design, synthesis and biological evaluation of4-(imidazolylmethyl)-2-(4-methylsulfonyl phenyl)-quinoline derivatives as selective cox-2 inhibitors and in-vitro anti-breast cancer agents

a new group of 4-(imidazolylmethyl) quinoline derivatives possessing a methylsulfonyl cox-2 pharmacophore at the para position of the c-2 phenyl ring were designed and synthesized as selective cox-2 inhibitors and in-vitro anti breast cancer agents. in-vitro cox-1 and cox-2 inhibition studies showed that all the compounds were potent and selective inhibitors of the cox-2 isozyme with ic50 values in the potent range 0.063-0.090 µm, and cox-2 selectivity indexes in the 179.9 to 547.6 range. molecular modeling studies indicated that the methylsulfonyl substituent can be inserted into the secondary pocket of cox-2 active site for interactions with arg513. cytotoxicity of quinolines 9a-e against human breast cancer mcf-7 and t47d cell lines were also evaluated. all the compounds 9a-e were more cytotoxic against mcf-7 cells in comparison with those of t47d which express aromatase mrna less than mcf-7 cells.the data showed that the increase of lipophilic properties of substituents on the c-7 and c-8 quinoline ring increased their cytotoxicity on mcf-7cells and cox-2 inhibitory activity. among the quinolines 9a-e, 4-((1h-imidazol-1-yl)methyl) 7,8,9,10-tetrahydro-2-(4-methylsulfonylphenyl)-benzo[h]quinoline (9d)was identified as the most potent andselective cox-2inhibitor as well as the most cytotoxic agent against mcf-7 cells.