Synthesis and Biological Screening of New Lawson Derivatives as Selective Substrate‐Based Inhibitors of Cytochrome bo₃ Ubiquinol Oxidase from Escherichia coli

Abstract

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.

Short-chain aurachin D derivatives are selective inhibitors of E. coli cytochrome bd-I and bd-II oxidases

“…For bo 3 —oxidase production a protocol from 33 was used. Purification protocol was modified according to 33 and described in detail in 34 .…”

Concise Synthesis of 1,4‐Benzoquinone‐Based Natural Products as Mitochondrial Complex I Substrates and Substrate‐Based Inhibitors

“…Furthermore, as a result of the introduction of the epoxy group, it was expected that 1 i would have an increased solubility compared to compound 1 f. Compound 1 i was synthesized by the epoxidation of 1 f in 27 % isolated yield. The solubility of compound i was measured experimentally by an absorbance-based solubility assay [32] and compared to 1 f ( Figure 5). First, the maximum peaks of the absorbance spectra for both compounds were determined (1 f λ = 275 nm; 1 i λ = 415 nm).…”