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4-Substituted benzenesulfonamides featuring cyclic imides moieties exhibit potent and isoform-selective carbonic anhydrase II/IX inhibition.
Bioorganic Chemistry ( IF 4.5 ) Pub Date : 2018-10-19 , DOI: 10.1016/j.bioorg.2018.10.037 Alaa A-M Abdel-Aziz 1 , Adel S El-Azab 2 , Adel H Ghiaty 3 , Paola Gratteri 4 , Claudiu T Supuran 5 , Alessio Nocentini 6
Bioorganic Chemistry ( IF 4.5 ) Pub Date : 2018-10-19 , DOI: 10.1016/j.bioorg.2018.10.037 Alaa A-M Abdel-Aziz 1 , Adel S El-Azab 2 , Adel H Ghiaty 3 , Paola Gratteri 4 , Claudiu T Supuran 5 , Alessio Nocentini 6
Affiliation
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The synthesis, characterization and biological evaluation of series of cyclic imides incorporating the 4-sulfamoylbenzamide scaffold (16-29) is disclosed. The compounds were designed by application of the "tail approach" to the aromatic sulfonamide scaffold and prepared by reacting the proper acid anhydride with 4-(hydrazinecarbonyl)benzenesulfonamide (15). Phtalimides and cyclic imides are biologically privileged scaffolds, endowed with versatile biological activity, such as an anti-proliferative action. The compounds were investigated for the inhibition of four human (h) isoforms of zinc enzyme carbonic anhydrase (CA, EC 4.2.1.1), and more specifically against the cytosolic hCA I and II and the transmembrane hCA IV and IX. Most screened sulfonamides exhibited great potency in inhibiting CA isoforms II, widely involved in glaucoma and other pathologies (KIs in the range of 0.7-62.3 nM), and IX, that is a validated anti-tumor target (KIs in the range of 3.0-50.9 nM), whereas interesting hydrophilicity-dependent inhibitory profiles were measured against isoform CA IV (KIs in the range of 3.9-428.6 nM). In silico studies were carried out to assess the binding mode of selected derivatives to hCA II, IV and IX.
中文翻译：
具有环酰亚胺部分的4-取代苯磺酰胺显示出有效的和同工型选择性碳酸酐酶II / IX抑制作用。
公开了结合有4-氨磺酰基苯甲酰胺支架（16-29）的一系列环状酰亚胺的合成，表征和生物学评价。通过将“尾巴法”应用于芳族磺酰胺支架上来设计化合物，并通过使适当的酸酐与4-（肼基羰基）苯磺酰胺（15）反应来制备。邻苯二甲酰亚胺和环状酰亚胺是具有生物学优势的支架，具有多种生物活性，例如抗增殖作用。研究了这些化合物对锌酶碳酸酐酶的四种人（h）同工型（CA，EC 4.2.1.1）的抑制作用，更具体地，针对胞质hCA I和II以及跨膜hCA IV和IX的抑制作用。大多数筛选出的磺酰胺类药物在抑制CA亚型II方面显示出强大的功效，广泛参与青光眼和其他病理（KIs在0.7-62.3 nM范围内）和IX，这是一个经过验证的抗肿瘤靶点（KIs在3.0-50.9 nM范围内），而有趣的亲水性依赖性抑制谱是针对同种型CA IV（KIs在3.9-428.6 nM范围内）进行测定。进行了计算机研究，以评估所选衍生物与hCA II，IV和IX的结合模式。
更新日期：2018-10-19
中文翻译：
具有环酰亚胺部分的4-取代苯磺酰胺显示出有效的和同工型选择性碳酸酐酶II / IX抑制作用。
公开了结合有4-氨磺酰基苯甲酰胺支架（16-29）的一系列环状酰亚胺的合成，表征和生物学评价。通过将“尾巴法”应用于芳族磺酰胺支架上来设计化合物，并通过使适当的酸酐与4-（肼基羰基）苯磺酰胺（15）反应来制备。邻苯二甲酰亚胺和环状酰亚胺是具有生物学优势的支架，具有多种生物活性，例如抗增殖作用。研究了这些化合物对锌酶碳酸酐酶的四种人（h）同工型（CA，EC 4.2.1.1）的抑制作用，更具体地，针对胞质hCA I和II以及跨膜hCA IV和IX的抑制作用。大多数筛选出的磺酰胺类药物在抑制CA亚型II方面显示出强大的功效，广泛参与青光眼和其他病理（KIs在0.7-62.3 nM范围内）和IX，这是一个经过验证的抗肿瘤靶点（KIs在3.0-50.9 nM范围内），而有趣的亲水性依赖性抑制谱是针对同种型CA IV（KIs在3.9-428.6 nM范围内）进行测定。进行了计算机研究，以评估所选衍生物与hCA II，IV和IX的结合模式。
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