Synthesis of 4-aryl-6-indolylpyridine-3-carbonitriles and evaluation of their antiproliferative activity

A novel class of 6-indolypyridine-3-carbonitrile derivatives were synthesized and evaluated for antiproliferative activities to establish structure-activity relationship. The synthesis was carried out through one-pot multicomponent reaction of 3-acetylindole, aromatic aldehydes, ethyl cyanoacetate, and ammonium acetate in the presence of piperidine as a catalyst, using a microwave irradiation method or a traditional thermal method. This was followed by chlorination for compounds 13a-e and subsequent nucleophilic substitution of the chlorine group by ethylenediamine at C-2 position of the pyridine ring. The antiproliferative activity of these new nicotinonitriles was evaluated against human ovarian adenocarcinoma (SK-OV-3), breast adenocarcinoma (MCF-7), and cervix adenocarcinoma (HeLa) cells. Among all compounds, 2((2-aminoethyl)amino)-4-aryl-6-indolylnicotinonitriles series (15a, 15b, 15d, and 15e) exhibited higher antiproliferative activity on the three cancer cell lines with IC50 values of 4.1-13.4 mu M. (C) 2014 Elsevier Ltd. All rights reserved.