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. 2022 Dec;37(1):333-338.
doi: 10.1080/14756366.2021.2012174.

Coumarins effectively inhibit bacterial α-carbonic anhydrases

Simone Giovannuzzi  1 , Chad S Hewitt  2 , Alessio Nocentini  1 , Clemente Capasso  3 , Daniel P Flaherty  2   4   5 , Claudiu T Supuran  1
Affiliations

Coumarins effectively inhibit bacterial α-carbonic anhydrases

Simone Giovannuzzi et al. J Enzyme Inhib Med Chem. 2022 Dec.

Abstract

Coumarins are known to act as prodrug inhibitors of mammalian α-carbonic anhydrases (CAs, EC 4.2.1.1) but they were not yet investigated for the inhibition of bacterial α-CAs. Here we demonstrate that such enzymes from the bacterial pathogens Neisseria gonorrhoeae (NgCAα) and Vibrio cholerae (VchCAα) are inhibited by a panel of simple coumarins incorporating hydroxyl, amino, ketone or carboxylic acid ester moieties in various positions of the ring system. The nature and the position of the substituents in the coumarin ring were the factors which strongly influenced inhibitory efficacy. NgCAα was inhibited with KIs in the range of 28.6-469.5 µM, whereas VchCAα with KIs in the range of 39.8-438.7 µM. The two human (h)CA isoforms included for comparison reason in the study, hCA I and II, were less prone to inhibition by these compounds, with KIs of 137-948.9 µM for hCA I and of 296.5-961.2 µM for hCA II, respectively. These findings are relevant for discovering coumarin bacterial CA inhibitors with selectivity for the bacterial over human isoform, with potential applications as novel antibacterial agents.

Keywords: Carbonic anhydrase; Neisseria gonorrhoeae; antibacterials; coumarins; inhibitor.

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Conflict of interest statement

CT Supuran is Editor-in-Chief of the Journal of Enzyme Inhibition and Medicinal Chemistry. He was not involved in the assessment, peer review, or decision-making process of this paper. The authors have no relevant affiliations of financial involvement with any organisation or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Figures

Figure 1.
Figure 1.
Surface representation of hCA II in adduct with the superimposed hydrolized (and active) coumarin species (cyan from 5BNL, green from PDB 3F8E). The hydrophobic half of the active site is coloured in red, the hydrophilic one in blue. His64, the proton shuttle residue, is in green.
See this image and copyright information in PMC

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