Synthesis, Biological Evaluation and Molecular Docking Studies of Novel 4-Propylsulfonylpiperazines-Based Thiosemicarbazones as Ecto-5′-Nucleotidase and NTPDase Inhibitors

IF 3.6 3区 医学 Q2 CHEMISTRY, MEDICINAL
Hina Aftab, Shireen Mona Dutt, Suraj N. Mali, Erica Vigiani, Julie Pelletier, Jean Sévigny, Shailesh S. Gurav, Rahul D. Jawarkar, Abdulraheem SA Almalki, Muhammad Safwan Akram, Zahra Batool, Silvia Schenone, Jamshed Iqbal, Zahid Shafiq
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引用次数: 0

Abstract

Purinergic signaling is modulated by extracellular enzymes known as ectonucleotidases. Ecto-5′-nucleotidase and NTPDases are part of the ectonucleotidase family. NTPDases control ATP levels through hydrolysis, whereas ecto-5′-NT collaborates with NTPDase to break down nucleotide molecule. Due to their roles in inflammation, infection, and cancer, both enzymes present promising targets for therapeutic interventions. In this study, we present a novel and environment-friendly synthetic approach for the creation of small molecules that are not based on nucleotides, specifically substituted sulfonyl-piperazine-based thiosemicarbazone derivatives 7(a–s). We assessed their inhibitory effects on ecto-5′-nucleotidase and NTPDase1, 2, 3, and 8. Most of the compounds displayed excellent inhibition against one or more forms, while some displayed selective inhibition. To gain a deeper understanding of how the synthesized compounds interact with the isoenzymes, we conducted molecular docking studies. Additionally, ADME analyses were performed to predict the pharmacokinetic properties of these compounds. The integration of in vitro and in silico studies enabled the identification of compounds with potential inhibitory activity and favorable binding orientations. The observed results provide compelling evidence for the potency of the biologically active scaffold, sulfonylpiperazine, as a powerful and selective NTPDase inhibitor.

新型4-丙基磺酰基哌嗪类硫代氨基脲类外5′-核苷酸酶和ntpase抑制剂的合成、生物学评价及分子对接研究
嘌呤能信号是由胞外酶,即外核苷酶调节的。外5′-核苷酸酶和ntpases是外核苷酸酶家族的一部分。ntpase通过水解控制ATP水平,而5′-NT与ntpase协同分解核苷酸分子。由于它们在炎症、感染和癌症中的作用,这两种酶都是治疗干预的有希望的靶点。在这项研究中,我们提出了一种新的、环境友好的合成方法,用于制造不基于核苷酸的小分子,特别是取代磺酰基哌嗪基硫代氨基脲衍生物7(a-s)。我们评估了它们对外5′-核苷酸酶和ntpase 1、2、3和8的抑制作用。大多数化合物对一种或多种形式表现出良好的抑制作用,而一些化合物则表现出选择性抑制作用。为了更深入地了解合成的化合物如何与同工酶相互作用,我们进行了分子对接研究。此外,ADME分析进行预测这些化合物的药代动力学性质。结合体外和计算机研究,鉴定出具有潜在抑制活性和有利结合取向的化合物。观察到的结果为生物活性支架磺酰基哌嗪作为一种强大的选择性ntpase抑制剂的效力提供了令人信服的证据。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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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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