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. 2022 Dec;37(1):680-685.
doi: 10.1080/14756366.2022.2036986.

Coumarins inhibit η-class carbonic anhydrase from Plasmodium falciparum

Simone Giovannuzzi  1 , Viviana De Luca  2 , Alessio Nocentini  1 , Clemente Capasso  2 , Claudiu T Supuran  1
Affiliations

Coumarins inhibit η-class carbonic anhydrase from Plasmodium falciparum

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

Abstract

Coumarins were discovered to act as inhibitors of α-carbonic anhydrases (CAs, EC 4.2.1.1) after undergoing hydrolysis mediated by the esterase activity of the enzyme to the corresponding 2-hydroxycinnamic acids. Other classes of CAs among the eight currently known do not possess esterase activity or this activity was poorly investigated. Hence, we decided to look at the potential of coumarins as inhibitors of the η-CA from the malaria-producing protozoan Plasmodium falciparum, PfaCA. A panel of simple coumarins incorporating hydroxyl, amino, ketone or carboxylic acid ester moieties in various positions of the ring system acted as low to medium micromolar PfaCA inhibitors, whereas their affinities for the cytosolic off-target human isoforms hCA I and II were in a much higher range. Thus, we confirm that η-CAs possess esterase activity and that coumarins effectively inhibit this enzyme. Elaboration of the simple coumarin scaffolds investigated here may probably lead to more effective PfaCA inhibitors.

Keywords: Carbonic anhydrase; Plasmodium falciparum; anti-protozoal agents; 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.
Homology modelling and coordination of the zinc ion in the active site of PfaCA. The zinc ion (central grey sphere) is coordinated by the imidazole moieties of residues His299, His301 and the nitrogen from the CONH2 moiety of Gln320. The numbering of the amino acid residues is not shown for the sake of simplicity, but the 61 amino acid residues insertion which could not be modelled is highlighted in blue. The protein backbone is shown in green.
See this image and copyright information in PMC

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Grants and funding

CC and CTS thank the Italian Ministry for University and Research (MIUR), project [FISR2019_04819 BacCAD].

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