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用单硫代和二硫代氨基甲酸盐抑制 -碳酸酐酶 3 及其对斑马鱼胚胎发育毒性的评估。

inhibition of -carbonic anhydrase 3 with Mono- and dithiocarbamates and evaluation of their toxicity using zebrafish developing embryos.

机构信息

Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland.

Oral and Maxillofacial Unit, Tampere University Hospital, Tampere, Finland.

出版信息

J Enzyme Inhib Med Chem. 2020 Dec;35(1):65-71. doi: 10.1080/14756366.2019.1683007.

Abstract

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.

摘要

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。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/73c4/6830242/ec9629efce3f/IENZ_A_1683007_F0001_B.jpg

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