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. 2023 Jul 28;13(1):12226.
doi: 10.1038/s41598-023-39430-w.

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

Jan Kägi  1 , Willough Sloan  2 , Johannes Schimpf  1 , Hamid R Nasiri  3 , Dana Lashley  4 , Thorsten Friedrich  5
Affiliations

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

Jan Kägi et al. Sci Rep. .

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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Conflict of interest statement

The authors declare no competing interests.

Figures

Figure 1
Figure 1
Structures and calculated partition coefficients (CLogP) of EVP4593, Telacebec, ND-011992 (1) and bromine derivative (2).
Figure 2
Figure 2
One-step synthesis of ND-011992 (1) and bromine derivative (2).
Figure 3
Figure 3
Proposed mechanism for the formation of ND-011992 (1) and bromine derivative (2).
Figure 4
Figure 4
Oxidoreductase activities of E. coli BL21*Δcyo membranes at various concentrations of ND-011992. (a) NADH oxidase activity, (b) d-NADH oxidase activity and (c) d-NADH:decyl-ubiquinone oxidoreductase activity of E coli CBO membranes plotted against concentration of ND-011992.
Figure 5
Figure 5
Duroquinol:oxygen oxidoreductase activity of isolated terminal E. coli oxidases at various concentrations of ND-011992 and compound 2. (a) and (b) show the inhibition of bd-I and bd-II oxidases by ND-011992. (c) and (d) show the inhibition of bd-I and bd-II oxidases by 2. Inhibition of bo3 oxidase with ND-011992 is shown in (e).
Figure 6
Figure 6
NADH oxidase activity of bovine mitochondrial membranes at various concentrations of ND-011992.
See this image and copyright information in PMC

References

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