Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland.
Oral and Maxillofacial Unit, Tampere University Hospital, Tampere, Finland.
J Enzyme Inhib Med Chem. 2020 Dec;35(1):65-71. doi: 10.1080/14756366.2019.1683007.
We investigated a panel of 14 compounds belonging to the monothiocarbamate () and dithiocarbamate () series against the β-carbonic anhydrase 3 (-CA3) of (Mtb). We also evaluated all compounds for toxicity using 1-5-day post fertilisation zebrafish embryos. 11 out of the 14 investigated derivatives showed effective nanomolar or submicromolar inhibition against the -CA3 (Ks 2.4-812.0 nM), and among them four of the series ( and ) showed very significant inhibition potencies with Ks between 2.4 and 43 nM. Out of 14 compounds screened for toxicity and safety 9 compounds showed no adverse phenotypic effects on the developing zebrafish larvae at five days of exposure. The results of inhibition and the toxicological evaluation of our study suggest that 5 compounds are suitable for further preclinical characterisation in zebrafish model.
我们研究了一组 14 种属于单硫代氨基甲酸盐(monothiocarbamate)和二硫代氨基甲酸盐(dithiocarbamate)系列的化合物,以对抗结核分枝杆菌()的β-碳酸酐酶 3(-CA3)。我们还使用受精后 1-5 天的斑马鱼胚胎评估了所有化合物的毒性。在所研究的 14 种衍生物中,有 11 种对 -CA3 表现出有效的纳摩尔或亚微米级抑制作用(Ks 2.4-812.0 nM),其中 4 种属于该系列(和)表现出非常显著的抑制作用,Ks 值在 2.4 到 43 nM 之间。在对毒性和安全性进行筛选的 14 种化合物中,有 9 种在暴露于斑马鱼幼虫 5 天内对其发育没有表现出不良表型影响。抑制实验的结果和我们的毒理学评价表明,有 5 种化合物适合在斑马鱼模型中进行进一步的临床前特征描述。