Browsing by Person "Friedrich, Thorsten"

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    Exploring ND-011992, a quinazoline-type inhibitor targeting quinone reductases and quinol oxidases
    (2023) Kägi, Jan; Sloan, Willough; Schimpf, Johannes; Nasiri, Hamid R.; Lashley, Dana; Friedrich, Thorsten; Kägi, Jan; Institut für Biochemie, Albert-Ludwigs-Universität Freiburg, Freiburg, Germany; Sloan, Willough; Department of Chemistry, William & Mary, Williamsburg, USA; Schimpf, Johannes; Institut für Biochemie, Albert-Ludwigs-Universität Freiburg, Freiburg, Germany; Nasiri, Hamid R.; Department of Cellular Microbiology, University Hohenheim, Stuttgart, Germany; Lashley, Dana; Department of Chemistry, William & Mary, Williamsburg, USA; Friedrich, Thorsten; Institut für Biochemie, Albert-Ludwigs-Universität Freiburg, Freiburg, Germany
    Bacterial energy metabolism has become a promising target for next-generation tuberculosis chemotherapy. One strategy to hamper ATP production is to inhibit the respiratory oxidases. The respiratory chain of Mycobacterium tuberculosis comprises a cytochrome bcc:aa3 and a cytochrome bd ubiquinol oxidase that require a combined approach to block their activity. A quinazoline-type compound called ND-011992 has previously been reported to ineffectively inhibit bd oxidases, but to act bactericidal in combination with inhibitors of cytochrome bcc:aa3 oxidase. Due to the structural similarity of ND-011992 to quinazoline-type inhibitors of respiratory complex I, we suspected that this compound is also capable of blocking other respiratory chain complexes. Here, we synthesized ND-011992 and a bromine derivative to study their effect on the respiratory chain complexes of Escherichia coli. And indeed, ND-011992 was found to inhibit respiratory complex I and bo3 oxidase in addition to bd-I and bd-II oxidases. The IC50 values are all in the low micromolar range, with inhibition of complex I providing the lowest value with an IC50 of 0.12 µM. Thus, ND-011992 acts on both, quinone reductases and quinol oxidases and could be very well suited to regulate the activity of the entire respiratory chain.