Akocak Suleyman, Lolak Nebih, Ammara Andrea, Güler Özen Özensoy, Supuran Claudiu T
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Adıyaman University, 02040 Adıyaman, Türkiye.
Università degli Studi di Firenze, NEUROFARBA Dept., Sezione di Scienze Farmaceutiche, via Ugo Schiff 6, 50019 Sesto Fiorentino (Florence), Italy.
Curr Top Med Chem. 2025 Jul 28. doi: 10.2174/0115680266373008250723064558.
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.
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.
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.
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.
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.
碳酸酐酶（CAs）是参与多种生理过程的关键酶，包括脑代谢和认知功能。hCA VII是一种与脑相关的同工型，在调节脑代谢中起重要作用。激活hCA VII可能对阿尔茨海默病及其他神经退行性疾病或与年龄相关的疾病具有治疗益处。本研究旨在通过开发具有选择性激活特性的创新药物，靶向与脑相关的CA同工型，从而增加对碳酸酐酶激活剂（CAAs）的关注。
通过在0-5°C下使苯胺和苯胺衍生物与丙二腈溶液反应，制备了一系列4-芳基偶氮-3,5-二氨基-1H-吡唑，得到化合物1（a-m）。然后，向芳基偶氮丙二腈化合物中加入水合肼，得到4-芳基偶氮-3,5-二氨基-1H-吡唑衍生物2（a-m）。检测合成化合物对人CA同工型I、II、IV和VII的活性，以确定激活效力和选择性。
合成化合物对人CA同工型表现出广泛的强微摩尔激活作用，对hCA VII的结果尤其令人鼓舞。发现的激活剂对与脑相关的hCA VII同工型具有高选择性，表明它们在神经治疗方法中的潜在用途。
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，使其成为治疗与CA相关的神经疾病的有前途的药理学候选物。
该研究成功发现了对hCA VII具有特异性活性的强效和选择性碳酸酐酶激活剂，hCA VII是脑代谢中的关键酶。这些结果为开发用于神经疾病的药物提供了新的可能性，并为进一步研究碳酸酐酶激活剂提供了关键分子。此外，该研究推进了我们对酶激活动力学的理解，并为基于酶的治疗研究的未来提供了重要见解。
