Neurofarba Department, Pharmaceutical and Nutraceutical Section, University of Florence, Sesto Fiorentino (FI), Italy.
Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland.
J Enzyme Inhib Med Chem. 2022 Dec;37(1):2417-2422. doi: 10.1080/14756366.2022.2119965.
The α-class carbonic anhydrase (CA, EC 4.2.1.1) from the protozoan pathogen , TcCA, was investigated earlier for its inhibition with anions, sulphonamides, thiols and hydroxamates, well-known classes of CA inhibitors (CAIs). Here we present the first inhibition study of this enzyme with phenols, which possess a diverse CA inhibition mechanism compared to the previously investigated compounds, which are all zinc binders. Indeed, phenols are known to anchor to the zinc coordinated water molecule within the enzyme active site. In a series of 22 diversely substituted phenols, the best inhibitors were simple phenol, pyrocatechol, salicylic acid, 3,5-difluorophenol, 3,4-dihydroxy-benzoic acid, 3,6- dihydroxy-benzoic acid, caffeic acid and its des-hydroxy analog, with Ks of 1.8 - 7.3 µM. The least effective TcCA inhibitor was 3-chloro-4-amino-phenol ( of 47.9 µM). Although it is not yet clear whether TcCA can be considered as an anti-Chagas disease drug target, as no animal model for investigating the antiprotozoan effects is available so far, finding effective inhibitors may be a first relevant step towards new antiprotozoal agents.
我们以前曾研究过原生动物病原体 的 α 类碳酸酐酶 (CA，EC 4.2.1.1) 与阴离子、磺胺类药物、硫醇和羟肟酸等 CA 抑制剂 (CAI) 的抑制作用。在这里，我们首次研究了这种酶与酚类化合物的抑制作用，与之前研究过的所有锌结合抑制剂相比，酚类化合物具有不同的 CA 抑制机制。事实上，众所周知，酚类化合物可以锚定在酶活性位点内锌配位的水分子上。在一系列 22 种不同取代的酚类化合物中，最好的抑制剂是简单的苯酚、邻苯二酚、水杨酸、3,5-二氟苯酚、3,4-二羟基苯甲酸、3,6-二羟基苯甲酸、咖啡酸及其去羟基类似物，其 Ks 值为 1.8-7.3μM。最无效的 TcCA 抑制剂是 3-氯-4-氨基酚（47.9μM）。尽管目前还不清楚 TcCA 是否可以被认为是治疗恰加斯病的药物靶点，因为到目前为止还没有用于研究抗原生动物作用的动物模型，但找到有效的抑制剂可能是开发新的抗原生动物药物的第一步。
