Synthesis and evaluation of novel 4H‐pyrazole and thiophene derivatives derived from chalcone as potential anti‐proliferative agents, Pim‐1 kinase inhibitors, and PAINS

Abstract

AbstractThe chalcone derivatives 3a‐d reacted with either malononitrile or ethyl cyanoacetate in ethanol in the presence of catalytic amount of ammonium acetate in an oil bath at 120°C to give the Knowevenagel condensation products 5a‐h. The latter compounds reacted with hydrazine hydrate and afforded the 4H‐pyrazole derivatives 7a‐h, respectively. The reaction of compounds 7a‐h with ethyl cyanoacetate in dimethylformamide under refluxing condition afforded the cyanoacetamido derivatives 8a‐h, respectively. When compounds 8a‐h reacted with elemental sulfur and either of malononitrile or ethyl cyanoacetate in ethanol containing triethylamine, the thiophene derivatives 9a‐h and 10a‐h, respectively, were obtained. The structure of the newly synthesized compounds was established by the analytical and spectral data. All the newly synthesized compounds were evaluated against the six cancer cell lines: A549, HT‐29, MKN‐45, U87MG, and SMMC‐7721 and H460. Compounds 3c, 5h, 7g, 7h, 8f, 9e, 9g, and 10g were selected to examine their Pim‐1 kinase inhibition activity as these compounds showed high inhibition toward the c‐Met kinase and the tested cancer cell lines. Furthermore, compounds 3b, 3c, 5g, 5h, 7f, 7g, 7h, 8e, 8f, 8g, 8h, 9e, 9f, 9g, 9h, 10g and 10h were selected to be tested for pan‐assay interference compounds analysis (PAINS). Almost all the tested compounds showed zero PAINS alert and can be used as drug compounds in the future.