Development of new piperazine tethered pyridine derivatives as inhibitors of BAD phosphorylation in human breast cancer

Breast cancer is a devastating disease responsible for many deaths worldwide. Although many drugs are available for its treatment, new anticancer agents are demand due to undesirable side effects of well accepted drugs. Many anticancer drugs contain piperazine and pyridine moieties. We previously discovered piperazine containing small molecule called NPB [ N -cyclopentyl-3-((4-(2,3-dichlorophenyl)piperazin-1-yl)(2-hydroxyphenyl)methyl)benzamide] that targeted pBAD (BCL-2-associated death) in human breast cancer cells. Inspired by these molecules, we have designed new piperazine tethered pyridine compounds. The synthesized compounds were evaluated for their cytotoxic activity against MCF-7 breast cancer cells. A compound, N -(3-(6-chloro-5-methylpyridin-3-yl)phenyl)-2-(4-(2-nitrophenyl)piperazin-1-yl)acetamide ( 7h ) showed the highest cytotoxic activity (6.15 μM) against MCF-7. A fair structure activity relationship has been discussed. The molecular modeling studies indicated that our title compounds induced cancer cell death via inhibition of phosphorylation of BCL-2-associated death (BAD) promoter. The results of these studies are presented in this article.