Synthesis of Tetrahydrobenzo[b]thiophene-3-carbohydrazide Derivatives as Potential Anti-cancer Agents and Pim-1 kinase Inhibitors.

Tetrahydrobenzo[b]thiophene derivatives were well known to be biologically active compounds and many of them occupy a wide range as anticancer agent drugs.One of our main aim of this work was to synthesize target molecules not only possess 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.Compound 3 was reacted with some aryldiazonium salts and the products were cyclised when react with either of malononitrile or ethyl cyanoacetate. Thiazole derivatives wee also obtained through the reaction of compound 3 with phenylisothiocyanate followed by heterocyclization with α-halocarbonyl derivatives. Pyrazole, triazole and pyridine derivatives were also obtained.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 gave high activities.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 tyrosin kinase (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 inhibition activity where compounds 7d, 7e, 11b, 11c, 16d, 18c and 23e showed high activities. All of the synthesized compounds has no impair effect toward the VERO normal cell line.