Novel Taurinamide-Based Compounds as Carbonic Anhydrase Inhibitors

IF 3.6 3区 医学 Q2 CHEMISTRY, MEDICINAL
Ozlem Akgul, Gioele Renzi, Andrea Angeli, Marta Ferraroni, Fabrizio Carta, Claudiu T. Supuran
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引用次数: 0

Abstract

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 KI values in the range of 0.65–0.83 and 0.59–0.96 µM, respectively (asetazolamide KI = 0.25 for CA I and KI = 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.

Abstract Image

新型牛磺酸胺类化合物作为碳酸酐酶抑制剂
研究了一系列牛磺酸酰胺基酰胺对人(h)碳酸酐酶(CA)的影响;EC 4.2.1.1)同工异构体I、II、VA、VII、IX和XII,它们都与生物医学应用相关。根据抑制数据,大多数衍生物对hCA I异构体的亲和力和选择性优于其他被测试的异构体,化合物1、2、4、8和9是hCA I和hCA IX的有效纳米级抑制剂,KI值分别在0.65 ~ 0.83和0.59 ~ 0.96µM之间(asetazolamide KI值为0.25µM, hCA IX KI值为0.03µM)。15和18与hCA II配合物的x射线结构提供了详细的结合模式和分子决定因素的见解。研究发现,替代模式对特定亚型的亲和力和选择性都有调节作用,从而为设计新的CA抑制剂提供了有价值的见解。
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来源期刊
Archiv der Pharmazie
Archiv der Pharmazie 医学-化学综合
CiteScore
7.90
自引率
5.90%
发文量
176
审稿时长
3.0 months
期刊介绍: Archiv der Pharmazie - Chemistry in Life Sciences is an international journal devoted to research and development in all fields of pharmaceutical and medicinal chemistry. Emphasis is put on papers combining synthetic organic chemistry, structural biology, molecular modelling, bioorganic chemistry, natural products chemistry, biochemistry or analytical methods with pharmaceutical or medicinal aspects such as biological activity. The focus of this journal is put on original research papers, but other scientifically valuable contributions (e.g. reviews, minireviews, highlights, symposia contributions, discussions, and essays) are also welcome.
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