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.

中文翻译：

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5-硝基咪唑系列人碳酸酐酶I，II和IX抑制剂的设计，合成，体外抑制和毒理学评估。

为了获得具有对人碳酸酐酶的强亲和力和低毒性的新型化合物，我们合成了新型硫脲和磺酰胺衍生物3、4和10，并研究了它们对人CA I，CA II和CA IX的体外抑制特性。我们还使用斑马鱼幼虫评估了这些化合物的毒性。在这三种化合物中，衍生物4显示出对hCA II的有效抑制（KI = 58.6 nM）。化合物10对hCA II（KI = 199.2 nM）和hCA IX（KI = 147.3 nM）表现出中等抑制作用，而在微摩尔浓度下（KI = 6428.4 nM），对hCA I的抑制作用较弱。这些化合物的所有其他抑制常数都在亚微摩尔范围内。毒性评估研究表明，对斑马鱼幼虫没有不利影响。