Synthesis and biological screening of new Lawson derivatives as selective substrate‐based inhibitors of cytochrome bo3 ubiquinol oxidase from escherichia coli

The respiratory chain of Escherichia coli contains two different types of terminal oxidase that are differentially regulated as a response to changing environmental conditions. These oxidoreductases catalyze the reductio
The respiratory chain of Escherichia coli contains two different types of terminal oxidase that are differentially regulated as a response to changing environmental conditions. These oxidoreductases catalyze the reduction of molecular oxygen to water and contribute to the proton motive force. The cytochrome bo3 oxidase (cyt bo3) acts as the primary terminal oxidase under atmospheric oxygen levels, whereas the bd‐type oxidase is most abundant under microaerobic conditions. In E. coli, both types of respiratory terminal oxidase (HCO and bd‐type) use ubiquinol‐8 as electron donor. Here, we assess the inhibitory potential of newly designed and synthesized 3‐alkylated Lawson derivatives through L‐proline‐catalyzed three‐component reductive alkylation (TCRA). The inhibitory effects of these Lawson derivatives on the terminal oxidases of E. coli (cyt bo3 and cyt bd‐I) were tested potentiometrically. Four compounds were able to reduce the oxidoreductase activity of cyt bo3 by more than 50 % without affecting the cyt bd‐I activity. Moreover, two inhibitors for both cyt bo3 and cyt bd‐I oxidase could be identified. Based on molecular‐docking simulations, we propose binding modes of the new Lawson inhibitors. The molecular fragment benzyl enhances the inhibitory potential and selectivity for cyt bo3, whereas heterocycles reduce this effect. This work extends the library of 3‐alkylated Lawson derivatives as selective inhibitors for respiratory oxidases and provides molecular probes for detailed investigations of the mechanisms of respiratory‐chain enzymes of E. coli.
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Author:Isam Elamri, Melanie Radloff, Katharina F. Hohmann, Vijaykumar D. Nimbarte, Hamid Reza Mirzaei, Michael Bolte, Schara Safarian, Hartmut Michel, Harald Schwalbe
URN:urn:nbn:de:hebis:30:3-565011
DOI:http://dx.doi.org/10.1002/cmdc.201900707
ISSN:1860-7187
Parent Title (German):ChemMedChem
Publisher:Wiley-VCH GmbH
Place of publication:Weinheim
Document Type:Article
Language:English
Date of Publication (online):2020/03/11
Date of first Publication:2020/03/11
Publishing Institution:Universitätsbibliothek Johann Christian Senckenberg
Release Date:2020/12/08
Tag:alkylation; cytochromes; hydroxynaphthoquinone; inhibitor design; oxidases; reductases
Volume:15
Issue:14
Pagenumber:10
First Page:1262
Last Page:1271
HeBIS PPN:477032397
Institutes:Biochemie und Chemie
Dewey Decimal Classification:540 Chemie und zugeordnete Wissenschaften
570 Biowissenschaften; Biologie
Sammlungen:Universitätspublikationen
Licence (German):License LogoCreative Commons - Namensnennung 4.0

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