Molecular modeling based approach, design synthesis and cytotoxic activity of 7-chloro-4-(2,5-dioxo-4- substitutedarylidine) piperazinoquinoline a hybrid pharmacophore, targeting EGFR, Tyrosine Kinase

A series of 7-chloro-4-[4-(substituted arylideneimino)] 2,5-dioxo-1,4 piperazinoquinoline VI was designed by molecular hybridization approach and synthesized for biological evaluation. Virtual screening was carried out through docking the designed compounds into the ATP binding site of epidermal growth factor receptor (EGFR) to predict if these compounds have similar binding mode as the EGFR inhibitors. Subsequently, the compounds were examined for their cytotoxic effect on human breast cell-line (MCF-7) in which the EGFR is highly expressed. Although most of the compounds were quite effective on the breast cancer cell line examined, the compounds II, III, IVa, IVc, VIa, VIc emerged as the most active among the prepared series. Thus 7-chloro-4- [4-(substitutedarylideneimino) 2,5-dioxo-1,4 piperazinoquinoline can serve as the prototype molecule for further development of a new class of EGFR Tyrosine Kinase inhibitors and anti-breast cancer agents.