Coumarins effectively inhibit bacterial α-carbonic anhydrases

• Published in: Journal of enzyme inhibition and medicinal chemistry 2022-12, Vol.37 (1), p.333-338
• Main Authors: Giovannuzzi, Simone, Hewitt, Chad S., Nocentini, Alessio, Capasso, Clemente, Flaherty, Daniel P., Supuran, Claudiu T.
• Format: Article
• Language: English
• Subjects: Anti-Bacterial Agents - chemical synthesis; Anti-Bacterial Agents - chemistry; Anti-Bacterial Agents - pharmacology; Antibacterial agents; antibacterials; Bacteria; Carbonic anhydrase; Carbonic Anhydrase Inhibitors - chemical synthesis; Carbonic Anhydrase Inhibitors - chemistry; Carbonic Anhydrase Inhibitors - pharmacology; Carbonic anhydrases; Carbonic Anhydrases - metabolism; Carboxylic acids; Coumarin; coumarins; Coumarins - chemical synthesis; Coumarins - chemistry; Coumarins - pharmacology; Dose-Response Relationship, Drug; Drug resistance; Enzymes; Functional foods & nutraceuticals; Gonorrhea; Humans; Hydration; inhibitor; Isoforms; Microbial Sensitivity Tests; Molecular Structure; Neisseria gonorrhoeae; Neisseria gonorrhoeae - drug effects; Neisseria gonorrhoeae - enzymology; Pathogens; Pharmaceutical sciences; Research Paper; Structure-Activity Relationship; Vibrio cholerae - drug effects; Vibrio cholerae - enzymology
• ISSN: 1475-6366; 1475-6374
• DOI: 10.1080/14756366.2021.2012174

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 K I s in the range of 28.6-469.5 µM, whereas VchCAα with K I s 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 K I s 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.