Akgul Ozlem, Renzi Gioele, Angeli Andrea, Ferraroni Marta, Carta Fabrizio, Supuran Claudiu T
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Ege University, Bornova, Turkey.
Dipartimento Neurofarba, Sezione di Scienze Farmaceutiche e Nutraceutiche, Università degli Studi di Firenze, Sesto Fiorentino, Florence, Italy.
Arch Pharm (Weinheim). 2025 Aug;358(8):e70073. doi: 10.1002/ardp.70073.
A series of taurinamide-based amides 1-19 were investigated for their effects on human (h) carbonic anhydrase (CA; EC 4.2.1.1) isoforms I, II, VA, VII, IX, and XII, which are all relevant for biomedical applications. According to inhibition data, most of the derivatives displayed affinity and selectivity for the hCA I isoform over the other isoforms tested, and compounds 1, 2, 4, 8, and 9 emerged as potent nanomolar inhibitors of hCA I and hCA IX, exhibiting K values in the range of 0.65-0.83 and 0.59-0.96 µM, respectively (asetazolamide K = 0.25 for CA I and K = 0.03 M for hCA IX). The X-ray structures of 15 and 18 in complex with hCA II provided detailed insights into the binding mode and molecular determinants. Substitution patterns were found to have a tuning effect on both affinity and selectivity toward specific isoforms, thus providing valuable insights for the design of new CA inhibitors.
研究了一系列基于牛磺酰胺的酰胺1-19对人（h）碳酸酐酶（CA；EC 4.2.1.1）同工型I、II、VA、VII、IX和XII的影响，这些同工型均与生物医学应用相关。根据抑制数据，大多数衍生物对hCA I同工型显示出比对其他测试同工型更高的亲和力和选择性，化合物1、2、4、8和9是hCA I和hCA IX的有效纳摩尔抑制剂，其K值分别在0.65-0.83和0.59-0.96 μM范围内（醋甲唑胺对CA I的K = 0.25，对hCA IX的K = 0.03 M）。与hCA II复合的15和18的X射线结构提供了关于结合模式和分子决定因素的详细见解。发现取代模式对特定同工型的亲和力和选择性都有调节作用，从而为新型CA抑制剂的设计提供了有价值的见解。
