TY  - JOUR
A1  - Elamri, Isam
A1  - Radloff, Melanie
A1  - Hohmann, Katharina Felicitas
A1  - Nimbarte, Vijaykumar D.
A1  - Mirzaei, Hamid Reza
A1  - Bolte, Michael
A1  - Safarian, Schara
A1  - Michel, Hartmut
A1  - Schwalbe, Harald
T1  - Synthesis and biological screening of new Lawson derivatives as selective substrate‐based inhibitors of cytochrome bo3 ubiquinol oxidase from escherichia coli
T2  - ChemMedChem
N2  - 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.
KW  - alkylation
KW  - cytochromes
KW  - hydroxynaphthoquinone
KW  - inhibitor design
KW  - oxidases
KW  - reductases
Y1  - 2020
UR  - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/56501
UR  - https://nbn-resolving.org/urn:nbn:de:hebis:30:3-565011
SN  - 1860-7187
VL  - 15
IS  - 14
SP  - 1262
EP  - 1271
PB  - Wiley-VCH GmbH
CY  - Weinheim
ER  -