Rhomboid proteases form one of the most widespread intramembrane protease families. They have been implicated in variety of human diseases. The currently reported rhomboid inhibitors display some selectivity, but their construction involves multistep synthesis protocols. Here, we report benzoxazin-4-ones as novel inhibitors of rhomboid proteases with a covalent, but slow reversible inhibition mechanism. Benzoxazin-4-ones can be synthesized from anthranilic acid derivatives in a one-step synthesis, making them easily accessible. We demonstrate that an alkoxy substituent at the 2-position is crucial for potency and results in low micromolar inhibitors of rhomboid proteases. Hence, we expect that these compounds will allow rapid synthesis and optimization of inhibitors of rhomboids from different organisms.

• MeSH
• Bacillus subtilis enzymologie   MeSH
• benzoxaziny chemická syntéza   chemie   farmakologie   MeSH
• chymotrypsin antagonisté a inhibitory   MeSH
• DNA vazebné proteiny antagonisté a inhibitory   MeSH
• endopeptidasy MeSH
• enzymatické testy MeSH
• Escherichia coli enzymologie   MeSH
• inhibitory serinových proteinas chemická syntéza   chemie   farmakologie   MeSH
• inhibitory trypsinu chemická syntéza   chemie   farmakologie   MeSH
• membránové proteiny antagonisté a inhibitory   MeSH
• molekulární struktura MeSH
• ortoaminobenzoáty chemie   MeSH
• proteiny z Escherichia coli antagonisté a inhibitory   MeSH
• skot MeSH
• trypsin chemie   MeSH
• vztahy mezi strukturou a aktivitou MeSH
• zvířata MeSH
• Check Tag
• skot MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH