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新型（）-1-（2-（2-（4-（二甲基氨基）亚苄基）肼基）-4-甲基噻唑-5-基）乙酮衍生物作为胞外5'-核苷酸酶抑制剂的合成

Synthesis of novel ()-1-(2-(2-(4(dimethylamino) benzylidene) hydrazinyl)-4-methylthiazol-5-yl)ethanone derivatives as ecto-5'-nucleotidase inhibitors.

作者信息

Hassan Sidra, Channar Pervaiz Ali, Larik Fayaz Ali, Saeed Aamer, Shah Hamid Saeed, Lecka Joanna, Sévigny Jean, Iqbal Jamshed

机构信息

Centre for Advanced Drug Research, COMSATS University Islamabad, Abbottabad Campus, Abbottabad 22060, Pakistan.

Department of Chemistry, Quaid-i-Azam University, 45320 Islamabad, Pakistan.

出版信息

R Soc Open Sci. 2018 Sep 12;5(9):180837. doi: 10.1098/rsos.180837. eCollection 2018 Sep.

DOI:10.1098/rsos.180837
PMID:30839737
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC6170555/
Abstract

Ecto-5'-nucleotidase (e5'NT), a membrane-bound enzyme and an essential member of ecto-nucleotidases which regulates extracellular purinergic signalling. Their upregulation results in various disease conditions, for example, inflammation, hypoxia and cancer. Therefore, efforts have been made to synthesize potent and selective inhibitors of e5'NT. Here we have synthesized, characterized and evaluated six thiazole derivatives as potent e5'NT inhibitors. Among all derivatives, the compound ()-1-(4-methyl-2-(2-(pyridin-3-ylmethylene)hydrazinyl) thiazol-5-yl)ethanone exhibited maximum inhibition towards both human and rat enzymes. However, their potency against -e5'NT was 24-fold higher than -e5'NT. Only two compounds exhibited inhibitory behaviour towards -e5'NT. The molecular structures of these derivatives were confirmed with the help of solid-state characterization through NMR (H and C), FTIR and elemental analysis. Additionally, molecular docking was also implemented to explain putative bonding interaction between the active site of an enzyme and potent inhibitors.

摘要

外5'-核苷酸酶（e5'NT）是一种膜结合酶，也是外核苷酸酶的重要成员，可调节细胞外嘌呤能信号传导。它们的上调会导致多种疾病状态，例如炎症、缺氧和癌症。因此，人们一直在努力合成有效的、选择性的e5'NT抑制剂。在此，我们合成、表征并评估了六种噻唑衍生物作为有效的e5'NT抑制剂。在所有衍生物中，化合物（）-1-（4-甲基-2-（2-（吡啶-3-基亚甲基）肼基）噻唑-5-基）乙酮对人和大鼠的酶均表现出最大抑制作用。然而，它们对-e5'NT的效力比对-e5'NT高24倍。只有两种化合物对-e5'NT表现出抑制行为。这些衍生物的分子结构通过NMR（H和C）、FTIR和元素分析的固态表征得到了证实。此外，还进行了分子对接，以解释酶的活性位点与有效抑制剂之间的推定键合相互作用。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e10e/6170555/a899e2e7fc2a/rsos180837-g4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e10e/6170555/81a78b27b106/rsos180837-g1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e10e/6170555/9572fffc3f7a/rsos180837-g2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e10e/6170555/f5911c9ad48a/rsos180837-g3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e10e/6170555/a899e2e7fc2a/rsos180837-g4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e10e/6170555/81a78b27b106/rsos180837-g1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e10e/6170555/9572fffc3f7a/rsos180837-g2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e10e/6170555/f5911c9ad48a/rsos180837-g3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e10e/6170555/a899e2e7fc2a/rsos180837-g4.jpg

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