Awadallah Fadi M, Bua Silvia, Mahmoud Walaa R, Nada Hossam H, Nocentini Alessio, Supuran Claudiu T
a Pharmaceutical Chemistry Department, Faculty of Pharmacy , Cairo University , Cairo , Egypt.
b Department NEUROFARBA - Pharmaceutical and Nutraceutical Section , University of Firenze , Firenze , Italy.
J Enzyme Inhib Med Chem. 2018 Dec;33(1):629-638. doi: 10.1080/14756366.2018.1446432.
Being the primary sulfonamide among the most efficient zinc binding group (ZBG) to design inhibitors for the metallo-enzymes carbonic anhydrases (CA, EC 4.2.1.1), herein, we propose an investigation on four physiologically important human (h) CAs (hCA I, II, IV, and IX) with N-substituted secondary sulfonamides incorporating thiazolinone or imidazolone-indole tails. The effect of the functionalisation of the sulfonamide group with five different substitution patterns, namely acetyl, pyridine, thiazole, pyrimidine, and carbamimidoyl, was evaluated in relation to the inhibition profile of the corresponding primary sulfonamide analogues. With most of these latter being nanomolar inhibitors of all four considered isoforms, a totally counterproductive effect on the inhibition potency can be ascribed to N-functionalisations of the ZBG primary sulfonamide structure with pyridine, thiazole, and pyrimidine moieties. On the other hand, incorporation of less hindered groups, such as sulfonylacetamides and sulfonylguanidines, maintained a certain degree of activity dependent on the tailing moiety, with Ks spanning in the low micromolar range.
作为设计金属酶碳酸酐酶（CA，EC 4.2.1.1）抑制剂时最有效的锌结合基团（ZBG）中的主要磺酰胺，在此，我们提出对四种具有生理重要性的人源（h）碳酸酐酶（hCA I、II、IV和IX）进行研究，这些酶与带有噻唑啉酮或咪唑啉酮 - 吲哚尾的N - 取代仲磺酰胺结合。评估了磺酰胺基团以五种不同取代模式（即乙酰基、吡啶、噻唑、嘧啶和氨基甲脒基）进行官能化对相应伯磺酰胺类似物抑制谱的影响。由于后者中的大多数是所有四种所考虑同工型的纳摩尔抑制剂，因此可以将ZBG伯磺酰胺结构用吡啶、噻唑和嘧啶部分进行N - 官能化归因于对抑制效力产生完全适得其反的效果。另一方面，引入位阻较小的基团，如磺酰基乙酰胺和磺酰基胍，根据尾基部分保持一定程度的活性，Ks范围在低微摩尔范围内。
