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Research Paper

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

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Pages 109-117 | Received 27 Sep 2019, Accepted 22 Oct 2019, Published online: 05 Nov 2019
 

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.

Acknowledgements

The authors thank Aulikki Lehmus and Marianne Kuuslahti for the histochemical analyses of the zebrafish samples. We also thank Leena Mäkinen and Hannaleena Piippo for the assistance with zebrafish embryos for the experiments.

Disclosure statement

No potential conflict of interest was reported by the authors.

Additional information

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).