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. 2024 Oct 31;29(21):5143.
doi: 10.3390/molecules29215143.

Beware of N-Benzoyloxybenzamides

Jonathan Cubitt  1 , Mari Davies  1 , Ross Riseley  1 , Gabrielle Evans  1 , Sian E Gardiner  1 , Benson M Kariuki  1 , Simon E Ward  1 , Emyr Lloyd-Evans  1 , Helen Waller-Evans  1 , D Heulyn Jones  1   2
Affiliations

Beware of N-Benzoyloxybenzamides

Jonathan Cubitt et al. Molecules. .

Abstract

Following a High-Throughput Screening campaign to discover inhibitors of acid ceramidase, we report the novel and extremely potent covalent inhibitor, 1. Following resynthesis and stability monitoring, we discovered that 1 is chemically unstable and reacts with DMSO at room temperature. This mode of decomposition is likely general for this class of compound, and we urge caution for their use in drug discovery research.

Keywords: N-benzoyloxybenzamides; PAINS; acid ceramidase.

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Conflict of interest statement

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Figures

Figure 1
Figure 1
Chemical structures and HTS IC50 curves.
Figure 2
Figure 2
Examples of biologically active hydroxamic acids and the Lossen rearrangement reaction.
Scheme 1
Scheme 1
Hydrolysis of isocyanate 7.
Scheme 2
Scheme 2
Synthesis of hit compound 1.
Figure 3
Figure 3
Single-crystal X-ray structure and dose–response curve of 1 in cell lysate assay.
Figure 4
Figure 4
1H and 19F NMR studies monitoring the reaction of 1 with d6-DMSO.
Scheme 3
Scheme 3
Degradation of 1 in DMSO.
Figure 5
Figure 5
Preincubation experiment at IC50 concentration.
See this image and copyright information in PMC

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