A novel 1-benzoazepine-derived Michael acceptor and its hetero-adducts active against MRSA

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F00216208%3A11310%2F24%3A10490780" target="_blank" >RIV/00216208:11310/24:10490780 - isvavai.cz</a>

Výsledek na webu

<a href="https://verso.is.cuni.cz/pub/verso.fpl?fname=obd_publikace_handle&handle=ZIK.J3Q7kO" target="_blank" >https://verso.is.cuni.cz/pub/verso.fpl?fname=obd_publikace_handle&handle=ZIK.J3Q7kO</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1039/d4ob01501k" target="_blank" >10.1039/d4ob01501k</a>

Jazyk výsledku

angličtina

Název v původním jazyce

A novel 1-benzoazepine-derived Michael acceptor and its hetero-adducts active against MRSA

Popis výsledku v původním jazyce

Multidrug-resistant bacterial infections continue to be a rising global health concern. Herein, we describe the development of a novel class of 3-substituted benzoazepinedione derivatives with promising antibacterial activity. The pivotal compound, benzoazepinedione carboxylate 9, represents a highly electrophilic Michael acceptor, enabling divergent access to a wide range of thia-, aza-, oxa-, and phospha-Michael adducts. Notably, most prepared compounds exhibited potent antibacterial activity against both drug-susceptible and drug-resistant strains of Staphylococcus aureus (MIC(90) of up to 2 μg mL(-1)). The cytotoxicity assessment in the VERO6 cell line revealed that thia-adduct 10d (IC(50) of 36.5 μg mL(-1)) exhibits lower toxicity compared to its parent electrophile 9 (IC(50) of 14.3 μg mL(-1)), which is in agreement with the hypothesis of covalently modified prodrugs. Additionally, stability studies of the prepared compounds in CD3OD and a DMSO-PBS mixture confirmed that thia-Michael adducts 10 are stable under neutral conditions while dynamic under mildly basic conditions. Moreover, 3D reconstructed tissue models (human lung epithelial EpiAirway (TM) and a human small intestine model) did not exhibit a viability decrease below 80% of the untreated control at all concentrations tested, indicating tolerance to higher concentrations of potential drugs and prodrugs.

Název v anglickém jazyce

A novel 1-benzoazepine-derived Michael acceptor and its hetero-adducts active against MRSA

Popis výsledku anglicky

Multidrug-resistant bacterial infections continue to be a rising global health concern. Herein, we describe the development of a novel class of 3-substituted benzoazepinedione derivatives with promising antibacterial activity. The pivotal compound, benzoazepinedione carboxylate 9, represents a highly electrophilic Michael acceptor, enabling divergent access to a wide range of thia-, aza-, oxa-, and phospha-Michael adducts. Notably, most prepared compounds exhibited potent antibacterial activity against both drug-susceptible and drug-resistant strains of Staphylococcus aureus (MIC(90) of up to 2 μg mL(-1)). The cytotoxicity assessment in the VERO6 cell line revealed that thia-adduct 10d (IC(50) of 36.5 μg mL(-1)) exhibits lower toxicity compared to its parent electrophile 9 (IC(50) of 14.3 μg mL(-1)), which is in agreement with the hypothesis of covalently modified prodrugs. Additionally, stability studies of the prepared compounds in CD3OD and a DMSO-PBS mixture confirmed that thia-Michael adducts 10 are stable under neutral conditions while dynamic under mildly basic conditions. Moreover, 3D reconstructed tissue models (human lung epithelial EpiAirway (TM) and a human small intestine model) did not exhibit a viability decrease below 80% of the untreated control at all concentrations tested, indicating tolerance to higher concentrations of potential drugs and prodrugs.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

10401 - Organic chemistry

Projekt

—

Návaznosti

I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Rok uplatnění

2024

Kód důvěrnosti údajů

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

Název periodika

Organic and Biomolecular Chemistry

ISSN

1477-0520

e-ISSN

1477-0539

Svazek periodika

22

Číslo periodika v rámci svazku

48

Stát vydavatele periodika

GB - Spojené království Velké Británie a Severního Irska

Počet stran výsledku

9

Strana od-do

9394-9402

Kód UT WoS článku

001345178900001

EID výsledku v databázi Scopus

2-s2.0-85208981641