Exploring the Carbonic Anhydrase Activation Properties of 4-arylazo-3,5- diamino-1H-pyrazoles against hCA I, II, IV, and VII isoenzymes.

IF 3.3 4区 医学 Q3 CHEMISTRY, MEDICINAL
Suleyman Akocak, Nebih Lolak, Andrea Ammara, Özen Özensoy Güler, Claudiu T Supuran
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引用次数: 0

Abstract

Introduction: CAs serve as crucial enzymes involved in a variety of physiological processes, including brain metabolism and cognitive function. hCA VII, a brain-associated isoform, plays an important role in modulating cerebral metabolism. Activating hCA VII may provide therapeutic benefits in Alzheimer's disease and other neurodegenerative or age-related illnesses. This study proposes to add to the growing interest in CAAs by developing innovative drugs with selective activation characteristics that target brain-associated CA isoforms.

Method: A series of 4-arylazo-3,5-diamino-1H-pyrazoles have been produced by reacting aniline and aniline derivatives with a malononitrile solution at 0-5 °C, resulting in compounds 1(a-m). Then, arylazo malononitrile compounds were added with hydrazine monohydrate to obtain 4- arylazo-3,5-diamino-1H-pyrazole derivatives 2(a-m). The activity of the synthesized compounds was examined on human CA isoforms I, II, IV, and VII to determine activation potency and selectivity.

Results: The synthesized compounds demonstrated a wide spectrum of strong micromolar activation on human CA isoforms, with particularly encouraging results for hCA VII. The discovered activators showed a high selectivity profile for the brain-associated hCA VII isoform, indicating their potential use in neurological methods of therapy.

Discussion: Among the most compelling findings of this study is the unprecedented potency of several synthesized derivatives, particularly 2i and 2m, in selectively activating hCA VII far beyond the benchmark histamine, positioning them as promising pharmacological candidates for addressing CA-related neurological disorders.

Conclusion: The research successfully discovered potent and selective CAAs with specific activity against hCA VII, a key enzyme in brain metabolism. These outcomes offer novel possibilities for developing medicinal products for neurological disorders and provide critical molecules for further study into CAAs. Furthermore, the study advances our understanding of enzyme activation kinetics and gives significant insights into the future of enzyme-based treatment research.

探索4-芳基偶氮-3,5-二氨基- 1h -吡唑对hCA I, II, IV和VII同工酶的碳酸酐酶活化特性。
CAs是参与多种生理过程的关键酶,包括脑代谢和认知功能。hca7是一种脑相关亚型,在调节脑代谢中起重要作用。激活hca7可能为阿尔茨海默病和其他神经退行性疾病或与年龄相关的疾病提供治疗益处。本研究提出通过开发具有选择性激活特性的创新药物来增加对CAAs日益增长的兴趣,这些药物靶向脑相关CA亚型。方法:通过苯胺及其衍生物与丙二腈溶液在0-5℃下反应,得到一系列4-芳基偶氮-3,5-二胺- 1h -吡唑,得到化合物1(A -m)。然后,将芳基偶氮丙二腈化合物与一水合肼加成,得到4-芳基偶氮-3,5-二氨基- 1h -吡唑衍生物2(a-m)。对合成的化合物在人CA亚型I、II、IV和VII上的活性进行了检测,以确定其活化效力和选择性。结果:合成的化合物对人CA异构体具有广谱的强微摩尔激活作用,对hCA VII具有特别令人鼓舞的结果。发现的激活剂对脑相关的hCA VII亚型具有高选择性,表明它们在神经学治疗方法中的潜在应用。讨论:本研究最引人注目的发现之一是几种合成衍生物,特别是2i和2m,在选择性激活hCA VII方面具有前所未有的效力,远远超过基准组胺,将它们定位为解决ca相关神经系统疾病的有希望的药理学候选者。结论:本研究成功发现了对脑代谢关键酶hca7具有特异性活性的强效选择性氨基酸。这些结果为开发治疗神经系统疾病的药物提供了新的可能性,并为进一步研究CAAs提供了关键分子。此外,该研究促进了我们对酶活化动力学的理解,并为未来基于酶的治疗研究提供了重要的见解。
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来源期刊
CiteScore
6.40
自引率
2.90%
发文量
186
审稿时长
3-8 weeks
期刊介绍: Current Topics in Medicinal Chemistry is a forum for the review of areas of keen and topical interest to medicinal chemists and others in the allied disciplines. Each issue is solely devoted to a specific topic, containing six to nine reviews, which provide the reader a comprehensive survey of that area. A Guest Editor who is an expert in the topic under review, will assemble each issue. The scope of Current Topics in Medicinal Chemistry will cover all areas of medicinal chemistry, including current developments in rational drug design, synthetic chemistry, bioorganic chemistry, high-throughput screening, combinatorial chemistry, compound diversity measurements, drug absorption, drug distribution, metabolism, new and emerging drug targets, natural products, pharmacogenomics, and structure-activity relationships. Medicinal chemistry is a rapidly maturing discipline. The study of how structure and function are related is absolutely essential to understanding the molecular basis of life. Current Topics in Medicinal Chemistry aims to contribute to the growth of scientific knowledge and insight, and facilitate the discovery and development of new therapeutic agents to treat debilitating human disorders. The journal is essential for every medicinal chemist who wishes to be kept informed and up-to-date with the latest and most important advances.
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