BACKGROUND Tetrahydrobenzo[b]thiophene derivatives are well known to be biologically active compounds and many of them occupy a wide range of anticancer agent drugs. OBJECTIVE One of the main aim of this work was to synthesize target molecules not only possessing anti-tumor activities but also kinase inhibitors. To achieve this goal, our strategy was to synthesize a series of 4,5,6,7- tetrahydrobenzo[b]thiophene-3-carbohydrazide derivatives using cyclohexan-1,4-dione and cyanoacetylhydrazine to give the 2-amino-6-oxo-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carbohydrazide (3) as the key starting material for many heterocyclization reactions. METHODS Compound 3 was reacted with some aryldiazonium salts and the products were cyclised when reacted with either malononitrile or ethyl cyanoacetate. Thiazole derivatives were also obtained through the reaction of compound 3 with phenylisothiocyanate followed by heterocyclization with α-halocarbonyl derivatives. Pyrazole, triazole and pyran derivatives were also obtained. RESULTS The compounds obtained in this work were evaluated for their in-vitro cytotoxic activity against c-Met kinase, and the six typical cancer cell lines (A549, H460, HT-29, MKN-45, U87MG, and SMMC-7721). The results of anti-proliferative evaluations and c-Met kinase, Pim-1 kinse inhibitions revealed that some compounds showed high activities. CONCLUSION The most promising compounds 5b, 5c, 7c, 7d, 11b, 14a, 16b, 18b, 19, 21a, 23c, 23d and 23i against c-Met kinase were further investigated against the five tyrosin kinases (c-Kit, Flt-3, VEGFR-2, EGFR, and PDGFR). Compounds 5b, 5c, 7d, 7e, 11b, 11c, 16c, 16d, 18c, 19, 23e, 23k and 23m were selected to examine their Pim-1 kinase inhibitions activity where compounds 7d, 7e, 11b, 11c, 16d, 18c and 23e showed high activities. All of the synthesized compounds have no impaired effect toward the VERO normal cell line.

中文翻译：

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合成四氢苯并[b]噻吩-3-碳酰肼衍生物作为潜在的抗癌药和Pim-1激酶抑制剂。

背景技术众所周知，四氢苯并[b]噻吩衍生物是具有生物活性的化合物，其中许多占据了广泛的抗癌药。目的这项工作的主要目的之一是合成不仅具有抗肿瘤活性而且具有激酶抑制剂的靶分子。为实现此目标，我们的策略是使用环己-1,4-二酮和氰基乙酰肼合成一系列4,5,6,7-四氢苯并[b]噻吩-3-碳酰肼衍生物，得到2-氨基-6-氧代-4,5,6,7-四氢苯并[b]噻吩-3-碳酰肼（3）是许多杂环化反应的关键起始原料。方法化合物3与一些芳基重氮盐反应，产物与丙二腈或氰基乙酸乙酯反应时被环化。噻唑衍生物还通过化合物3与异硫氰酸苯酯反应，然后与α-卤代羰基衍生物杂环化而获得。还获得了吡唑，三唑和吡喃衍生物。结果评估了这项工作中获得的化合物对c-Met激酶和六种典型癌细胞系（A549，H460，HT-29，MKN-45，U87MG和SMMC-7721）的体外细胞毒活性。抗增殖评估和c-Met激酶，Pim-1激酶抑制作用的结果表明，某些化合物显示出高活性。结论针对5种酪氨酸激酶，进一步研究了针对c-Met激酶的最有前途的化合物5b，5c，7c，7d，11b，14a，16b，18b，19、21a，23c，23d和23i（c-Kit，Flt- 3，VEGFR-2，EGFR和PDGFR）。化合物5b，5c，7d，7e，11b，11c，16c，16d，18c，19、23e，选择23k和23m以检查其Pim-1激酶抑制活性，其中化合物7d，7e，11b，11c，16d，18c和23e表现出高活性。所有合成的化合物对VERO正常细胞系均无损害作用。