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.

Institute of Organic Chemistry and Biochemistry Academy of Sciences of the Czech Republic Flemingovo n 2 Prague 166 10 Czech Republic

KU Leuven University of Leuven Laboratory of Chemical Biology Department of Cellular and Molecular Medicine Herestraat 49 Box 802 3000 Leuven Belgium

KU Leuven University of Leuven Laboratory of Chemical Biology Department of Cellular and Molecular Medicine Herestraat 49 Box 802 3000 Leuven Belgium; Leibniz Institute for Analytical Sciences ISAS Otto Hahn Str 6b 44227 Dortmund Germany

Leibniz Institute for Analytical Sciences ISAS Otto Hahn Str 6b 44227 Dortmund Germany

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