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

doi:10.1080/14756366.2019.1685510

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

J Enzyme Inhib Med Chem. 2020 Dec;35(1):109-117. doi: 10.1080/14756366.2019.1685510.

Authors

Ashok Aspatwar¹, Nanda Kumar Parvathaneni^{2

3}, Harlan Barker¹, Emilie Anduran^{2

3}, Claudiu T Supuran⁴, Ludwig Dubois², Philippe Lambin², Seppo Parkkila^{1

5}, Jean-Yves Winum³

Affiliations

¹ Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland.
² Department of Precision Medicine, The M-Lab, GROW - School for Oncology and Developmental Biology, Maastricht Comprehensive Cancer Centre, Maastricht University Medical Centre, Maastricht, The Netherlands.
³ Institut des Biomolécules, Max Mousseron (IBMM) UMR 5247 CNRS, ENSCM, Université de Montpellier, Bâtiment de Recherche Max Mousseron, Ecole Nationale Supérieure de Montpellier, Montpellier, France.
⁴ NEUROFARBA Department, Section of Pharmaceutical and Nutraceutical Sciences, University of Florence, Polo Scientifico, Firenze, Italy.
⁵ Fimlab Ltd and Tays Cancer Center, Tampere University Hospital, Tampere, Finland.

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.

Keywords: Carbonic anhydrases; carbonic anhydrase inhibitors; lethal concentration; synthesis; toxicity evaluation; zebrafish embryos.

MeSH terms

Animals
Carbonic Anhydrase I / antagonists & inhibitors*
Carbonic Anhydrase I / metabolism
Carbonic Anhydrase II / antagonists & inhibitors*
Carbonic Anhydrase II / metabolism
Carbonic Anhydrase IV / antagonists & inhibitors*
Carbonic Anhydrase IV / metabolism
Carbonic Anhydrase Inhibitors / chemical synthesis
Carbonic Anhydrase Inhibitors / chemistry
Carbonic Anhydrase Inhibitors / pharmacology*
Dose-Response Relationship, Drug
Humans
Larva / drug effects
Molecular Structure
Nitroimidazoles / chemical synthesis
Nitroimidazoles / chemistry
Nitroimidazoles / pharmacology*
Structure-Activity Relationship
Zebrafish

Substances

Carbonic Anhydrase Inhibitors
Nitroimidazoles
Carbonic Anhydrase I
Carbonic Anhydrase II
Carbonic Anhydrase IV
CA2 protein, human
CA4 protein, human
4-nitroimidazole

Grants and funding

The work was supported by grants from Sigrid Jusélius Foundation (SP, MP), Finnish Cultural Foundation (HB, AA), Academy of Finland (SP), and Jane & Aatos Erkko Foundation (SP). Authors acknowledge financial support from ERC advanced grant (ERC-ADG-2015, no. 694812 – Hypoximmuno).