Isocoumarins: a new class of selective carbonic anhydrase IX and XII inhibitors

Abstract

Isocoumarins, isomeric to comarins which act as effective carbonic anhydrase (CA, EC 4.2.1.1) inhibitors, were investigated for the first time as inhibitors of this enzyme. A series of 3-substituted and 3,4-disubstituted isocoumarins incorporating phenylhydrazone, 1-phenyl-pyrazole and pyrazolo-substituted pyrimidine trione/thioxo-pyrimidine dione moieties were investigated for their interaction with four human (h) CA isoforms, hCA I, II, IX and XII, known to be important drug targets. hCA I and II were not inhibited by these compounds, whereas hCA IX and XII were inhibited in the low micromolar range by the less bulky derivatives. The inhibition constants ranged between 2.7–78.9 µM against hCA IX and of 1.2–66.5 µM against hCA XII. As for the coumarins, we hypothesise that the isocoumarins are hydrolysed by the esterase activity of the enzyme with formation of 2-carboxy-phenylacetic aldehydes which act as CA inhibitors. Isocoumarins represent a new class of CA inhibitors.

Keywords:

• Carbonic anhydrase
• inhibitors
• isocoumarin
• carboxy-phenylacetic aldehydes

Acknowledgements

The authors thank Harran University Scientific Research Projects Coordination Department for financial support (HÜBAP, Project number: 21089). This research was also financed by the Italian Ministry for Education and Science (MIUR), grant PRIN: rot. 2017XYBP2R and by Ente Cassa di Risparmio di Firenze (ECRF), grant CRF2020.1395.

Disclosure 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.

Additional information

Funding

This research was financed by the Harran University Scientific Research Projects Coordination Department for financial support, The Italian Ministry for Education and Science (MIUR) [2017XYBP2R] and by Ente Cassa di Risparmio di Firenze (ECRF) [CRF2020.1395].