1. Academic Validation
  2. Exploring ND-011992, a quinazoline-type inhibitor targeting quinone reductases and quinol oxidases

Exploring ND-011992, a quinazoline-type inhibitor targeting quinone reductases and quinol oxidases

  • Sci Rep. 2023 Jul 28;13(1):12226. doi: 10.1038/s41598-023-39430-w.
Jan Kägi 1 Willough Sloan 2 Johannes Schimpf 1 Hamid R Nasiri 3 Dana Lashley 4 Thorsten Friedrich 5
Affiliations

Affiliations

  • 1 Institut für Biochemie, Albert-Ludwigs-Universität Freiburg, Freiburg, Germany.
  • 2 Department of Chemistry, William & Mary, Williamsburg, VA, USA.
  • 3 Department of Cellular Microbiology, University Hohenheim, Stuttgart, Germany.
  • 4 Department of Chemistry, William & Mary, Williamsburg, VA, USA. dlashley@wm.edu.
  • 5 Institut für Biochemie, Albert-Ludwigs-Universität Freiburg, Freiburg, Germany. Friedrich@bio.chemie.uni-freiburg.de.
Abstract

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.

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