Novel Quinazolinones Active against Multidrug-Resistant Mycobacterium Tuberculosis: Synthesis, Antimicrobial Evaluation, and in Silico Exploration of Penicillin-Binding Protein 1A as a Potential Target

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F00179906%3A_____%2F25%3A10499788" target="_blank" >RIV/00179906:_____/25:10499788 - isvavai.cz</a>

Nalezeny alternativní kódy

RIV/00216208:11160/25:10499788

Výsledek na webu

<a href="https://verso.is.cuni.cz/pub/verso.fpl?fname=obd_publikace_handle&handle=BWYhXnXDmR" target="_blank" >https://verso.is.cuni.cz/pub/verso.fpl?fname=obd_publikace_handle&handle=BWYhXnXDmR</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1002/cmdc.202500147" target="_blank" >10.1002/cmdc.202500147</a>

Jazyk výsledku

angličtina

Název v původním jazyce

Novel Quinazolinones Active against Multidrug-Resistant Mycobacterium Tuberculosis: Synthesis, Antimicrobial Evaluation, and in Silico Exploration of Penicillin-Binding Protein 1A as a Potential Target

Popis výsledku v původním jazyce

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 mu g 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-beta-lactam PBP inhibitors, addressing the urgent need for new antitubercular therapies.

Název v anglickém jazyce

Novel Quinazolinones Active against Multidrug-Resistant Mycobacterium Tuberculosis: Synthesis, Antimicrobial Evaluation, and in Silico Exploration of Penicillin-Binding Protein 1A as a Potential Target

Popis výsledku anglicky

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 mu g 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-beta-lactam PBP inhibitors, addressing the urgent need for new antitubercular therapies.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

30104 - Pharmacology and pharmacy

Projekt

—

Návaznosti

I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Rok uplatnění

2025

Kód důvěrnosti údajů

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Název periodika

ChemMedChem

ISSN

1860-7179

e-ISSN

1860-7187

Svazek periodika

20

Číslo periodika v rámci svazku

13

Stát vydavatele periodika

DE - Spolková republika Německo

Počet stran výsledku

12

Strana od-do

e202500147

Kód UT WoS článku

001507990500001

EID výsledku v databázi Scopus

2-s2.0-105006847508