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

ABSTRACT

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 IC[50] values in the potent range 0.063-0.090 microM, 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 Arg[513]. 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 and selective COX-2 inhibitor as well as the most cytotoxic agent against MCF-7 cells