Design, synthesis, in vitro inhibition and toxicological evaluation of human carbonic anhydrases I, II and IX inhibitors in 5-nitroimidazole series

Ashok Aspatwar*, Nanda Kumar Parvathaneni, Harlan Barker, Emilie Anduran, Claudiu T. Supuran, Ludwig Dubois, Philippe Lambin, Seppo Parkkila, Jean-Yves Winum*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

10 Citations (Web of Science)

Abstract

With the aim to obtain novel compounds possessing both strong affinity against human carbonic anhydrases and low toxicity, we synthesised novel thiourea and sulphonamide derivatives 3, 4 and 10, and studied their in?vitro inhibitory properties against human CA I, CA II and CA IX. We also evaluated the toxicity of these compounds using zebrafish larvae. Among the three compounds, derivative 4 showed efficient inhibition against hCA II (KI = 58.6?nM). Compound 10 showed moderate inhibition against hCA II (KI = 199.2?nM) and hCA IX (KI = 147.3?nM), whereas it inhibited hCA I less weakly at micromolar concentrations (KI = 6428.4?nM). All other inhibition constants for these compounds were in the submicromolar range. The toxicity evaluation studies showed no adverse effects on the zebrafish larvae. Our study suggests that these compounds are suitable for further preclinical characterisation as potential inhibitors of hCA I, II and IX.

Original languageEnglish
Pages (from-to)109-117
Number of pages9
JournalJournal of Enzyme Inhibition and Medicinal Chemistry
Volume35
Issue number1
DOIs
Publication statusPublished - 1 Jan 2020

Keywords

  • Carbonic anhydrases
  • carbonic anhydrase inhibitors
  • synthesis
  • toxicity evaluation
  • lethal concentration
  • zebrafish embryos
  • HYPOXIA

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