Peng Z., Bastian M., Lastochkin E., Song W., Suckow M. A., Schroeder V. A., Wolter W. R., Mobashery S., Chang M., J. Med. Chem. 2016, 59, 5011. PubMed PMC

Fishovitz J., Hermoso J. A., Chang M., Mobashery S., IUBMB Life 2014, 66, 572. PubMed PMC

Janardhanan J., Bouley R., Martínez‐Caballero S., Peng Z., Batuecas‐Mordillo M., Meisel J. E., Ding D., Schroeder V. A., Wolter W. R., Mahasenan K. V., Hermoso J. A., Mobashery S., Chang M., Antimicrob. Agents Chemother. 2019, 63, e02637. PubMed PMC

Kang S.‐M., Kim D.‐H., IJMS 2024, 25, 983 (accessed: February 2025).

Ramachandran V., Chandrakala B., Kumar V. P., Usha V., Solapure S. M., De Sousa S. M., Antimicrob. Agents Chemother. 2006, 50, 1425. PubMed PMC

Filippova E. V., Kieser K. J., Luan C., Wawrzak Z., Kiryukhina O., Rubin E. J., Anderson W. F., The FEBS Journal 2016, 283, 2206. PubMed PMC

Patru M.‐M., Pavelka M. S., J Bacteriol 2010, 192, 3043. PubMed PMC

SwissADME: a free web tool to evaluate pharmacokinetics , drug‐likeness and medicinal chemistry friendliness of small molecules | Scientific Reports,” can be found under https://www.nature.com/articles/srep42717, (accessed: February 2025). PubMed PMC

WHO consolidated guidelines on tuberculosis . Module 4: treatment ‐ drug‐resistant tuberculosis treatment, 2022 update,” can be found under https://www.who.int/publications/i/item/9789240063129, (accessed: February 2025). PubMed