Inhibition survey with phenolic compounds against the δ- and η-class carbonic anhydrases from the marine diatom thalassiosira weissflogii and protozoan Plasmodium falciparum

J Enzyme Inhib Med Chem. 2020 Dec;35(1):377-382. doi: 10.1080/14756366.2019.1706089.

Abstract

The inhibition of δ- and η-class carbonic anhydrases (CAs; EC 4.2.1.1) was poorly investigated so far. Only one δ-CA, TweCA from the diatom Thalassiosira weissflogii, and one η-CA, PfCA, from Plasmodium falciparum, have been cloned and characterised to date. To enrich δ- and η-CAs inhibition profiles, a panel of 22 phenols was investigated for TweCA and PfCA inhibition. Some derivatives showed effective, sub-micromolar inhibition of TweCA (KIs 0.81-65.4 µM) and PfCA (KIs 0.62-78.7 µM). A subset of compounds demonstrated a significant selectivity for the target CAs over the human physiologically relevant ones. This study promotes the identification of new potent and selective inhibitors of TweCA and PfCA, which could be considered as leads for finding molecular probes in the study of carbon fixation processes (in which TweCA and orthologue enzymes are involved) or drug candidates in the treatment of malaria.

Keywords: Diatom; inhibition; metalloenzyme; protozoan; δ-/η-class.

MeSH terms

  • Antiprotozoal Agents / chemical synthesis
  • Antiprotozoal Agents / chemistry
  • Antiprotozoal Agents / pharmacology*
  • Carbonic Anhydrase Inhibitors / chemical synthesis
  • Carbonic Anhydrase Inhibitors / chemistry
  • Carbonic Anhydrase Inhibitors / pharmacology*
  • Carbonic Anhydrases / metabolism*
  • Diatoms / enzymology*
  • Dose-Response Relationship, Drug
  • Humans
  • Molecular Structure
  • Parasitic Sensitivity Tests
  • Phenols / chemical synthesis
  • Phenols / chemistry
  • Phenols / pharmacology*
  • Plasmodium falciparum / drug effects*
  • Plasmodium falciparum / enzymology
  • Structure-Activity Relationship

Substances

  • Antiprotozoal Agents
  • Carbonic Anhydrase Inhibitors
  • Phenols
  • Carbonic Anhydrases

Grants and funding

This work was funded by the Deanship of Scientific Research at Princess Nourah bint Abdulrahman University, through the Research Groups Programme Grant no. [RGP-1440–0024].