Fadaly Wael A A, Nemr Mohamed T M, Abd El-Hameed Abeer M, Giovannuzzi Simone, Alkabbani Mahmoud Abdelrahman, Hefina Mohamed M, Nocentini Alessio, Mohamed Mamdouh F A, Supuran Claudiu T, Eldehna Wagdy M, Zidan Taha H
Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Beni-Suef University, Beni-Suef, 62514, Egypt.
Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Cairo University, Kasr El-Eini street 11562, Cairo, Egypt.
Eur J Med Chem. 2025 Jul 5;291:117619. doi: 10.1016/j.ejmech.2025.117619. Epub 2025 Apr 9.
Two new series of 1,2,3-triazole benzenesulfonamide derivatives 16a-f and imino-thiazolidinone benzenesulfonamide derivatives 19a-f with diaryl pyrazole tail were synthesized as carbonic anhydrase (CA) II, VII inhibitors and assessed for antiepileptic activity. All compounds were tested in vitro for their inhibition activity against the human (h) carbonic anhydrase I, II, and VII isoforms. Among these series, compounds 16b, 16d, 19b, and 19d exhibited exceptional inhibitory activity against hCA II, with K 10.9-47.1 nM, and hCA VII, with K 8.4-23.6 nM, while the two series did not show significant activity against hCA I. Furthermore, 16b, 16d, 19b, and 19d were tested against in vivo pilocarpine-induced seizure model, and they showed excellent neuroprotective activity; they delayed seizure onset, reduced seizure severity, and improved survival rates compared to the pilocarpine group, which highlighted their efficacy in regulating neuronal excitability through CA inhibition and chloride homeostasis. Also, hippocampal levels of KCC2 and mTOR were analyzed, as these markers are critical in regulating neuronal excitability and are closely linked to epilepsy. Noteworthy, Compounds 16d and 19b surpassed the standard anti-convulsant valproic acid in key parameters, underscoring their superior efficacy. In addition, they do not show any significant neurotoxic effects or alterations in liver and kidney function. Moreover, the results of in vitro cytotoxicity of compounds 16d and 19b against Vero cells indicate their safety at the doses given (IC = 59.7, 71.9 μM respectively) compared to acetazolamide (IC = 32.3 μM). Finally, molecular docking of sulfonamide derivatives with hCA II (PDB code: 2h4h) and hCA VII (PDB code: 3ml5) was performed.
合成了两个新系列带有二芳基吡唑尾的1,2,3 - 三唑苯磺酰胺衍生物16a - f和亚氨基噻唑烷酮苯磺酰胺衍生物19a - f，作为碳酸酐酶（CA）II、VII抑制剂，并评估其抗癫痫活性。所有化合物均在体外测试了它们对人（h）碳酸酐酶I、II和VII同工型的抑制活性。在这些系列中，化合物16b、16d、19b和19d对hCA II表现出优异的抑制活性，K值为10.9 - 47.1 nM，对hCA VII表现出优异的抑制活性，K值为8.4 - 23.6 nM，而这两个系列对hCA I未显示出显著活性。此外，对16b、16d、19b和19d进行了体内毛果芸香碱诱导的癫痫模型测试，它们表现出优异的神经保护活性；与毛果芸香碱组相比，它们延迟了癫痫发作的起始，降低了癫痫发作的严重程度，并提高了存活率，这突出了它们通过抑制CA和氯稳态来调节神经元兴奋性的功效。此外，还分析了海马中KCC2和mTOR的水平，因为这些标志物在调节神经元兴奋性方面至关重要，且与癫痫密切相关。值得注意的是，化合物16d和19b在关键参数上超过了标准抗惊厥药丙戊酸，强调了它们的卓越疗效。此外，它们未显示出任何显著的神经毒性作用或肝肾功能改变。此外，化合物16d和19b对Vero细胞的体外细胞毒性结果表明，与乙酰唑胺（IC = 32.3 μM）相比，在给定剂量下（IC分别为59.7、71.9 μM）它们是安全的。最后，进行了磺酰胺衍生物与hCA II（PDB代码：2h4h）和hCA VII（PDB代码：3ml5）的分子对接。
