期刊
JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY
卷 35, 期 1, 页码 109-117出版社
TAYLOR & FRANCIS LTD
DOI: 10.1080/14756366.2019.1685510
关键词
Carbonic anhydrases; carbonic anhydrase inhibitors; synthesis; toxicity evaluation; lethal concentration; zebrafish embryos
资金
- Sigrid Juselius Foundation
- Finnish Cultural Foundation
- Academy of Finland
- Jane & Aatos Erkko Foundation
- ERC [694812 -Hypoximmuno]
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.
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