Eco-friendly synthesis, in vitro anti-proliferative evaluation, and 3D-QSAR analysis of a novel series of monocationic 2-aryl/heteroaryl-substituted 6-(2-imidazolinyl)benzothiazole mesylates
Eco-friendly synthesis, in vitro anti-proliferative evaluation, and 3D-QSAR analysis of a novel series of monocationic 2-aryl/heteroaryl-substituted 6-(2-imidazolinyl)benzothiazole mesylates
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一系列新型单阳离子2-芳基/杂芳基取代的6-(2-咪唑啉基)苯并噻唑甲磺酸盐的环保合成、体外抗增殖评估和3D-QSAR分析
DOI：
10.1007/s11030-018-9827-2
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发表时间：
2018
影响因子：
3.8
通讯作者：
G. Karminski
中科院分区：
文献类型：
--
作者：
L. Racané;Lucija Ptiček;Mirela Sedić;Petra Grbčić;Sandra Kraljević Pavelić;B. Bertoša;Irena Sović;G. Karminski
本文报道了21个新型水溶性单阳离子2-芳基/杂芳基取代6-(2-咪唑基)苯并噻唑甲磺酸酯3a-3u的合成及其抗增殖活性。基于芳基/杂芳基甲醛或羧酸的缩合反应，通过三个互补的简单的两步合成方案实现了高效的合成。我们开发了一种以甘油为绿色溶剂的环保合成方案，特别适用于呋喃、苯并呋喃、吡咯和吲哚等热敏性和酸敏性杂环的缩合反应。对胰腺癌(CFPAC-1)、转移性结肠癌(SW620)、肝细胞癌(HepG2)和宫颈癌(HeLa)等4种人肿瘤细胞系和正常人成纤维细胞系进行了体外抗增殖活性筛选。所有受试化合物对受试细胞株均表现出较强到中等的抗增殖活性，这取决于含有与6-(2-咪唑基)苯并噻唑部分偶联的芳基/杂芳基的结构。对所有受试细胞系的细胞抑制作用最强的是IC50\DocumentClass[12pt]{Minimum}\Usepackage{amsath}\Usepackage{wa ysym}\usepackage{amsFonts}\usepackage{amsbsy}\usepackage{mathsfs}\usepackage{upgreek}\setLong{\oddsidemargin}{-69pt}\Begin{Document}$\HBox{IC}_{50}$\End{Document}值从0.1到3.70μM\DocumentClass[12pt]{Minimal\usepackage{amsath}用萘-2-基3c取代的苯并噻唑，观察到了usepackage\usepackage{amsfonts}\usepackage{amssymb}\usepackage{amsbsy}\usepackage{upgreek}\setlong{oddsidemargin}{-69pt}\Begin{Document}$$\upu\Hbox{M}$\end{Document}，苯并呋喃-2-基3E、吲哚-3-基3J、吲哚-2-基3K、喹啉-2-基3S和喹啉-3-基3T和取代苯基3a、萘-1-基3b、苯并噻唑-2-基3g、苯并噻唑-6-基3h、N-甲基吲哚-3-基3l、苯并咪唑-2-基3n、苯并咪唑-5(6)-基3o，和喹诺酮-4-基3U，IC50\DocumentCLASS[12pt]{Minimum}\Usepackage{amsath}\Usepackage{waysym}\Usepackage{amsFonts}\Usepackage{amsbsy}\Usepackage{mathsfs}\usepackage{upgreek}\setlong{\oddsidemargin}{-69pt}\Begin{Document$\Hbox{IC}_{50}$\End{Document}值从1.1到29.1M\DocumentClass[12pt]{Minimal\Usepackage{amsath}\Usepackage{wa ysym}\usepackage{amsfonts}\usepackage{amssymb}\usepackage{amsbsy}\usepackage{mathsfs}\usepackage{upgreek}\setlong{\oddsidemargin}{-69pt}\Begin{Document}$$\upu\Hbox{M}$$\end{Document}。在获得抗增殖活性的基础上，建立了5种细胞系的3D-QSAR模型。QSAR分析表明，分子体积、分子表面积、疏水表面积之和、分子质量和形成分散力的可能性与抗增殖活性呈正相关，而化合物接受氢键的能力与抗增殖活性呈负相关。对不同细胞系鉴定的分子性质的比较使人们能够假设作用方式相似，通过这些相似的作用方式实现了对不同细胞系的抗增殖活性。以3D-QSAR分析为指导，设计了与本文提出的化合物相比具有更强活性的新化合物。
Herein, we describe the synthesis of twenty-one novel water-soluble monocationic 2-aryl/heteroaryl-substituted 6-(2-imidazolinyl)benzothiazole mesylates 3a–3u and present the results of their anti-proliferative assays. Efficient syntheses were achieved by three complementary simple two-step synthetic protocols based on the condensation reaction of aryl/heteroaryl carbaldehydes or carboxylic acid. We developed an eco-friendly synthetic protocol using glycerol as green solvent, particularly appropriate for the condensation of thermally and acid-sensitive heterocycles such as furan, benzofuran, pyrrole, and indole. Screening of anti-proliferative activity was performed on four human tumour cell lines in vitro including pancreatic cancer (CFPAC-1), metastatic colon cancer (SW620), hepatocellular carcinoma (HepG2), and cervical cancer (HeLa), as well as in normal human fibroblast cell lines. All tested compounds showed strong to moderate anti-proliferative activity on tested cell lines depending on the structure containing aryl/heteroaryl moiety coupled to 6-(2-imidazolinyl)benzothiazole moiety. The most potent cytostatic effects on all tested cell lines with IC50\documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$\hbox {IC}_{50}$$\end{document} values ranging from 0.1 to 3.70 μM\documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$\upmu \hbox {M}$$\end{document} were observed for benzothiazoles substituted with naphthalene-2-yl 3c, benzofuran-2-yl 3e, indole-3-yl 3j, indole-2-yl 3k, quinoline-2-yl 3s, and quinoline-3-yl 3t and derivatives substituted with phenyl 3a, naphthalene-1-yl 3b, benzothiazole-2-yl 3g, benzothiazole-6-yl 3h, N-methylindole-3-yl 3l, benzimidazole-2-yl 3n, benzimidazole-5(6)-yl 3o, and quinolone-4-yl 3u with IC50\documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$\hbox {IC}_{50}$$\end{document} values ranging from 1.1 to 29.1 μM\documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$\upmu \hbox {M}$$\end{document}. Based on obtained anti-proliferative activities, 3D-QSAR models for five cell lines were derived. Molecular volume, molecular surface, the sum of hydrophobic surface areas, molecular mass, and possibility of making dispersion forces were identified by QSAR analyses as molecular properties that are positively correlated with anti-proliferative activity, while compound’s capability to accept H-bond was identified as a negatively correlated property. Comparison of molecular properties identified for different cell lines enabled assumptions about similarity of mode of action through which anti-proliferative activities against different cell lines are accomplished. Novel compounds that are predicted to have enhanced activities in comparison with herein presented ones were designed using 3D-QSAR analysis as guideline.